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  • 1.
    Brohlin, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Biomedicinsk laboratorievetenskap.
    Kelk, Peyman
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Effects of a defined xeno-free medium on the growth and neurotrophic and angiogenic properties of human adult stem cells2017Ingår i: Cytotherapy, ISSN 1465-3249, E-ISSN 1477-2566, Vol. 19, nr 5, s. 629-639Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. The growth properties and neurotrophic and angiogenic effects of human mesenchymal stromal cells (MSCs) cultured in a defined xeno-free, serum-free medium (MesenCult-XF) were investigated. Methods. Human MSCs from adipose tissue (ASCs) and bone marrow (BMSCs) were cultured in Minimum Essential Medium-alpha (alpha-MEM) containing fetal calf serum or in MesenCult-XF. Proliferation was measured over 10 passages and the colony-forming unit (CFU) assay and expression of cluster of differentiation (CD) surface markers were determined. Neurite outgrowth and angiogenic activity of the MSCs were determined. Results. At early passage, both ASCs and BMSCs showed better proliferation in MesenCult-XF compared with standard a-MEM containing serum. However, CFUs were significantly lower in MesenCult-XF. ASCs cultured in MesenCult-XF continued to expand at faster rates than cells grown in serum. BMSCs showed morphological changes at late passage in MesenCult-XF and stained positive for senescence beta-galactosidase activity. Expression levels of CD73 and CD90 were similar in both cell types under the various culture conditions but CD105 was significantly reduced at passage 10 in MesenCult-XF. In vitro stimulation of the cells enhanced the expression of brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF-A) and angiopoietin-1. Stimulated ASCs grown in MesenCult-XF evoked the longest neurite outgrowth in a neuron co-culture model. Stimulated BMSCs grown in MesenCult-XF produced the most extensive network of capillary-like tube structures in an in vitro angiogenesis assay. Conclusions. ASCs and BMSCs exhibit high levels of neurotrophic and angiogenic activity when grown in the defined serum free medium indicating their suitability for treatment of various neurological conditions. However, long-term expansion in MesenCult-XF might be restricted to ASCs.

  • 2.
    Brohlin, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikova, Liudmila
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Aging effect on neurotrophic activity of human mesenchymal stem cells2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 9, s. e45052-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Clinical efficacy of stem cells for nerve repair is likely to be influenced by issues including donor age and in vitro expansion time. We isolated human mesenchymal stem cells (MSC) from bone marrow of young (16–18 years) and old (67–75 years) donors and analyzed their capacity to differentiate and promote neurite outgrowth from dorsal root ganglia (DRG) neurons. Treatment of MSC with growth factors (forskolin, basic fibroblast growth factor, platelet derived growth factor-AA and glial growth factor-2) induced protein expression of the glial cell marker S100 in cultures from young but not old donors. MSC expressed various neurotrophic factor mRNA transcripts. Growth factor treatment enhanced the levels of BDNF and VEGF transcripts with corresponding increases in protein release in both donor cell groups. MSC in co-culture with DRG neurons significantly enhanced total neurite length which, in the case of young but not old donors, was further potentiated by treatment of the MSC with the growth factors. Stem cells from young donors maintained their proliferation rate over a time course of 9 weeks whereas those from the old donors showed increased population doubling times. MSC from young donors, differentiated with growth factors after long-term culture, maintained their ability to enhance neurite outgrowth of DRG. Therefore, MSC isolated from young donors are likely to be a favourable cell source for nerve repair.

  • 3.
    Ching, Rosanna C.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    The role of exosomes in peripheral nerve regeneration2015Ingår i: Neural Regeneration Research, ISSN 1673-5374, E-ISSN 1876-7958, Vol. 10, nr 5, s. 743-747Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Peripheral nerve injuries remain problematic to treat, with poor functional recovery commonly observed. Injuries resulting in a nerve gap create specific difficulties for axonal regeneration. Approaches to address these difficulties include autologous nerve grafts (which are currently the gold standard treatment) and synthetic conduits, with the latter option being able to be impregnated with Schwann cells or stem cells which provide an appropriate micro-environment for neuronal regeneration to occur. Transplanting stem cells, however, infers additional risk of malignant transformation as well as manufacturing difficulties and ethical concerns, and the use of autologous nerve grafts and Schwann cells requires the sacrifice of a functioning nerve. A new approach utilizing exosomes, secreted extracellular vesicles, could avoid these complications. In this review, we summarize the current literature on exosomes, and suggest how they could help to improve axonal regeneration following peripheral nerve injury.

  • 4.
    Ching, Rosanna C.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Schwann cell-like differentiated adipose stem cells promote neurite outgrowth via secreted exosomes and RNA transfer2018Ingår i: Stem Cell Research & Therapy, E-ISSN 1757-6512, Vol. 9, artikel-id 266Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Adipose derived stem cells can be stimulated to produce a growth factor rich secretome which enhances axon regeneration. In this study we investigated the importance of exosomes, extracellular vesicles released by many different cell types, including stem cells and endogenous nervous system Schwann cells (SCs), on neurite outgrowth.

    Methods: Adipose derived stem cells were differentiated towards a Schwann cell-like phenotype (dADSCs) by in vitro stimulation with a mix of factors (basic fibroblast growth factor, platelet derived growth factor-AA, neuregulin-1 and forskolin). Using a precipitation and low-speed centrifugation protocol the extracellular vesicles were isolated from the medium of the stem cells cultures and also from primary SCs. The conditioned media or concentrated vesicles were applied to neurons in vitro and computerised image analysis was used to assess neurite outgrowth. Total RNA was purified from the extracellular vesicles and investigated using qRT-PCR.

    Results: Application of exosomes derived from SCs significantly enhanced in vitro neurite outgrowth and this was replicated by the exosomes from dADSCs. qRT-PCR demonstrated that the exosomes contained mRNAs and miRNAs known to play a role in nerve regeneration and these molecules were up-regulated by the Schwann cell differentiation protocol. Transfer of fluorescently tagged exosomal RNA to neurons was detected and destruction of the RNA by UV-irradiation significantly reduced the dADSCs exosome effects on neurite outgrowth. In contrast, this process had no significant effect on the SCs-derived exosomes.

    Conclusions: In summary, this work suggests that stem cell-derived exosomes might be a useful adjunct to other novel therapeutic interventions in nerve repair.

  • 5.
    di Summa, Pietro G
    et al.
    University Hospital of Lausanne, University of Manchester.
    Kalbermatten, Daniel F
    University Hospital of Lausanne, University Hospital of Basel.
    Pralong, E
    University Hospital of Lausanne.
    Raffoul, W
    University Hospital of Lausanne.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Terenghi, Giorgio
    University of Manchester.
    Long-term in vivo regeneration of peripheral nerves through bioengineered nerve grafts2011Ingår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 181, nr 5, s. 278-291Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although autologous nerve graft is still the first choice strategy in nerve reconstruction, it has the severe disadvantage of the sacrifice of a functional nerve. Cell transplantation in a bioartificial conduit is an alternative strategy to improve nerve regeneration. Nerve fibrin conduits were seeded with various cell types: primary Schwann cells (SC), SC-like differentiated bone marrow-derived mesenchymal stem cells (dMSC), SC-like differentiated adipose-derived stem cells (dASC). Two further control groups were fibrin conduits without cells and autografts. Conduits were used to bridge a 1 cm rat sciatic nerve gap in a long term experiment (16 weeks). Functional and morphological properties of regenerated nerves were investigated. A reduction in muscle atrophy was observed in the autograft and in all cell-seeded groups, when compared with the empty fibrin conduits. SC showed significant improvement in axon myelination and average fiber diameter of the regenerated nerves. dASC were the most effective cell population in terms of improvement of axonal and fiber diameter, evoked potentials at the level of the gastrocnemius muscle and regeneration of motoneurons, similar to the autografts. Given these results and other advantages of adipose derived stem cells such as ease of harvest and relative abundance, dASC could be a clinically translatable route towards new methods to enhance peripheral nerve repair.

  • 6.
    di Summa, Pietro G
    et al.
    University of Manchester, University Hospital of Lausanne.
    Kalbermatten, Daniel F
    University Hospital of Basel.
    Raffoul, Wassim
    University Hospital of Lausanne.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. University of Manchester.
    Extracellular matrix molecules enhance the neurotrophic effect of Schwann cell-like differentiated adipose-derived stem cells and increase cell survival under stress conditions2013Ingår i: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 19, nr 3-4, s. 368-379Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Since the first reports of induction of adipose-derived stem cells (ASC) into neuronal and glial cell phenotypes, expectations have increased regarding their use in tissue engineering applications for nerve repair. Cell adhesion to extracellular matrix (ECM) is a basic feature of survival, differentiation, and migration of Schwann cells (SC) during nerve regeneration, and fibronectin and laminin are two key molecules of this process. Interaction between ECM and SC-like differentiated ASC (dASC) could potentially improve the neurotrophic potential of the stem cells. We have investigated the effect of ECM molecules on SC-like dASC in terms of proliferation, adhesion, and cell viability. Fibronectin and laminin did not affect the proliferation of dASC when compared with cell adherent tissue culture plastic, but significantly improved viability and cell attachment when dASC were exposed to apoptotic conditions. To assess the influence of the ECM molecules on dASC neurotrophic activity, dASC were seeded onto ECM-coated culture inserts suspended above dorsal root ganglia (DRG) sensory neurons. Neurite outgrowth of DRG neurons was enhanced when dASC were seeded on fibronectin and laminin when compared with controls. When DRG neurons and dASC were in direct contact on the various surfaces there was significantly enhanced neurite outgrowth and coculture with laminin-conditioned dASC produced the longest neurites. Compared with primary SCs, dASC grown on laminin produced similar levels of neurite outgrowth in the culture insert experiments but neurite length was shorter in the direct contact groups. Anti beta 1 integrin blocking antibody could inhibit baseline and dASC evoked neurite elongation but had no effect on outgrowth mediated by laminin-conditioned dASC. ECM molecules had no effect on the levels of nerve growth factor and brain-derived neurotrophic factor secretion from dASC. The results of the study suggest that ECM molecules can significantly improve the potential of dASC for nerve regeneration.

