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  • 1.
    Brohlin, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Aging effect on neurotrophic activity of human mesenchymal stem cells2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, e45052- p.Article in journal (Refereed)
    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.

  • 2.
    Ching, Rosanna C.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    The role of exosomes in peripheral nerve regeneration2015In: Neural Regeneration Research, ISSN 1673-5374, E-ISSN 1876-7958, Vol. 10, no 5, 743-747 p.Article, review/survey (Refereed)
    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.

  • 3.
    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 University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Terenghi, Giorgio
    University of Manchester.
    Long-term in vivo regeneration of peripheral nerves through bioengineered nerve grafts2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 181, no 5, 278-291 p.Article in journal (Refereed)
    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.

  • 4.
    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 University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. 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 conditions2013In: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 19, no 3-4, 368-379 p.Article in journal (Refereed)
    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.

  • 5.
    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 University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    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 repair2014In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 572, 26-31 p.Article in journal (Refereed)
    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.

  • 6.
    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 University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Raffoul, W
    Chirurgie Plastique et Reconstructive CHUV, Université de Lausanne, Rue de Bugnon 46, 1005 Lausanne, CH, Switzerland.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Terenghi, Giorgio
    Blond McIndoe Research Laboratories. The University of Manchester, Manchester, UK.
    Kalbermatten, Daniel F
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Adipose-derived stem cells enhance peripheral nerve regeneration2010In: Journal of plastic, reconstructive and aesthetic surgery, ISSN 1878-0539, Vol. 63, no 9, 1544-1552 p.Article in journal (Refereed)
    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.

  • 7.
    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 University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    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 injury2013In: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 8, no 6, 739-746 p.Article in journal (Refereed)
    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.

  • 8.
    Engels, Patricia E.
    et al.
    University Hospital Basel.
    Tremp, Mathias
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    di Summa, Pietro G.
    Largo, Rene D.
    Schaefer, Dirk J.
    Kalbermatten, Daniel F
    Harvest site influences the growth properties of adipose derived stem cells2013In: Cytotechnology (Dordrecht), ISSN 0920-9069, E-ISSN 1573-0778, Vol. 65, no 3, 437-445 p.Article in journal (Refereed)
    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.

  • 9.
    Erba, P
    et al.
    University of Manchester, University Hospital of Basel.
    Mantovani, Cristina
    University of Manchester.
    Kalbermatten, Daniel F
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pierer, G
    University Hospital of Basel.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Regeneration potential and survival of transplanted undifferentiated adipose tissue-derived stem cells in peripheral nerve conduits2010In: Journal of plastic, reconstructive & aesthetic surgery : JPRAS, ISSN 1878-0539, Vol. 63, no 12, e811-e817 p.Article in journal (Refereed)
    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.

  • 10.
    Erba, Paolo
    et al.
    University Hospitals of Basel and Lausanne.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Neural differentiation and therapeutic potential of adipose tissue derived stem cells2010In: Current stem cell research & therapy, ISSN 1574-888X, Vol. 5, no 2, 153-160 p.Article, review/survey (Refereed)
    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.

  • 11. Faroni, Alessandro
    et al.
    Mobasseri, S. Atefeh
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Reid, Adam J.
    Peripheral nerve regeneration: experimental strategies and future perspectives2015In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 82-83, 160-167 p.Article, review/survey (Refereed)
    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. 

  • 12. Georgiou, M.
    et al.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    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 vivo2012In: Journal of tissue engineering and regenerative medicine, ISSN 1932-6254, Vol. 6, no Suppl. 1, 259- p.Article in journal (Other academic)
  • 13. Georgiou, Melanie
    et al.
    Golding, Jon P.
    Loughlin, Alison J.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    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 nerve2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 37, 242-251 p.Article in journal (Refereed)
    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. 

  • 14.
    Jonsson, Samuel
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Rebecca
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    McGrath, Aleksandra M
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Effect of delayed peripheral nerve repair on nerve regeneration, Schwann cell function and target muscle recovery2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, e56484Article in journal (Refereed)
    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.

  • 15.
    Kalbermatten, Daniel F
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Mahay, Daljeet
    Mantovani, Cristina
    Pettersson, Jonas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Raffoul, W
    Balcin, H
    Pierer, G
    Terenghi, Giorgio
    Fibrin matrix for suspension of regenerative cells in an artificial nerve conduit2008In: Journal of plastic, reconstructive and aesthetic surgery, ISSN 1878-0539, Vol. 61, no 6, 669-675 p.Article in journal (Refereed)
    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.