  • 7.
    di Summa, Pietro G.
    et al.
    Department of Plastic, Reconstructive Surgery, University Hospital of Lausanne (CHUV), Rue du Bugnon 46, 1011 Lausanne, Switzerland. Electronic address: Pietro.Di-Summa@chuv.ch..
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Campisi, Corrado C.
    Department of Plastic, Reconstructive Surgery, University Hospital of Genova, Ospedale S. Martino, Largo Rossana Benzi 10, 16132 Genova, Italy.
    Raffoul, Wassim
    Department of Plastic, Reconstructive Surgery, University Hospital of Lausanne (CHUV), Rue du Bugnon 46, 1011 Lausanne, Switzerland.
    Kalbermatten, Daniel F.
    Department of Plastic, Reconstructive Surgery, University Hospital of Basel, Spitalstrasse 21, CH-4031 Basel, Switzerland.
    Collagen (NeuraGen(®)) nerve conduits and stem cells for peripheral nerve gap repair2014Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 572, s. 26-31Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Collagen nerve guides are used clinically for peripheral nerve defects, but their use is generally limited to lesions up to 3cm. In this study we combined collagen conduits with cells as an alternative strategy to support nerve regeneration over longer gaps. In vitro cell adherence to collagen conduits (NeuraGen(®) nerve guides) was assessed by scanning electron microscopy. For in vivo experiments, conduits were seeded with either Schwann cells (SC), SC-like differentiated bone marrow-derived mesenchymal stem cells (dMSC), SC-like differentiated adipose-derived stem cells (dASC) or left empty (control group), conduits were used to bridge a 1cm gap in the rat sciatic nerve and after 2-weeks immunohistochemical analysis was performed to assess axonal regeneration and SC infiltration. The regenerative cells showed good adherence to the collagen walls. Primary SC showed significant improvement in distal stump sprouting. No significant differences in proximal regeneration distances were noticed among experimental groups. dMSC and dASC-loaded conduits showed a diffuse sprouting pattern, while SC-loaded showed an enhanced cone pattern and a typical sprouting along the conduits walls, suggesting an increased affinity for the collagen type I fibrillar structure. NeuraGen(®) guides showed high affinity of regenerative cells and could be used as efficient vehicle for cell delivery. However, surface modifications (e.g. with extracellular matrix molecule peptides) of NeuraGen(®) guides could be used in future tissue-engineering applications to better exploit the cell potential.

  • 8.
    di Summa, Pietro G
    et al.
    Chirurgie Plastique et Reconstructive CHUV, Université de Lausanne, Rue de Bugnon 46, 1005 Lausanne, CH, Switzerland.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Raffoul, W
    Chirurgie Plastique et Reconstructive CHUV, Université de Lausanne, Rue de Bugnon 46, 1005 Lausanne, CH, Switzerland.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Terenghi, Giorgio
    Blond McIndoe Research Laboratories. The University of Manchester, Manchester, UK.
    Kalbermatten, Daniel F
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Adipose-derived stem cells enhance peripheral nerve regeneration2010Ingår i: Journal of plastic, reconstructive and aesthetic surgery, ISSN 1878-0539, Vol. 63, nr 9, s. 1544-1552Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Traumatic injuries resulting in peripheral nerve lesions often require a graft to bridge the gap. Although autologous nerve auto-graft is still the first-choice strategy in reconstructions, it has the severe disadvantage of the sacrifice of a functional nerve. Cell transplantation in a bioartificial conduit is an alternative strategy to create a favourable environment for nerve regeneration. We decided to test new fibrin nerve conduits seeded with various cell types (primary Schwann cells and adult stem cells differentiated to a Schwann cell-like phenotype) for repair of sciatic nerve injury. Two weeks after implantation, the conduits were removed and examined by immunohistochemistry for axonal regeneration (evaluated by PGP 9.5 expression) and Schwann cell presence (detected by S100 expression). The results show a significant increase in axonal regeneration in the group of fibrin seeded with Schwann cells compared with the empty fibrin conduit. Differentiated adipose-derived stem cells also enhanced regeneration distance in a similar manner to differentiated bone marrow mesenchymal stem cells. These observations suggest that adipose-derived stem cells may provide an effective cell population, without the limitations of the donor-site morbidity associated with isolation of Schwann cells, and could be a clinically translatable route towards new methods to enhance peripheral nerve repair.

  • 9.
    East, Emma
    et al.
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Johns, Noémie
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Georgiou, Melanie
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Golding, Jon P.
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Loughlin, A. Jane
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Phillips, James B.
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK, Department of Biomaterials & Tissue Engineering, UCL Eastman Dental Institute, 256 Gray’s Inn Road, London WC1X 8LD, UK.
    A 3D in vitro model reveals differences in the astrocyte response elicited by potential stem cell therapies for CNS injury2013Ingår i: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 8, nr 6, s. 739-746Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIM: This study aimed to develop a 3D culture model to test the extent to which transplanted stem cells modulate astrocyte reactivity, where exacerbated glial cell activation could be detrimental to CNS repair success.

    MATERIALS & METHODS: The reactivity of rat astrocytes to bone marrow mesenchymal stem cells, neural crest stem cells (NCSCs) and differentiated adipose-derived stem cells was assessed after 5 days. Schwann cells were used as a positive control.

    RESULTS: NCSCs and differentiated Schwann cell-like adipose-derived stem cells did not increase astrocyte reactivity. Highly reactive responses to bone marrow mesenchymal stem cells and Schwann cells were equivalent.

    CONCLUSION: This approach can screen therapeutic cells prior to in vivo testing, allowing cells likely to trigger a substantial astrocyte response to be identified at an early stage. NCSCs and differentiated Schwann cell-like adipose-derived stem cells may be useful in treating CNS damage without increasing astrogliosis.

  • 10.
    El-Habta, Roine
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Adipose stem cells enhance myoblast proliferation via acetylcholine and extracellular signal-regulated kinase 1/2 signaling2018Ingår i: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 57, nr 2, s. 305-311Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: In this study we investigated the interaction between adipose tissue-derived stem cells (ASCs) and myoblasts in co-culture experiments. Methods: Specific inductive media were used to differentiate ASCs in vitro into a Schwann cell-like phenotype (differentiated adipose tissuederived stem cells, or dASCs) and, subsequently, the expression of acetylcholine (ACh)-related machinery was determined. In addition, the expression of muscarinic ACh receptors was examined in denervated rat gastrocnemius muscles. Results: In contrast to undifferentiated ASCs, dASCs expressed more choline acetyltransferase and vesicular acetylcholine transporter. When co-cultured with myoblasts, dASCs enhanced the proliferation rate, as did ACh administration alone. Western blotting and pharmacological inhibitor studies showed that phosphorylated extracellular signal-regulated kinase 1/2 signaling mediated these effects. In addition, denervated muscle showed higher expression of muscarinic ACh receptors than control muscle. Discussion: Our findings suggest that dASCs promote proliferation of myoblasts through paracrine secretion of ACh, which could explain some of their regenerative capacity in vivo.

  • 11.
    El-Habta, Roine
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Sloniecka, Marta
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Backman, L. J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    The adipose tissue stromal vascular fraction secretome enhances the proliferation but inhibits the differentiation of myoblasts2018Ingår i: Stem Cell Research & Therapy, E-ISSN 1757-6512, Vol. 9, artikel-id 352Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Adipose tissue is an excellent source for isolation of stem cells for treating various clinical conditions including injuries to the neuromuscular system. Many previous studies have focused on differentiating these adipose stem cells (ASCs) towards a Schwann cell-like phenotype (dASCs), which can enhance axon regeneration and reduce muscle atrophy. However, the stromal vascular fraction (SVF), from which the ASCs are derived, also exerts broad regenerative potential and might provide a faster route to clinical translation of the cell therapies for treatment of neuromuscular disorders.

    Methods: The aim of this study was to establish the effects of SVF cells on the proliferation and differentiation of myoblasts using indirect co-culture experiments. A Growth Factor PCR Array was used to compare the secretomes of SVF and dASCs, and the downstream signaling pathways were investigated.

    Results: SVF cells, unlike culture-expanded dASCs, expressed and secreted hepatocyte growth factor (HGF) at concentrations sufficient to enhance the proliferation of myoblasts. Pharmacological inhibitor studies revealed that the signal is mediated via ERK1/2 phosphorylation and that the effect is significantly reduced by the addition of 100 pM Norleual, a specific HGF inhibitor. When myoblasts were differentiated into multinucleated myotubes, the SVF cells reduced the expression levels of fast-type myosin heavy chain (MyHC2) suggesting an inhibition of the differentiation process.

    Conclusions: In summary, this study shows the importance of HGF as a mediator of the SVF effects on myoblasts and provides further evidence for the importance of the secretome in cell therapy and regenerative medicine applications.

  • 12.
    Engels, Patricia E.
    et al.
    University Hospital Basel.
    Tremp, Mathias
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    di Summa, Pietro G.
    Largo, Rene D.
    Schaefer, Dirk J.
    Kalbermatten, Daniel F
    Harvest site influences the growth properties of adipose derived stem cells2013Ingår i: Cytotechnology (Dordrecht), ISSN 0920-9069, E-ISSN 1573-0778, Vol. 65, nr 3, s. 437-445Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The therapeutic potential of adult stem cells may become a relevant option in clinical care in the future. In hand and plastic surgery, cell therapy might be used to enhance nerve regeneration and help surgeons and clinicians to repair debilitating nerve injuries. Adipose-derived stem cells (ASCs) are found in abundant quantities and can be harvested with a low morbidity. In order to define the optimal fat harvest location and detect any potential differences in ASC proliferation properties, we compared biopsies from different anatomical sites (inguinal, flank, pericardiac, omentum, neck) in Sprague-Dawley rats. ASCs were expanded from each biopsy and a proliferation assay using different mitogenic factors, basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) was performed. Our results show that when compared with the pericardiac region, cells isolated from the inguinal, flank, omental and neck regions grow significantly better in growth medium alone. bFGF significantly enhanced the growth rate of ASCs isolated from all regions except the omentum. PDGF had minimal effect on ASC proliferation rate but increases the growth of ASCs from the neck region. Analysis of all the data suggests that ASCs from the neck region may be the ideal stem cell sources for tissue engineering approaches for the regeneration of nervous tissue.

  • 13.
    Erba, P
    et al.
    University of Manchester, University Hospital of Basel.
    Mantovani, Cristina
    University of Manchester.
    Kalbermatten, Daniel F
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Pierer, G
    University Hospital of Basel.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Regeneration potential and survival of transplanted undifferentiated adipose tissue-derived stem cells in peripheral nerve conduits2010Ingår i: Journal of plastic, reconstructive & aesthetic surgery : JPRAS, ISSN 1878-0539, Vol. 63, nr 12, s. e811-e817Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adipose tissue-derived stem cells (ADSCs) have shown potential for the treatment of nerve injuries. Most previous efforts have aimed at stimulating regeneration by using neural-differentiation protocols, but the potential of undifferentiated ADSCs to enhance axonal growth as well as their ability to transdifferentiate in situ have been poorly investigated. In this study, using a rat sciatic nerve model we show that ADSCs, transplanted in an artificial nerve conduit, stimulate axonal outgrowth from the proximal nerve stump and evoke greater Schwann cell (SC) proliferation/intrusion in the distal stump. To track the fate of the transplanted cells, we used green fluorescent protein (GFP)-labelling and polymerase chain reaction (PCR) for the detection of the sex determining region Y (SRY) gene in the donor male cells. Both methods indicated a lack of significant quantities of viable cells 14 days after transplantation. These results suggest that any regenerative effect of transplanted ADSCs is more likely to be mediated by an initial boost of released growth factors and/or by an indirect effect on endogenous SCs activity. Future studies need to address long-term cell survival in tissue-engineered nerve conduits to improve the neuroregenerative potential of ADSCs.

  • 14.
    Erba, Paolo
    et al.
    University Hospitals of Basel and Lausanne.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Neural differentiation and therapeutic potential of adipose tissue derived stem cells2010Ingår i: Current stem cell research & therapy, ISSN 1574-888X, Vol. 5, nr 2, s. 153-160Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Neural tissue has historically been regarded as having poor regenerative capacity but recent advances in the growing fields of tissue engineering and regenerative medicine have opened new hopes for the treatment of nerve injuries and neurodegenerative disorders. Adipose tissue has been shown to contain a large quantity of adult stem cells (ASC). These cells can be easily harvested with low associated morbidity and because of their potential to differentiate into multiple cell types, their use has been suggested for a wide variety of therapeutic applications. In this review we examine the evidence indicating that ASC can stimulate nerve regeneration by both undergoing neural differentiation and through the release of a range of growth factors. We also discuss some of the issues that need to be addressed before ASC can be developed as an effective cellular therapy for the treatment of neural tissue disorders.

  • 15. Faroni, Alessandro
    et al.
    Mobasseri, S. Atefeh
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Reid, Adam J.
    Peripheral nerve regeneration: experimental strategies and future perspectives2015Ingår i: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 82-83, s. 160-167Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Peripheral nerve injuries represent a substantial clinical problem with insufficient or unsatisfactory treatment options. This review summarises all the events occurring after nerve damage at the level of the cell body, the site of injury and the target organ. Various experimental strategies to improve neuronal survival, axonal regeneration and target reinnervation are described including pharmacological approaches and cell-based therapies. Given the complexity of nerve regeneration, further studies are needed to address the biology of nerve injury, to improve the interaction with implantable scaffolds, and to implement cell-based therapies in nerve tissue engineering. 

  • 16. Georgiou, M.
    et al.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Bunting, S. C.
    Golding, J. P.
    Loughlin, A. J.
    Phillips, J. B.
    A nerve repair conduit containing differentiated adipose-derived stem cells within engineered neural tissue can support and guide neuronal growth in vitro and in vivo2012Ingår i: Journal of tissue engineering and regenerative medicine, ISSN 1932-6254, Vol. 6, nr Suppl. 1, s. 259-Artikel i tidskrift (Övrigt vetenskapligt)
  • 17. Georgiou, Melanie
    et al.
    Golding, Jon P.
    Loughlin, Alison J.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Phillips, James B.
    Engineered neural tissue with aligned, differentiated adipose-derived stem cells promotes peripheral nerve regeneration across a critical sized defect in rat sciatic nerve2015Ingår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 37, s. 242-251Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adipose-derived stem cells were isolated from rats and differentiated to a Schwann cell-like phenotype in vitro. The differentiated cells (dADSCs) underwent self-alignment in a tethered type-1 collagen gel, followed by stabilisation to generate engineered neural tissue (EngNT-dADSC). The pro-regenerative phenotype of dADSCs was enhanced by this process, and the columns of aligned dADSCs in the aligned collagen matrix supported and guided neurite extension in vitro. EngNT-dADSC sheets were rolled to form peripheral nerve repair constructs that were implanted within NeuraWrap conduits to bridge a 15 mm gap in rat sciatic nerve. After 8 weeks regeneration was assessed using immunofluorescence imaging and transmission electron microscopy and compared to empty conduit and nerve graft controls. The proportion of axons detected in the distal stump was 3.5 fold greater in constructs containing EngNT-dADSC than empty tube controls. Our novel combination of technologies that can organise autologous therapeutic cells-within an artificial tissue construct provides a promising new cellular biomaterial for peripheral nerve repair. 

  • 18.
    Jones, Iwan
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Novikova, Liudmila N.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Novikov, Lev N.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Renardy, Monika
    Ullrich, Andreas
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Regenerative effects of human embryonic stem cell-derived neural crest cells for treatment of peripheral nerve injury2018Ingår i: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 12, nr 4, s. E2099-E2109Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Surgical intervention is the current gold standard treatment following peripheral nerve injury. However, this approach has limitations, and full recovery of both motor and sensory modalities often remains incomplete. The development of artificial nerve grafts that either complement or replace current surgical procedures is therefore of paramount importance. An essential component of artificial grafts is biodegradable conduits and transplanted cells that provide trophic support during the regenerative process. Neural crest cells are promising support cell candidates because they are the parent population to many peripheral nervous system lineages. In this study, neural crest cells were differentiated from human embryonic stem cells. The differentiated cells exhibited typical stellate morphology and protein expression signatures that were comparable with native neural crest. Conditioned media harvested from the differentiated cells contained a range of biologically active trophic factors and was able to stimulate in vitro neurite outgrowth. Differentiated neural crest cells were seeded into a biodegradable nerve conduit, and their regeneration potential was assessed in a rat sciatic nerve injury model. A robust regeneration front was observed across the entire width of the conduit seeded with the differentiated neural crest cells. Moreover, the up-regulation of several regeneration-related genes was observed within the dorsal root ganglion and spinal cord segments harvested from transplanted animals. Our results demonstrate that the differentiated neural crest cells are biologically active and provide trophic support to stimulate peripheral nerve regeneration. Differentiated neural crest cells are therefore promising supporting cell candidates to aid in peripheral nerve repair.