  • 16.
    Kalbermatten, Daniel F
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pettersson, Jonas
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pierer, Gerhard
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Terenghi, Giorgio
    New fibrin conduit for peripheral nerve repair2009In: Journal of reconstructive microsurgery, ISSN 0743-684X, E-ISSN 1098-8947, Vol. 25, no 1, 27-33 p.Article in journal (Refereed)
    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.

  • 17.
    Kalbermatten, Daniel F
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Schaakxs, Dominique
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Neurotrophic activity of human adipose stem cells isolated from deep and superficial layers of abdominal fat2011In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 344, no 2, 251-260 p.Article in journal (Refereed)
    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.

  • 18.
    Kalbermatten, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Schaakxs, Dominique
    Kingham, Paul
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Neurotrophic activity of human adipose stem cells isolated from deep and superficial layers of abdominal fatManuscript (preprint) (Other academic)
    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.

  • 19.
    Karalija, Amar
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Neuroprotective Effects of N-Acetyl-Cysteine and Acetyl-L-Carnitine after Spinal Cord Injury in Adult Rats2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, e41086- p.Article in journal (Refereed)
    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.

  • 20.
    Karalija, Amar
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Ludmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The effects of N-acetyl-cysteine and acetyl-l-carnitine on neural survival, neuroinflammation and regeneration following spinal cord injury2014In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 269, 143-151 p.Article in journal (Refereed)
    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.

  • 21.
    Kingham, Paul J
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kolar, Mallappa K
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair2014In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 23, no 7, 741-754 p.Article in journal (Refereed)
    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.

  • 22.
    Kingham, Paul J
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. 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 regeneration2011In: 3D Cell Culture: Methods and Protocols / [ed] John W. Haycock, New York: Humana Press, 2011, Vol. 695, 115-127 p.Chapter in book (Refereed)
    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.

  • 23.
    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 cells2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 467, no 2, 164-168 p.Article in journal (Refereed)
    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.

  • 24.
    Kingham, Paul J.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Reid, Adam J.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Adipose-Derived Stem Cells for Nerve Repair: Hype or Reality?2014In: Cells Tissues Organs, ISSN 1422-6405, E-ISSN 1422-6421, Vol. 200, no 1, 23-30 p.Article, review/survey (Refereed)
    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.

  • 25.
    Kolar, Mallappa K.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Regenerative effects of adipose-tissue-derived stem cells for treatment of peripheral nerve injuries2014In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 42, 697-701 p.Article in journal (Refereed)
    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.

  • 26.
    Kolar, Mallappa K
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The therapeutic effects of human adipose derived stem cells in a rat cervical spinal cord injury model2014In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 23, no 14, 1659-1674 p.Article in journal (Refereed)
    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.

  • 27.
    Kolar, Mallappa Kadappa
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Itte, Vinay N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kelk, Peyman
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The neurotrophic effects of different human dental mesenchymal stem cells2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, 12605Article in journal (Refereed)
  • 28. Louw, Andrew M
    et al.
    Kolar, Mallappa K
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Kjems, Jørgen
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Chitosan polyplex mediated delivery of miRNA-124 reduces activation of microglial cells in vitro and in rat models of spinal cord injury2016In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 12, no 3, 643-653 p.Article in journal (Refereed)
    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.

  • 29.
    Mantovani, Cristina
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Mahay, Daljeet
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Terenghi, Giorgio
    Shawcross, Susan G
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Bone marrow- and adipose-derived stem cells show expression of myelin mRNAs and proteins2010In: Regenerative medicine, ISSN 1746-076X, Vol. 5, no 3, 403-410 p.Article in journal (Refereed)
    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.

  • 30.
    McGrath, Aleksandra
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Brohlin, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Paul, Kingham
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Fibrin conduit supplemented with human mesenchymal stem cells supports regeneration after peripheral nerve injury   Manuscript (preprint) (Other academic)
    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.

  • 31.
    McGrath, Aleksandra M
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Brohlin, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Fibrin conduit supplemented with human mesenchymal stem cells and immunosuppressive treatment enhances regeneration after peripheral nerve injury2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 516, no 2, 171-176 p.Article in journal (Refereed)
    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.