  • 19.
    Jones, Iwan
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Yelhekar, Tushar D.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Wiberg, Rebecca
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Johansson, Staffan
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Development and validation of an in vitro model system to study peripheral sensory neuron development and injury2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 15961Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The ability to discriminate between diverse types of sensation is mediated by heterogeneous populations of peripheral sensory neurons. Human peripheral sensory neurons are inaccessible for research and efforts to study their development and disease have been hampered by the availability of relevant model systems. The in vitro differentiation of peripheral sensory neurons from human embryonic stem cells therefore provides an attractive alternative since an unlimited source of biological material can be generated for studies that specifically address development and injury. The work presented in this study describes the derivation of peripheral sensory neurons from human embryonic stem cells using small molecule inhibitors. The differentiated neurons express canonical- and modality-specific peripheral sensory neuron markers with subsets exhibiting functional properties of human nociceptive neurons that include tetrodotoxin-resistant sodium currents and repetitive action potentials. Moreover, the derived cells associate with human donor Schwann cells and can be used as a model system to investigate the molecular mechanisms underlying neuronal death following peripheral nerve injury. The quick and efficient derivation of genetically diverse peripheral sensory neurons from human embryonic stem cells offers unlimited access to these specialised cell types and provides an invaluable in vitro model system for future studies.

  • 20.
    Jonsson, Samuel
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Rebecca
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    McGrath, Aleksandra M
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Novikova, Liudmila N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Effect of delayed peripheral nerve repair on nerve regeneration, Schwann cell function and target muscle recovery2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 2, artikel-id e56484Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite advances in surgical techniques for peripheral nerve repair, functional restitution remains incomplete. The timing of surgery is one factor influencing the extent of recovery but it is not yet clearly defined how long a delay may be tolerated before repair becomes futile. In this study, rats underwent sciatic nerve transection before immediate (0) or 1, 3, or 6 months delayed repair with a nerve graft. Regeneration of spinal motoneurons, 13 weeks after nerve repair, was assessed using retrograde labeling. Nerve tissue was also collected from the proximal and distal stumps and from the nerve graft, together with the medial gastrocnemius (MG) muscles. A dramatic decline in the number of regenerating motoneurons and myelinated axons in the distal nerve stump was observed in the 3- and 6-months delayed groups. After 3 months delay, the axonal number in the proximal stump increased 2-3 folds, accompanied by a smaller axonal area. RT-PCR of distal nerve segments revealed a decline in Schwann cells (SC) markers, most notably in the 3 and 6 month delayed repair samples. There was also a progressive increase in fibrosis and proteoglycan scar markers in the distal nerve with increased delayed repair time. The yield of SC isolated from the distal nerve segments progressively fell with increased delay in repair time but cultured SC from all groups proliferated at similar rates. MG muscle at 3- and 6-months delay repair showed a significant decline in weight (61% and 27% compared with contra-lateral side). Muscle fiber atrophy and changes to neuromuscular junctions were observed with increased delayed repair time suggestive of progressively impaired reinnervation. This study demonstrates that one of the main limiting factors for nerve regeneration after delayed repair is the distal stump. The critical time point after which the outcome of regeneration becomes too poor appears to be 3-months.

  • 21.
    Kalbermatten, Daniel F
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Mahay, Daljeet
    Mantovani, Cristina
    Pettersson, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Raffoul, W
    Balcin, H
    Pierer, G
    Terenghi, Giorgio
    Fibrin matrix for suspension of regenerative cells in an artificial nerve conduit2008Ingår i: Journal of plastic, reconstructive and aesthetic surgery, ISSN 1878-0539, Vol. 61, nr 6, s. 669-675Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Peripheral nerve injury presents with specific problems of neuronal reconstructions, and from a clinical viewpoint a tissue engineering approach would facilitate the process of repair and regeneration. We have previously used artificial nerve conduits made from bioresorbable poly-3-hydroxybutyrate (PHB) in order to refine the ways in which peripheral nerves are repaired and reconnected to the target muscles and skin. The addition of Schwann cells (SC) or differentiated mesenchymal stem cells (dMSC) to the conduits enhances regeneration. In this study, we have used a matrix based on fibrin (Tisseel) to fill optimally the nerve-conduits with cells. In vitro analysis showed that both SC and MSC adhered significantly better to PHB in the presence of fibrin and cells continued to maintain their differentiated state. Cells were more optimally distributed throughout the conduit when seeded in fibrin than by delivery in growth medium alone. Transplantation of the nerve conduits in vivo showed that cells in combination with fibrin matrix significantly increased nerve regeneration distance (using PGP9.5 and S100 distal and proximal immunohistochemistry) when compared with empty PHB conduits. This study shows the beneficial combinatory effect of an optimised matrix, cells and conduit material as a step towards bridging nerve gaps which should ultimately lead to improved functional recovery following nerve injury.

  • 22.
    Kalbermatten, Daniel F
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Pettersson, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Pierer, Gerhard
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Terenghi, Giorgio
    New fibrin conduit for peripheral nerve repair2009Ingår i: Journal of reconstructive microsurgery, ISSN 0743-684X, E-ISSN 1098-8947, Vol. 25, nr 1, s. 27-33Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An ideal substitute to treat a nerve gap has not been found. Initially, silicone conduits were employed. Later, conduits were fabricated from collagen or polyesters carbonates. More recently, it has been shown that a bioresorbable material, poly-3-hydroxybutyrate (PHB), can enhance nerve repair. The present investigation shows the use of fibrin as a conduit to guide nerve regeneration and bridge nerve defects. In this study we prepared and investigated a novel nerve conduit made from fibrin glue. Using a rodent sciatic nerve injury model (10-mm gap), we compared the extent of nerve regeneration through the new fibrin conduits versus established PHB conduits. After 2 and 4 weeks, conduits containing proximal and distal stumps were harvested. We evaluated the initial axon and Schwann cell stimulation using immunohistochemistry. The conduits presented full tissue integration and were completely intact. Axons crossed the gap after 1 month. Immunohistochemistry using the axonal marker PGP 9.5 showed a superior nerve regeneration distance in the fibrin conduit compared with PHB (4.1 mm versus 1.9 mm). Schwann cell intrusion (S100 staining) was similarly enhanced in the fibrin conduits, both from the proximal (4.2 mm versus 2.1 mm) and distal ends (3.2 mm versus 1.7 mm). These findings suggest an advantage of the new fibrin conduit for the important initial phase of peripheral nerve regeneration. The use of fibrin glue as a conduit is a step toward a usable graft to bridge peripheral nerve lesions. This might be clinically interesting, given the widespread acceptance of fibrin glue among the surgical community.

  • 23.
    Kalbermatten, Daniel F
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Schaakxs, Dominique
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Neurotrophic activity of human adipose stem cells isolated from deep and superficial layers of abdominal fat2011Ingår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 344, nr 2, s. 251-260Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    New approaches to the clinical treatment of traumatic nerve injuries may one day utilize stem cells to enhance nerve regeneration. Adipose-derived stem cells (ASC) are found in abundant quantities and can be harvested by minimally invasive procedures that should facilitate their use in such regenerative applications. We have analyzed the properties of human ASC isolated from the deep and superficial layers of abdominal fat tissue obtained during abdominoplasty procedures. Cells from the superficial layer proliferate significantly faster than those from the deep layer. In both the deep and superficial layers, ASC express the pluripotent stem cell markers oct4 and nanog and also the stro-1 cell surface antigen. Superficial layer ASC induce the significantly enhanced outgrowth of neurite-like processes from neuronal cell lines when compared with that of deep layer cells. However, analysis by reverse transcription with the polymerase chain reaction and by enzyme-linked immunosorbent assay has revealed that ASC isolated from both layers express similar levels of the following neurotrophic factors: nerve growth factor, brain-derived neurotrophic factor and glial-derived neurotrophic factor. Thus, human ASC show promising potential for the treatment of traumatic nerve injuries. In particular, superficial layer ASC warrant further analysis of their neurotrophic molecules.

  • 24.
    Kalbermatten, Daniel
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Schaakxs, Dominique
    Kingham, Paul
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Neurotrophic activity of human adipose stem cells isolated from deep and superficial layers of abdominal fatManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    New approaches to the clinical treatment of traumatic nerve injuries may one day utilize stem cells to enhance nerve regeneration.  Adipose derived stem cells (ASC) are found in abundant quantities and can be harvested by minimally invasive procedures which should facilitate their use in such regenerative applications.  In this study, we have analyzed the properties of human ASC isolated from the deep and superficial layers of abdominal fat tissue obtained during abdominoplasty procedures.  Cells from the superficial layer proliferated significantly faster than those from the deep layer. Both in the deep and superficial layers, ASC expressed the pluripotent stem cell markers oct4 and nanog and also the stro-1 cell surface antigen.  Superficial layer ASC induced significantly enhanced neurite outgrowth from NG108-15 motor neuron like cells when compared with the deep layer cells.  However, RT-PCR analysis showed that ASC isolated from both layers expressed similar levels of the neurotrophic factors NGF, BDNF, GDNF and NT-3.  These results indicate that human ASC have promising potential for the treatment of traumatic nerve injuries and that superficial layer ASC might represent the more optimal cell type for such applications.