  • 32.
    McGrath, Aleksandra M.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Wiberg, Rebecca
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Brohlin, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Long-term effects of fibrin conduit with human mesenchymal stem cells and immunosuppression after peripheral nerve repair in a xenogenic modelManuscript (preprint) (Other academic)
  • 33.
    Novikova, Liudmila N
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Brohlin, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Neuroprotective and growth-promoting effects of bone marrow stromal cells after cervical spinal cord injury in adult rats2011In: Cytotherapy, ISSN 1465-3249, E-ISSN 1477-2566, Vol. 13, no 7, 873-887 p.Article in journal (Refereed)
    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.

  • 34.
    Ouasti, Sihem
    et al.
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. 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 acid2012In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 33, no 4, 1120-1134 p.Article in journal (Refereed)
    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.

  • 35.
    Pettersson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    McGrath, Aleksandra
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kalbermatten, Daniel
    University Hospital of Basel.
    Novikova, Liudmila
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Muscle recovery after repair of short and long peripheral nerve gaps using fibrin conduits2011In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 500, no 1, 41-46 p.Article in journal (Refereed)
    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.

  • 36.
    Reid, Adam J
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. 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 University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Long term peripheral nerve regeneration using a novel PCL nerve conduit2013In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 544, 125-30 p.Article in journal (Refereed)
    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.

  • 37.
    Reid, Adam J
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. University of Manchester.
    Sun, M
    University of Manchester.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Downes, S
    University of Manchester.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. University of Manchester.
    Nerve repair with adipose-derived stem cells protects dorsal root ganglia neurons from apoptosis2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 199, 515-522 p.Article in journal (Refereed)
    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.

  • 38.
    Schaakxs, Dominique
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Division of Plastic, Reconstructive and Aesthetic Surgery, CHUV, University Hospital of Lausanne, Switzerland.
    Kalbermatten, Daniel F
    Pralong, Etienne
    Raffoul, Wassim
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Poly-3-hydroxybutyrate strips seeded with regenerative cells are effective promoters of peripheral nerve repair2017In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 11, no 3, 812-821 p.Article in journal (Refereed)
    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.

  • 39.
    Schaakxs, Dominique
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. University Hospital of Lausanne.
    Kalbermatten, Daniel F
    University Hospital of Basel.
    Raffoul, Wassim
    University Hospital of Lausanne.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Regenerative cell injection in denervated muscle reduces atrophy and enhances recovery following nerve repair2013In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 47, no 5, 691-701 p.Article in journal (Refereed)
    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.

  • 40.
    Schaakxs, Dominique
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. 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 University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kingham, Paul
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (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 atrophyManuscript (preprint) (Other academic)
    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.

  • 41.
    Schaakxs, Dominique
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Plastic and Reconstructive Surgery (CHUV), University Hospital of Lausanne, Lausanne, Switzerland.
    Vermeille, Matthieu
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Department of Plastic, Reconstructive and Aesthetic Surgery, University Hospital of Basel, Switzerland.
    Kalbermatten, Daniel
    Department of Plastic, Reconstructive and Aesthetic Surgery, University Hospital of Basel, Switzerland.
    Raffoul, Wassim
    Plastic and Reconstructive Surgery (CHUV), University Hospital of Lausanne, Switzerland.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kingham, Paul
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Mechanisms of adipose stem cell interactions with muscle cells and Schwann cellsManuscript (preprint) (Other academic)
    Abstract [en]

    Peripheral nerve injury leads to muscle atrophy due to prolonged denervation. In a previous study, we showed the benefits of injecting Schwann cell and Schwann cell-like differentiated adipose stem cells (dASC) into the muscle to help nerve regeneration and prevent muscle atrophy. In this in vitro study, we have analyzed the possible mechanisms of how adipose stem cells interact with muscle cells and Schwann cells. Myoblast cell lines (C2C12 and L6) or rat primary Schwann cells treated with conditioned media prepared from either undifferentiated adipose stem cells or dASC proliferated more than control cultures. Stem cell mediated proliferation of myoblasts and Schwann cells was blocked by the inhibition of MAP kinase signaling (using U0126 drug) whereas the PKA pathway (inhibited with H89 drug) was only involved in myoblast proliferation. In order to assess the direct interaction of the stem cells with the muscle, we established direct in vitro co-culture of L6 myoblasts and stem cells for 2 weeks.  Under these conditions a small fraction of cells fused together forming multi-nucleated elongated structures, characteristic of myotubes.  These structures stained positive for fast type myosin heavy chain protein and myogenin. These effects were most pronounced in the dASC-myoblast co-cultures. ELISA analysis of the co-cultures showed high levels of secreted vascular endothelial growth factor-A (VEGF-A) and insulin like growth factor 1 proteins. Western blot analysis of denervated rat muscle tissue also showed elevated levels of VEGF-A expression in animals treated with stem cell injections. In conclusion, this study provides evidence of possible mechanisms how stem cells might influence cells of the neuromuscular system and supports the beneficial effect of using these cells for future clinical application in treatment of peripheral nerve injuries.