  • 25.
    Karalija, Amar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kelk, Peyman
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    The effects of acetyl-­L-­carnitine treatment on neuroinflammation: An in vitro studyManuskript (preprint) (Övrigt vetenskapligt)
  • 26.
    Karalija, Amar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikova, Liudmila N.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev N.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Neuroprotective Effects of N-Acetyl-Cysteine and Acetyl-L-Carnitine after Spinal Cord Injury in Adult Rats2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 7, s. e41086-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Following the initial acute stage of spinal cord injury, a cascade of cellular and inflammatory responses will lead to progressive secondary damage of the nerve tissue surrounding the primary injury site. The degeneration is manifested by loss of neurons and glial cells, demyelination and cyst formation. Injury to the mammalian spinal cord results in nearly complete failure of the severed axons to regenerate. We have previously demonstrated that the antioxidants N-acetyl-cysteine (NAC) and acetyl-L-carnitine (ALC) can attenuate retrograde neuronal degeneration after peripheral nerve and ventral root injury. The present study evaluates the effects of NAC and ALC on neuronal survival, axonal sprouting and glial cell reactions after spinal cord injury in adult rats. Tibial motoneurons in the spinal cord were pre-labeled with fluorescent tracer Fast Blue one week before lumbar L5 hemisection. Continuous intrathecal infusion of NAC (2.4 mg/day) or ALC (0.9 mg/day) was initiated immediately after spinal injury using Alzet 2002 osmotic minipumps. Neuroprotective effects of treatment were assessed by counting surviving motoneurons and by using quantitative immunohistochemistry and Western blotting for neuronal and glial cell markers 4 weeks after hemisection. Spinal cord injury induced significant loss of tibial motoneurons in L4-L6 segments. Neuronal degeneration was associated with decreased immunostaining for microtubular-associated protein-2 (MAP2) in dendritic branches, synaptophysin in presynaptic boutons and neurofilaments in nerve fibers. Immunostaining for the astroglial marker GFAP and microglial marker OX42 was increased. Treatment with NAC and ALC rescued approximately half of the motoneurons destined to die. In addition, antioxidants restored MAP2 and synaptophysin immunoreactivity. However, the perineuronal synaptophysin labeling was not recovered. Although both treatments promoted axonal sprouting, there was no effect on reactive astrocytes. In contrast, the microglial reaction was significantly attenuated. The results indicate a therapeutic potential for NAC and ALC in the early treatment of traumatic spinal cord injury.

  • 27.
    Karalija, Amar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Novikova, Ludmila N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    The effects of N-acetyl-cysteine and acetyl-l-carnitine on neural survival, neuroinflammation and regeneration following spinal cord injury2014Ingår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 269, s. 143-151Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Traumatic spinal cord injury induces a long-standing inflammatory response in the spinal cord tissue, leading to a progressive apoptotic death of spinal cord neurons and glial cells. We have recently demonstrated that immediate treatment with the antioxidants N-acetyl-cysteine (NAC) and acetyl-l-carnitine (ALC) attenuates neuroinflammation, induces axonal sprouting, and reduces the death of motoneurons in the vicinity of the trauma zone 4weeks after initial trauma. The objective of the current study was to investigate the effects of long-term antioxidant treatment on the survival of descending rubrospinal neurons after spinal cord injury in rats. It also examines the short- and long-term effects of treatment on apoptosis, inflammation, and regeneration in the spinal cord trauma zone. Spinal cord hemisection performed at the level C3 induced a significant loss of rubrospinal neurons 8weeks after injury. At 2weeks, an increase in the expression of the apoptosis-associated markers BCL-2-associated X protein (BAX) and caspase 3, as well as the microglial cell markers OX42 and ectodermal dysplasia 1 (ED1), was seen in the trauma zone. After 8weeks, an increase in immunostaining for OX42 and the serotonin marker 5HT was detected in the same area. Antioxidant therapy reduced the loss of rubrospinal neurons by approximately 50%. Treatment also decreased the expression of BAX, caspase 3, OX42 and ED1 after 2weeks. After 8weeks, treatment decreased immunoreactivity for OX42, whereas it was increased for 5HT. In conclusion, this study provides further insight in the effects of treatment with NAC and ALC on descending pathways, as well as short- and long-term effects on the spinal cord trauma zone.

  • 28.
    Kingham, Paul J
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kolar, Mallappa K
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Novikova, Liudmila N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair2014Ingår i: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 23, nr 7, s. 741-754Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In future, adipose-derived stem cells (ASC) might be used to treat neurological disorders. In this study, the neurotrophic and angiogenic properties of human ASC were evaluated, and their effects in a peripheral nerve injury model were determined. In vitro growth factor stimulation of the cells resulted in increased secretion of brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), vascular endothelial growth factor-A (VEGF-A), and angiopoietin-1 proteins. Conditioned medium from stimulated cells increased neurite outgrowth of dorsal root ganglia (DRG) neurons. Similarly, stimulated cells showed an enhanced ability to induce capillary-like tube formation in an in vitro angiogenesis assay. ASC were seeded into a fibrin conduit that was used to bridge a 10 mm rat nerve gap. After 2 weeks, the animals treated with control or stimulated ASC showed an enhanced axon regeneration distance. Stimulated cells evoked more total axon growth. Analysis of regeneration and apoptosis-related gene expression showed that both ASC and stimulated ASC enhanced GAP-43 and activating transcription factor 3 (ATF-3) expression in the spinal cord and reduced c-jun expression in the DRG. Caspase-3 expression in the DRG was reduced by stimulated ASC. Both ASC and stimulated ASC also increased the vascularity of the fibrin nerve conduits. Thus, ASC produce functional neurotrophic and angiogenic factors, creating a more desirable microenvironment for nerve regeneration.

  • 29.
    Kingham, Paul J
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Blond McIndoe Laboratories, School of Clinical and Laboratory Sciences, University of Manchester, Manchester, UK.
    Mantovani, Cristina
    Blond McIndoe Laboratories, School of Clinical and Laboratory Sciences, University of Manchester, Manchester, UK.
    Terenghi, Giorgio
    Blond McIndoe Laboratories, School of Clinical and Laboratory Sciences, University of Manchester, Manchester, UK.
    Stem cell and neuron co-cultures for the study of nerve regeneration2011Ingår i: 3D Cell Culture: Methods and Protocols / [ed] John W. Haycock, New York: Humana Press, 2011, Vol. 695, s. 115-127Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Many experimental in vivo studies have indicated that Schwann cells are key facilitators of peripheral nerve regeneration but their clinical therapeutic potential may be limited. Recent advances suggest that stem cell therapy could one day be used to treat nerve traumas. We have shown how adult stem cells can be differentiated into a Schwann cell phenotype, characterised by expression of glial cell proteins and promotion of neurite outgrowth. The development of new cell culture models which mimic the in vivo regeneration environment will help us to better understand the functional benefits of these cells. Here, we describe a stepwise approach towards this, moving from traditional two-dimensional non-contact co-cultures to new three-dimensional models utilising fibrin matrices.

  • 30.
    Kingham, Paul J
    et al.
    Blond McIndoe Laboratories, Tissue Injury & Repair Research Group, School of Clinical and Laboratory Sciences, The University of Manchester, Manchester, UK.
    Mantovani, Maria Cristina
    Blond McIndoe Laboratories, Tissue Injury & Repair Research Group, School of Clinical and Laboratory Sciences, The University of Manchester, Manchester, UK.
    Terenghi, Giorgio
    Blond McIndoe Laboratories, Tissue Injury & Repair Research Group, School of Clinical and Laboratory Sciences, The University of Manchester, Manchester, UK.
    Notch independent signalling mediates Schwann cell-like differentiation of adipose derived stem cells2009Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 467, nr 2, s. 164-168Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adipose derived stem cells (ASC) differentiate into a Schwann cell (SC)-like phenotype but the signalling pathways mediating this are unknown. We hypothesised that notch might be involved, given its important role in regulating SC development. Rat ASC were differentiated using bFGF, PDGF, GGF-2 and forskolin. RT-PCR analysis showed that mRNA for notch-1 and notch-2 receptors and the notch responsive gene, hes-1, were expressed throughout the differentiation process whereas jagged-1 a notch ligand, and the hey-1 gene were markedly down-regulated. In contrast delta-1 was up-regulated with differentiation and was strongly expressed by rat primary SC. Treatment of ASC with N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor which blocks notch signalling, had no effect on up-regulation of SC proteins S100 or GFAP during differentiation. Furthermore, when co-cultured with NG108-15 neurons, differentiated ASC cultures treated in the absence or presence of DAPT enhanced neurite outgrowth to similar levels. Differentiated ASC expressed PMP-22 but P0 was only present when co-cultured with dorsal root ganglia neurons. DAPT did not affect the expression of these myelin proteins. Thus, ASC express components of the notch signalling pathway but our studies suggest notch is unlikely to play a role in the neurotrophic activity and myelination capability of ASC differentiated into SC-like cells.

  • 31.
    Kingham, Paul J.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Reid, Adam J.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Adipose-Derived Stem Cells for Nerve Repair: Hype or Reality?2014Ingår i: Cells Tissues Organs, ISSN 1422-6405, E-ISSN 1422-6421, Vol. 200, nr 1, s. 23-30Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Peripheral nerve injury is a relatively commonly occurring trauma which seriously compromises the quality of life for many individuals. There is a major need to devise new treatment strategies, and one possible approach is to develop cellular therapies to bioengineer new nerve tissue and/or modulate the endogenous regenerative mechanisms within the peripheral nervous system. In this short review we describe how stem cells isolated from adipose tissue could be a suitable element of this approach. We describe the possible mechanisms through which the stem cells might exert a positive influence on peripheral nerve regeneration. These include their ability to differentiate into cells resembling Schwann cells and their secretion of a plethora of neurotrophic growth factors. We also review the literature describing the effects of these cells when tested using in vivo peripheral nerve injury models.

  • 32.
    Kolar, Mallappa K.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Regenerative effects of adipose-tissue-derived stem cells for treatment of peripheral nerve injuries2014Ingår i: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 42, s. 697-701Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Peripheral nerve injuries are a common occurrence affecting the nerves found outside the central nervous system. Complete nerve transections necessitate surgical re-anastomosis, and, in cases where there is a significant gap between the two ends of the injured nerve, bridging strategies are required to repair the defect. The current clinical gold standard is the nerve graft, but this has a number of limitations, including donor site morbidity. An active area of research is focused on developing other techniques to replace these grafts, by creating tubular nerve-guidance conduits from natural and synthetic materials, which are often supplemented with biological cues such as growth factors and regenerative cells. In the present short review, we focus on the use of adipose-tissue-derived stem cells and the possible mechanisms through which they may exert a positive influence on peripheral nerve regeneration, thereby enabling more effective nerve repair.

  • 33.
    Kolar, Mallappa K
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikova, Liudmila N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    The therapeutic effects of human adipose derived stem cells in a rat cervical spinal cord injury model2014Ingår i: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 23, nr 14, s. 1659-1674Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Spinal cord injury triggers a cascade of degenerative changes leading to cell death and cavitation. Severed axons fail to regenerate across the scar tissue and are only capable of limited sprouting. In this study we investigated the effects of adult human adipose derived stem cells (ASC) on axonal regeneration following transplantation into the injured rat cervical spinal cord. ASC did not induce activation of astrocytes in culture and supported neurite outgrowth from adult rat sensory DRG neurons. After transplantation into the lateral funiculus 1mm rostral and caudal to the cervical C3-C4 hemisection, ASC continued to express BDNF, VEGF and FGF-2 for 3 weeks but only in animals treated with cyclosporine A. Transplanted ASC stimulated extensive ingrowth of 5HT-positive raphaespinal axons into the trauma zone with some terminal arborisations reaching the caudal spinal cord. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure of the lesion scar with numerous astrocytic processes extended into the middle of the trauma zone in a chain-like pattern and in close association with regenerating axons. The density of the astrocytic network was also significantly decreased. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the activity of OX42-positive microglial cells was markedly reduced. However, ASC did not support recovery of forelimb function. The results suggest that transplanted ASC can modify the structure of the glial scar and stimulate axonal sprouting.

  • 34.
    Kolar, Mallappa Kadappa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Itte, Vinay N.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev N.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kelk, Peyman
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    The neurotrophic effects of different human dental mesenchymal stem cells2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 12605Artikel i tidskrift (Refereegranskat)
  • 35.
    Lauvrud, Anne Therese
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kelk, Peyman
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Characterization of human adipose tissue-derived stem cells with enhanced angiogenic and adipogenic properties2017Ingår i: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 11, nr 9, s. 2490-2502Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Autologous fat grafting is a popular method for soft tissue reconstructions but graft survival remains highly unpredictable. Supplementation of the graft with the stromal vascular fraction (SVF) or cultured adipose tissue-derived stem cells (ASCs) can enhance graft viability. In this study we have examined the phenotypic properties of a selected population of cells isolated from ASCs, with a view to determining their suitability for transplantation into grafts. ASCs were isolated from the SVF of human abdominal fat (n = 8 female patients) and CD146(+) cells were selected using immunomagnetic beads. The angiogenic and adipogenic properties of the positively selected cells were compared with the negative fraction. CD146(+) cells expressed the immunophenotypic characteristics of pericytes. With prolonged in vitro expansion, CD146(-) cells exhibited increased population doubling times and morphological signs of senescence, whereas CD146(+) cells did not. CD146(+) cells expressed higher levels of the angiogenic molecules VEGF-A, angiopoietin-1 and FGF-1. Conditioned medium taken from CD146(+) cells significantly increased formation of in vitro endothelial cell tube networks, whereas CD146(-) cells did not. CD146(+) cells could be differentiated into adipocytes in greater numbers than CD146(-) cells. Consistent with this, differentiated CD146(+) cells expressed higher levels of the adipocyte markers adiponectin and leptin. These results suggest that CD146(+) cells selected from a heterogeneous mix of ASCs have more favourable angiogenic and adipogenic properties, which might provide significant benefits for reconstructive and tissue-engineering applications. Copyright © 2016 John Wiley & Sons, Ltd.

  • 36. Louw, Andrew M
    et al.
    Kolar, Mallappa K
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Novikova, Liudmila N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Kjems, Jørgen
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Chitosan polyplex mediated delivery of miRNA-124 reduces activation of microglial cells in vitro and in rat models of spinal cord injury2016Ingår i: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 12, nr 3, s. 643-653Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Traumatic injury to the central nervous system (CNS) is further complicated by an increase in secondary neuronal damage imposed by activated microglia/macrophages. MicroRNA-124 (miR-124) is responsible for mouse monocyte quiescence and reduction of their inflammatory cytokine production. We describe the formulation and ex vivo transfection of chitosan/miR-124 polyplex particles into rat microglia and the resulting reduction of reactive oxygen species (ROS) and TNF-α and lower expression of MHC-II. Upon microinjection into uninjured rat spinal cords, particles formed with Cy3-labeled control sequence RNA, were specifically internalized by OX42 positive macrophages and microglia cells. Alternatively particles injected in the peritoneum were transported by macrophages to the site of spinal cord injury 72h post injection. Microinjections of chitosan/miR-124 particles significantly reduced the number of ED-1 positive macrophages in the injured spinal cord. Taken together, these data present a potential treatment technique to reduce inflammation for a multitude of CNS neurodegenerative conditions.

  • 37.
    Mantovani, Cristina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Mahay, Daljeet
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Terenghi, Giorgio
    Shawcross, Susan G
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Bone marrow- and adipose-derived stem cells show expression of myelin mRNAs and proteins2010Ingår i: Regenerative medicine, ISSN 1746-076X, Vol. 5, nr 3, s. 403-410Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: PNS myelin is formed by Schwann cells (SCs). In this study, we applied an in vitro model to study myelin formation, using bone marrow mesenchymal stem cells and adipose-derived stem cells differentiated into SC-like cells and co-cultured with dissociated adult dorsal root ganglia neurons.

    Methods: Immunocytochemistry, reverse transcription-PCR and western blotting techniques were used to investigate the expression of myelin proteins at both the transcriptional and translational level.

    Results: Transcripts for protein zero, peripheral myelin protein 22 and myelin basic protein were detected in differentiated stem cells following co-culture with neuronal cells. Furthermore, protein zero, peripheral myelin protein 22 and myelin basic proteins were recognized in the co-cultures. These results were consistent with immunostaining of myelin proteins and with observation by electron microscopy.

    Conclusion: Both types of adult stems cells differentiated into SC-like cells have potential to myelinate neuronal cells during regeneration, being functionally identical to SCs of the PNS.

  • 38.
    McGrath, Aleksandra
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Brohlin, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Paul, Kingham
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Novikova, Liudmila
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Fibrin conduit supplemented with human mesenchymal stem cells supports regeneration after peripheral nerve injury   Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    To address the need for the development of bioengineered replacement of a nerve graft for treatment of peripheral nerve injuries a novel two component fibrin glue conduit was combined with human mesenchymal stem cells (hMSC) and immunosupressive treatment with cyclosporine. MSC possess the advantage of lower donor site morbidity and easier expandability in vitro compared with Schwann cells. The effects of hMSC on axonal regeneration in the conduit and reaction of activated macrophages was investigated using sciatic nerve injury model. The experiments were performed on 20 female Fischer rats (8-10 weeks old). A 10mm gap in the sciatic nerve was created and repaired either with fibrin glue conduit containing diluted fibrin matrix or fibrin glue conduit containing fibrin matrix with hMSC at concentration of 80x106 cells per ml. Cells were labeled with PKH26 prior to transplantation. The animals were allowed to survive for 3 weeks and some groups were treated with daily injections of cyclosporine. After 3 weeks the conduits were harvested and the distance of regeneration and area occupied by regenerating axons together with ED1 staining of activated macrophages was measured. hMSC survived in the conduit and enhanced axonal regeneration only when transplantation was combined with cyclosporine treatment. Moreover, cyclosporine significantly reduced the ED1 macrophage reaction.

  • 39.
    McGrath, Aleksandra M
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Brohlin, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Novikova, Liudmila N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Fibrin conduit supplemented with human mesenchymal stem cells and immunosuppressive treatment enhances regeneration after peripheral nerve injury2012Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 516, nr 2, s. 171-176Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To address the need for the development of bioengineered replacement of a nerve graft, a novel two component fibrin glue conduit was combined with human mesenchymal stem cells (MSC) and immunosupressive treatment with cyclosporine A. The effects of MSC on axonal regeneration in the conduit and reaction of activated macrophages were investigated using sciatic nerve injury model. A 10mm gap in the sciatic nerve of a rat was created and repaired either with fibrin glue conduit containing diluted fibrin matrix or fibrin glue conduit containing fibrin matrix with MSC at concentration of 80×10(6)cells/ml. Cells were labeled with PKH26 prior to transplantation. The animals received daily injections of cyclosporine A. After 3 weeks the distance of regeneration and area occupied by regenerating axons and ED1 positives macrophages was measured. MSC survived in the conduit and enhanced axonal regeneration only when transplantation was combined with cyclosporine A treatment. Moreover, addition of cyclosporine A to the conduits with transplanted MSC significantly reduced the ED1 macrophage reaction.