  • 42. Sun, M
    et al.
    Kingham, Paul J
    Blond McIndoe Laboratories, School of Medicine, Stopford Building, The University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
    Reid, Adam J
    Armstrong, Stephanie J
    Terenghi, Giorgio
    Downes, S
    In vitro and in vivo testing of novel ultrathin PCL and PCL/PLA blend films as peripheral nerve conduit2010In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 93, no 4, 1470-1481 p.Article in journal (Refereed)
    Abstract [en]

    In an attempt to obviate the drawbacks of nerve autograft, ultrathin microporous biodegradable PCL and PCL/PLA films were tested for their compatibility with motor neuron-like NG108-15 cells and primary Schwann cells. Data obtained from MTS colorimetric and DNA fluorimetric assays showed that both cell lines readily attached and proliferated on these materials. Images taken using scanning electron microscope and fluorescence microscope confirmed these observations. Enhanced cell-surface interaction was achieved by pretreating the films in NaOH solution. Importantly, NG108-15 cells could be induced into differentiated phenotype with long, un-branched neurites growing across the surface of the materials. The bipolar spindle-shaped phenotype of Schwann cells was also retained on these scaffolds. Positive immunochemical staining using antibodies against neurofilament for NG108-15 cells and S100 for Schwann cells indicated the expression of these marker proteins. In a small-scaled pilot testing, the performance of PCL conduits in bridging up a 10 mm gap in rat sciatic nerve model was assessed. Immunohistochemical staining showed that regenerated nerve tissue and penetrated Schwann cells have the potential to span the whole length of the conduit in 2 weeks.

  • 43.
    Sun, Mingzhu
    et al.
    University of Manchester.
    McGowan, Malachy
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. University of Manchester.
    Terenghi, Giorgio
    University of Manchester.
    Downes, Sandra
    University of Manchester.
    Novel thin-walled nerve conduit with microgrooved surface patterns for enhanced peripheral nerve repair2010In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 21, no 10, 2765-2774 p.Article in journal (Refereed)
    Abstract [en]

    Randomly aligned nerve cells in vitro on conventional culture substrata do not represent the complex neuronal network in vivo and neurites growing in uncontrolled manner may form neuroma. It is of great importance to mimic the organised growth pattern of nerve cells in the study of peripheral nerve repair. The aim of this work was to modify and optimize the photolithographic technique in creating a reusable template in the form of a silicon wafer that could be used to produce contact guidance on biodegradable polymer surface for the orientated growth of nerve cells. Micro-grooves (approximately 3 μm in depth) were etched into the silicon template using KOH at increased temperature. The originality of this work lies in the low cost and high efficiency method in producing microgrooves on the surface of biodegradable ultra-thin polymer substrates (50-100 μm), which can be readily rolled up to form clinically implantable nerve conduits. The design of a pattern with small ridge width (i.e., 5 μm) and bigger groove width (i.e., 20 μm) favored the alignment of cells along the grooves rather than on the ridges of the patterns, which minimized the effect of cross growing of neurites between adjacent grooves. Effectively, enhanced nerve regeneration could be anticipated from these patterned conduits.

  • 44. Terenghi, Giorgio
    et al.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Chapter 21: Use of stem cells for improving nerve regeneration2009In: International review of neurobiology, ISSN 0074-7742, E-ISSN 2162-5514, Vol. 87, 393-403 p.Article, review/survey (Refereed)
    Abstract [en]

    A clear need exists for new surgical approaches to enhance the recuperation of functions after peripheral nerve injury and repair. At present, advances in the regenerative medicine fields of biomaterials, cellular engineering, and molecular biology are all contributing to the development of a bioengineered nerve implant, which could be used clinically as an alternative to nerve autograft. In this review we examine the recent progress in this field, looking in particular at the applicability of Schwann cells and stem cell transplantation to enhance nerve regeneration.