  • 40.
    McGrath, Aleksandra M.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Norrlands Univ Hosp, Sect Hand & Plast Surg, Dept Surg & Perioperat Sci, Umea, Sweden.
    Brohlin, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Wiberg, Rebecca
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Norrlands Univ Hosp, Sect Hand & Plast Surg, Dept Surg & Perioperat Sci, Umea, Sweden.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Norrlands Univ Hosp, Sect Hand & Plast Surg, Dept Surg & Perioperat Sci, Umea, Sweden.
    Novikova, Liudmila N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Long-Term Effects of Fibrin Conduit with Human Mesenchymal Stem Cells and Immunosuppression after Peripheral Nerve Repair in a Xenogenic Model2018Ingår i: Cell Medicine, ISSN 2155-1790, Vol. 10, s. 1-13Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Previously we showed that a fibrin glue conduit with human mesenchymal stem cells (hMSCs) and cyclosporine A (CsA) enhanced early nerve regeneration. In this study long term effects of this conduit are investigated. Methods: In a rat model, the sciatic nerve was repaired with fibrin conduit containing fibrin matrix, fibrin conduit containing fibrin matrix with CsA treatment and fibrin conduit containing fibrin matrix with hMSCs and CsA treatment, and also with nerve graft as control. Results: At 12 weeks 34% of motoneurons of the control group regenerated axons through the fibrin conduit. CsA treatment alone or with hMSCs resulted in axon regeneration of 67% and 64% motoneurons respectively. The gastrocnemius muscle weight was reduced in the conduit with fibrin matrix. The treatment with CsA or CsA with hMSCs induced recovery of the muscle weight and size of fast type fibers towards the levels of the nerve graft group. Discussion: The transplantation of hMSCs for peripheral nerve injury should be optimized to demonstrate their beneficial effects. The CsA may have its own effect on nerve regeneration.

  • 41.
    Novikova, Liudmila N
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Brohlin, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Neuroprotective and growth-promoting effects of bone marrow stromal cells after cervical spinal cord injury in adult rats2011Ingår i: Cytotherapy, ISSN 1465-3249, E-ISSN 1477-2566, Vol. 13, nr 7, s. 873-887Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background aims. Bone marrow stromal cells (BMSC) have been shown to provide neuroprotection after transplantation into the injured central nervous system. The present study investigated whether adult rat BMSC differentiated along a Schwann cell lineage could increase production of trophic factors and support neuronal survival and axonal regeneration after transplantation into the injured spinal cord.

    Methods. After cervical C4 hemi-section, 5-bromo-2-deoxyuridine (BrdU)/green fluorescent protein (GFP)-labeled BMSC were injected into the lateral funiculus at 1 mm rostral and caudal to the lesion site. Spinal cords were analyzed 2-13 weeks after transplantation.

    Results and Conclusions. Treatment of native BMSC with Schwann cell-differentiating factors significantly increased production of brain-derived neurotrophic factor in vitro. Transplanted undifferentiated and differentiated BMSC remained at the injection sites, and in the trauma zone were often associated with neurofilament-positive fibers and increased levels of vascular endothelial growth factor. BMSC promoted extensive in-growth of serotonin-positive raphaespinal axons and calcitonin gene-related peptide (CGRP)-positive dorsal root sensory axons into the trauma zone, and significantly attenuated astroglial and microglial cell reactions, but induced aberrant sprouting of CGRP-immunoreactive axons in Rexed's lamina III. Differentiated BMSC provided neuroprotection for axotomized rubrospinal neurons and increased the density of rubrospinal axons in the dorsolateral funiculus rostral to the injury site. The present results suggest that BMSC induced along the Schwann cell lineage increase expression of trophic factors and have neuroprotective and growth-promoting effects after spinal cord injury.

  • 42.
    Novikova, Liudmila N.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Kolar, Mallappa K.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Ullrich, Andreas
    Oberhoffner, Sven
    Renardy, Monika
    Doser, Michael
    Müller, Erhard
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Novikov, Lev N.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Trimethylene carbonate-caprolactone conduit with poly-p-dioxanone microfilaments to promote regeneration after spinal cord injury2018Ingår i: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 66, s. 177-191Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Spinal cord injury (SCI) is often associated with scarring and cavity formation and therefore bridging strategies are essential to provide a physical substrate for axonal regeneration. In this study we investigated the effects of a biodegradable conduit made from trimethylene carbonate and c-caprolactone (TC) containing poly-p-dioxanone microfilaments (PDO) with longitudinal grooves on regeneration after SCI in adult rats. In vitro studies demonstrated that different cell types including astrocytes, meningeal fibroblasts, Schwann cells and adult sensory dorsal root ganglia neurons can grow on the TC and PDO material. For in vivo experiments, the TC/PDO conduit was implanted into a small 2-3 mm long cavity in the C3-C4 cervical segments immediately after injury (acute SCI) or at 2-5 months after initial surgery (chronic SCI). At 8 weeks after implantation into acute SCI, numerous 5HT-positive descending raphaespinal axons and sensory CGRP-positive axons regenerated across the conduit and were often associated with PDO microfilaments and migrated host cells. Implantation into chronically injured SCI induced regeneration mainly of the sensory CGRP-positive axons. Although the conduit had no effect on the density of OX42-positive microglial cells when compared with SCI control, the activity of GFAP-positive astrocytes was reduced. The results suggest that a TC/PDO conduit can support axonal regeneration after acute and chronic SCI even without addition of exogenous glial or stem cells.

  • 43.
    Ouasti, Sihem
    et al.
    University of Manchester.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. University of Manchester.
    Terenghi, Giorgio
    University of Manchester.
    Tirelli, Nicola
    University of Manchester.
    The CD44/integrins interplay and the significance of receptor binding and re-presentation in the uptake of RGD-functionalized hyaluronic acid2012Ingår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 33, nr 4, s. 1120-1134Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have studied the interplay between two endocytic receptors for a carrier structure bearing two complementary ligands. Hyaluronic acid (HA; three different molecular weights) was functionalized with an RGD-containing peptide; this ancillary ligand allows the macromolecule to bind to alpha(v) integrins in addition to the classical HA internalization receptor (CD44). The uptake of HA-RGD and of native HA was assessed in a phagocytic cell model (J774.2 murine macrophages), studying the kinetics of internalization and its mechanistic details. Indications of a synergic binding to integrins and CD44 emerged for HA-RGD; possibly, a first binding to integrins allows for a pre-concentration of the macromolecule on the cell surface, which is then followed by its binding to CD44. The endocytic mechanism and kinetics appeared then dominated by CD44, which has a much slower turnover than integrins. In this study we have demonstrated that the knowledge of the rate-determining steps of the internalization of a carrier is necessary for assessing its performance. In this case, the presence of multiple ligands on a carrier was beneficial in some respect (e.g. in improved binding/targeting), but may not be sufficient to overcome penetration barriers that arise from slow receptor re-presentation. (C) 2011 Elsevier Ltd. All rights reserved.

  • 44.
    Pettersson, Jonas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    McGrath, Aleksandra
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kalbermatten, Daniel
    University Hospital of Basel.
    Novikova, Liudmila
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Muscle recovery after repair of short and long peripheral nerve gaps using fibrin conduits2011Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 500, nr 1, s. 41-46Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Peripheral nerve injuries with loss of nervous tissue are a significant clinical problem and are currently treated using autologous nerve transplants. To avoid the need for donor nerve, which results in additional morbidity such as loss of sensation and scarring, alternative bridging methods have been sought. Recently we showed that an artificial nerve conduit moulded from fibrin glue is biocompatible to nerve regeneration. In this present study, we have used the fibrin conduit or a nerve graft to bridge either a 10 mm or 20 mm sciatic nerve gap and analyzed the muscle recovery in adult rats after 16 weeks. The gastrocnemius muscle weights of the operated side were similar for both gap sizes when treated with nerve graft. In contrast, muscle weight was 48.32 ± 4.96% of the contra-lateral side for the 10 mm gap repaired with fibrin conduit but only 25.20 ± 2.50% for the 20 mm gap repaired with fibrin conduit. The morphology of the muscles in the nerve graft groups showed an intact, ordered structure, with the muscle fibers grouped in fascicles whereas the 20 mm nerve gap fibrin group had a more chaotic appearance. The mean area and diameter of fast type fibers in the 20 mm gap repaired with fibrin conduits were significantly (P < 0.01) worse than those of the corresponding 10 mm gap group. In contrast, both gap sizes treated with nervegraft showed similar fiber size. Furthermore, the 10 mm gaps repaired with either nerve graft or fibrin conduit showed similar muscle fiber size. These results indicate that the fibrin conduit can effectively treat short nerve gaps but further modification such as the inclusion of regenerative cells may be required to attain the outcomes of nerve graft for long gaps.