  • 45. Thornton, Martin R
    et al.
    Shawcross, Susan G
    Mantovani, Cristina
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Birchall, Martin A
    Terenghi, Giorgio
    Neurotrophins 3 and 4 differentially regulate NCAM, L1 and N-cadherin expression during peripheral nerve regeneration.2008In: Biotechnology and applied biochemistry, ISSN 0885-4513, E-ISSN 1470-8744, Vol. 49, no Pt 2, 165-74 p.Article in journal (Refereed)
    Abstract [en]

    The addition of NT-3 (neurotrophin 3) or NT-4 to injured nerves improves their regeneration potential and may aid axon guidance. It is not well defined whether NTs (neurotrophins) influence other elements, such as the cell-adhesion molecules, which promote nerve guidance and regeneration. Using poly-3-hydroxybutyrate conduits, we applied either NT-3 or NT-4 to axotomized rat sciatic nerves and monitored nerve regeneration and cell-adhesion molecule expression. Regenerating nerves were stained with antibodies against NCAM (neural cell-adhesion molecule) and N-cadherin 2 weeks after injury and staining intensity was quantified. NCAM, N-cadherin and L1 (L1 cell-adhesion molecule) transcription was measured in the proximal and distal stumps and ipsilateral DRG (dorsal root ganglia) (fourth and fifth DRG) using RT (reverse transcriptase)-PCR. Both NT-3 and NT-4 increased NCAM and L1 transcript levels in the DRG of axotomized nerves. This is reflected in the increased NCAM expression at the proximal stump and regeneration front. Increased levels of NCAM were also observed in the distal stump. NT-4 administration increased N-cadherin levels proximal to the injury, but not distally. Following NT-3 administration, N-cadherin expression decreased in proximal and distal stumps compared with the control. In conclusion, NTs differentially alter adhesion molecule expression in regenerating nerves and transcription in the corresponding DRG, although these changes in expression do not alter NT-enhanced regeneration. Thus we propose that retrograde transport of the NTs to the DRG affects adhesion molecule transcription, reflected by protein expression in peripheral nerve axons.

  • 46.
    Tse, Kai-Hei
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    The reactions of adipose tissue and bone marrow-derived stem cells in an ischaemia-like microenvironment2012In: Journal of tissue engineering and regenerative medicine, ISSN 1932-7005, Vol. 6, no 6, 473-485 p.Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stem cells (MSCs) from adipose tissue and bone marrow are promising cell sources for autologous cell therapy of nerve injuries, as demonstrated by their intrinsic neurotrophic potential. However, extensive death of transplanted cells limits their full benefits. This study investigated the effects of ischaemia (metabolically induced by sodium azide and 2-deoxyglucose) and serum-derived mitogens on the viability and functional profile of MSCs in vitro. MSCs were more susceptible to combined, rather than individual, blockade of glycolysis and oxidative phosphorylation. Apoptosis and autophagy were involved in ischaemia-induced cell death. Chemical ischaemia alone and serum withdrawal alone induced a similar amount of cell death, with significantly different intracellular ATP maintenance. Combined ischaemia and serum deprivation had additive effects on cell death. Expression of the extracellular matrix (ECM) molecules laminin and fibronectin was attenuated under ischaemia and independent of serum level; however, BDNF and NGF levels remained relatively constant. Strong upregulation of VEGF and to a lesser extent angiopoietin-1 was observed under ischaemia but not in serum withdrawal conditions. Importantly, this study demonstrated similar reactions of MSCs derived from adipose and bone marrow tissue, in ischaemia-like and mitogen-deprived microenvironments in terms of viability, cellular energetics, cell death mechanisms and expression levels of various growth-promoting molecules. Also, the results suggest that ischaemia has a larger impact on the ability of MSCs to survive transplantation than withdrawal of mitogens. Copyright © 2011 John Wiley & Sons, Ltd.

  • 47.
    Tse, Kai-Hei
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Intrinsic mechanisms underlying the de novo BDNF expression of mesenchymal stem cellsManuscript (preprint) (Other academic)
  • 48.
    Tse, Kai-Hei
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Intrinsic mechanisms underlying the neurotrophic activity of adipose derived stem cells2015In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 331, no 1, 142-151 p.Article in journal (Refereed)
    Abstract [en]

    Adipose derived stem cells (ADSC) can be differentiated into Schwann cell-like cells which enhance nerve function and regeneration. However, the signalling mechanisms underlying the neurotrophic potential of ADSC remain largely unknown. In this study, we hypothesised that ADSC, upon stimulation with a combination of growth factors, could rapidly produce brain derived neurotrophic factor (BDNF) with a similar molecular mechanism to that functioning in the nervous system. Within 48h of stimulation, ADSC demonstrated potent neurotrophic effects on dorsal root ganglion neurons, at a magnitude equivalent to that of the longer term differentiated Schwann cell-like cells. Stimulated ADSC showed rapid up-regulation of the neuronal activity dependent promoter BDNF exon IV along with an augmented expression of full length protein encoding BDNF exon IX. BDNF protein was secreted at a concentration similar to that produced by differentiated Schwann cell-like cells. Stimulation also activated the BDNF expression gating transcription factor, cAMP responsive element binding (CREB) protein. However, blocking phosphorylation of CREB with the protein kinase A small molecule inhibitor H89 did not suppress secretion of BDNF protein. These results suggest rapid BDNF production in ADSC is mediated through multiple compensatory pathways independent of, or in addition to, the CREB neuronal activation cascade.

  • 49.
    Tse, Kai-Hei
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Sun, Mingzhu
    University of Manchester.
    Mantovani, Cristina
    University of Manchester.
    Terenghi, Giorgio
    University of Manchester.
    Downes, Sandra
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    In vitro evaluation of polyester-based scaffolds seeded with adipose derived stem cells for peripheral nerve regeneration2010In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 95, no 3, 701-708 p.Article in journal (Refereed)
    Abstract [en]

    To overcome the disadvantages of autografts for peripheral nerve repair, different methods such as artificial nerve conduits have been investigated for an alternative approach. This study demonstrated that solvent casting is a simple but efficient method to create thin polyester-based scaffolds for stem cell delivery. Using poly (ε-caprolactone) and poly (D,L-lactic acid), we produced scaffold films containing heterogenous depressions (pits) on the air surface with a size ranging from 0.5 to 30 μm(2). These scaffolds were moderately hydrophobic; however, they supported the differentiation of adipose derived stem cells (ADSC) into a Schwann cell-like phenotype. The differentiated ADSC (dADSC) expressed S100 protein and glial fibrillary acidic protein and readily adhered to the films and proliferated at a similar rate to those cultured on tissue culture polystyrene. Cells were also positive for proliferating cell nuclear antigen. Furthermore, dADSC retained functional activity and significantly enhanced neurite outgrowth from dorsal root ganglia neurons. This study suggests polymer scaffolds combined with dADSCs could be a promising therapy for peripheral nerve injuries.

  • 50.
    Wiberg, Rebecca
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Jonsson, Samuel
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Investigation of the Expression of Myogenic Transcription Factors, microRNAs and Muscle-Specific E3 Ubiquitin Ligases in the Medial Gastrocnemius and Soleus Muscles following Peripheral Nerve Injury2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, e0142699Article in journal (Refereed)
    Abstract [en]

    Despite surgical innovation, the sensory and motor outcome after a peripheral nerve injury remains incomplete. One contributing factor to the poor outcome is prolonged denervation of the target organ, leading to apoptosis of both mature myofibres and satellite cells with subsequent replacement of the muscle tissue with fibrotic scar and adipose tissue. In this study, we investigated the expression of myogenic transcription factors, muscle specific microRNAs and muscle-specific E3 ubiquitin ligases at several time points following denervation in two different muscles, the gastrocnemius (containing predominantly fast type fibres) and soleus (slow type) muscles, since these molecules may influence the degree of atrophy following denervation. Both muscles exhibited significant atrophy (compared with the contra-lateral sides) at 7 days following either a nerve transection or crush injury. In the crush model, the soleus muscle showed significantly increased muscle weights at days 14 and 28 which was not the case for the gastrocnemius muscle which continued to atrophy. There was a significantly more pronounced up-regulation of MyoD expression in the denervated soleus muscle compared with the gastrocnemius muscle. Conversely, myogenin was more markedly elevated in the gastrocnemius versus soleus muscles. The muscles also showed significantly contrasting transcriptional regulation of the microRNAs miR-1 and miR-206. MuRF1 and Atrogin-1 showed the highest levels of expression in the denervated gastrocnemius muscle. This study provides further insights regarding the intracellular regulatory molecules that generate and maintain distinct patterns of gene expression in different fibre types following peripheral nerve injury.

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