  • 45.
    Pettersson, Linda F.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Kelk, Peyman
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    In Vitro Osteogenic Differentiation of Human Mesenchymal Stem Cells from Jawbone Compared with Dental Tissue2017Ingår i: Tissue Engineering and Regenerative Medicine, ISSN 1738-2696, Vol. 14, nr 6, s. 763-774Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Autologous bone transplantation is the current gold standard for reconstruction of jawbone defects. Bone regeneration using mesenchymal stem cells (MSC) is an interesting alternative to improve the current techniques, which necessitate a second site of surgery resulting in donor site morbidity. In this study, we compared the osteogenic ability of jawbone MSC (JB-MSC) with MSC from tissues with neural crest origin, namely, the dental pulp, apical papilla and periodontal ligament. All four types of MSC were isolated from the same patient (n = 3 donors) to exclude inter-individual variations. The MSC growth and differentiation properties were characterized. The osteogenic differentiation potential in each group of cells was assessed quantitatively to determine if there were any differences between the cell types. All cells expressed the MSC-associated surface markers CD73, CD90, CD105, and CD146 and were negative for CD11b, CD19, CD34, CD45 and HLA-DR. All cell types proliferated at similar rates, exhibited similar clonogenic activity and could differentiate into adipocytes and osteoblasts. An alkaline phosphatase assay, OsteoImageTM assay for mineralization and qRT-PCR measuring the genes runx2, ALP and OCN, indicated that there were no significant differences in the osteogenic differentiation ability between the various MSCs. In conclusion, we show that from a small segment of jawbone it is possible to isolate sufficient quantities of MSC and that these cells can easily be expanded and differentiated into osteoblasts. JB-MSC appear to be good candidates for future bone regeneration applications in the craniofacial region.

  • 46.
    Reid, Adam J
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. University of Manchester.
    de Luca, Alba C
    University of Manchester.
    Faroni, Alessandro
    University of Manchester.
    Downes, Sandra
    University of Manchester.
    Sun, Mingzhu
    University of Manchester.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Long term peripheral nerve regeneration using a novel PCL nerve conduit2013Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 544, s. 125-30Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The gold standard in surgical management of a peripheral nerve gap is currently autologous nerve grafting. This confers patient morbidity and increases surgical time therefore innovative experimental strategies towards engineering a synthetic nerve conduit are welcome. We have developed a novel synthetic conduit made of poly ε-caprolactone (PCL) that has demonstrated promising peripheral nerve regeneration in short-term studies. This material has been engineered to permit translation into clinical practice and here we demonstrate that histological outcomes in a long-term in vivo experiment are comparable with that of autologous nerve grafting. A 1cm nerve gap in a rat sciatic nerve injury model was repaired with a PCL nerve conduit or an autologous nerve graft. At 18 weeks post surgical repair, there was a similar volume of regenerating axons within the nerve autograft and PCL conduit repair groups, and similar numbers of myelinated axons in the distal stump of both groups. Furthermore, there was evidence of comparable re-innervation of end organ muscle and skin with the only significant difference the lower wet weight of the muscle from the PCL conduit nerve repair group. This study stimulates further work on the potential use of this synthetic biodegradable PCL nerve conduit in a clinical setting.

  • 47.
    Reid, Adam J
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. University of Manchester.
    Sun, M
    University of Manchester.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Downes, S
    University of Manchester.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. University of Manchester.
    Nerve repair with adipose-derived stem cells protects dorsal root ganglia neurons from apoptosis2011Ingår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 199, s. 515-522Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Novel approaches are required in the clinical management of peripheral nerve injuries because current surgical techniques result in deficient sensory recovery. Microsurgery alone fails to address extensive cell death in the dorsal root ganglia (DRG), in addition to poor axonal regeneration. Incorporation of cultured cells into nerve conduits may offer a novel approach in which to combine nerve repair and enhance axonal regeneration with neuroprotective therapies. We examined apoptotic mediator expression in rat DRG neurons following repair of a 10-mm sciatic nerve gap using a novel synthetic conduit made of poly epsilon-caprolactone (PCL) and primed with adipose-derived stem cells (ADSC) differentiated towards a Schwann cell phenotype or with primary adult Schwann cells. Differentiated ADSC expressed a range of neurotrophic factors including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and neurotrophin-4 (NT4). Incorporation of either differentiated ADSC or Schwann cells significantly increased anti-apoptotic Bcl-2 mRNA expression (P<0.001) in the DRG, while significantly decreasing proapoptotic Bax (P<0.001) and caspase-3 mRNA (P<0.01) expression. Cleaved caspase-3 protein was observed in the DRG following nerve injury which was attenuated when nerve repair was performed using conduits seeded with cells. Cell incorporation into conduit repair of peripheral nerves demonstrates experimental promise as a novel intervention to prevent DRG neuronal loss. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  • 48.
    Schaakxs, Dominique
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Division of Plastic, Reconstructive and Aesthetic Surgery, CHUV, University Hospital of Lausanne, Switzerland.
    Kalbermatten, Daniel F
    Pralong, Etienne
    Raffoul, Wassim
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Poly-3-hydroxybutyrate strips seeded with regenerative cells are effective promoters of peripheral nerve repair2017Ingår i: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 11, nr 3, s. 812-821Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Peripheral nerve injuries are often associated with loss of nerve tissue and require a graft to bridge the gap. Autologous nerve grafts are still the 'gold standard' in reconstructive surgery but have several disadvantages, such as sacrifice of a functional nerve, neuroma formation and loss of sensation at the donor site. Bioengineered grafts represent a promising approach to address this problem. In this study, poly-3-hydroxybutyrate (PHB) strips were used to bridge a 10 mm rat sciatic nerve gap and their effects on long-term (12 weeks) nerve regeneration were compared. PHB strips were seeded with different cell types, either primary Schwann cells (SCs) or SC-like differentiated adipose-derived stem cells (dASCs) suspended in a fibrin glue matrix. The control group was PHB and fibrin matrix without cells. Functional and morphological properties of the regenerated nerve were assessed using walking track analysis, EMGs, muscle weight ratios and muscle and nerve histology. The animals treated with PHB strips seeded with SCs or dASCs showed significantly better functional ability than the control group. This correlated with less muscle atrophy and greater axon myelination in the cell groups. These findings suggest that the PHB strip seeded with cells provides a beneficial environment for nerve regeneration. Furthermore, dASCs, which are abundant and easily accessible, constitute an attractive cell source for future applications of cell therapy for the clinical repair of traumatic nerve injuries.

  • 49.
    Schaakxs, Dominique
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. University Hospital of Lausanne.
    Kalbermatten, Daniel F
    University Hospital of Basel.
    Raffoul, Wassim
    University Hospital of Lausanne.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Regenerative cell injection in denervated muscle reduces atrophy and enhances recovery following nerve repair2013Ingår i: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 47, nr 5, s. 691-701Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Functional muscle recovery after peripheral nerve injury is far from optimal, partly due to atrophy of the muscle arising from prolonged denervation. We hypothesized that injecting regenerative cells into denervated muscle would reduce this atrophy. Methods: A rat sciatic nerve lesion was performed, and Schwann cells or adipose-derived stem cells, untreated or induced to a Schwann-celllike phenotype (dASC), were injected into the gastrocnemius muscle. Nerves were either repaired immediately or capped to prevent muscle reinnervation. One month later, functionality was measured using a walking track test, and muscle atrophy was assessed by examining muscle weight and histology. Results: Schwann cells and dASC groups showed significantly better scores on functional tests when compared with injections of growth medium alone. Muscle weight and histology were also significantly improved in these groups. Conclusion: Cell injections may reduce muscle atrophy and could benefit nerve injury patients.

  • 50.
    Schaakxs, Dominique
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi. Plastic and Reconstructive Surgery (CHUV), University Hospital of Lausanne, Lausanne, Switzerland.
    Raffoul, Wassim
    Plastic and Reconstructive Surgery (CHUV), University Hospital of Lausanne, Lausanne, Switzerland.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Kingham, Paul
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Kalbermatten, Daniel
    Department of Plastic, Reconstructive and Aesthetic Surgery, University Hospital of Basel, Switzerland.
    A comparison of an artificial nerve repair construct and nerve grafting when used in combination with intramuscular injections of stem cells for reduction of muscle atrophyManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Peripheral nerve injuries represent a clinical challenge, especially when they are accompanied by loss of neural tissue. We tried to attain a better outcome after a peripheral nerve injury (in a rat sciatic nerve experimental model) by both repairing the nerve lesion and treating the denervated muscle at the same time.  We compared artificial nerve constructs made from strips of poly-3-hydroxybutyrate (PHB), seeded with or without Schwann cell-like differentiated adipose stem cells (dASC), and autografts (reverse sciatic nerve grafts) in combination with stem cell injections in the gastrocnemius muscle. dASC expressed Schwann cell markers (GFAP, S100B and p75-NTR) and secreted a range of nerve, angiogenic and muscle growth factors. Six weeks after nerve injury, the effects of the stem cells on nerve regeneration and reduction of muscle atrophy were assessed. PHB strips showed a high number of βIII-tubulin positive axons entering the distal stump and abundant endothelial cells. Animals treated with PHB strips without cells in combination with control growth medium intramuscular injections showed significantly more atrophy than the other groups.  Best results were obtained in the autograft group combined with intramuscular stem cell injections. This bioengineering research is a promising approach to treat nerve lesions and associated muscle atrophy.

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