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Wiberg, Mikael
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Publications (10 of 97) Show all publications
Jones, I., Yelhekar, T. D., Wiberg, R., Kingham, P. J., Johansson, S., Wiberg, M. & Carlsson, L. (2018). Development and validation of an in vitro model system to study peripheral sensory neuron development and injury. Scientific Reports, 8, Article ID 15961.
Open this publication in new window or tab >>Development and validation of an in vitro model system to study peripheral sensory neuron development and injury
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 15961Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-153701 (URN)10.1038/s41598-018-34280-3 (DOI)000448589200037 ()30374154 (PubMedID)
Funder
Swedish Research Council, 22292Gunvor och Josef Anérs stiftelseVästerbotten County Council
Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2018-12-05Bibliographically approved
Bourke, G., McGrath, A. M., Wiberg, M. & Novikov, L. N. (2018). Effects of early nerve repair on experimental brachial plexus injury in neonatal rats. Journal of Hand Surgery, European Volume, 43(3), 275-281
Open this publication in new window or tab >>Effects of early nerve repair on experimental brachial plexus injury in neonatal rats
2018 (English)In: Journal of Hand Surgery, European Volume, ISSN 1753-1934, E-ISSN 2043-6289, Vol. 43, no 3, p. 275-281Article in journal (Refereed) Published
Abstract [en]

Obstetrical brachial plexus injury refers to injury observed at the time of delivery, which may lead to major functional impairment in the upper limb. In this study, the neuroprotective effect of early nerve repair following complete brachial plexus injury in neonatal rats was examined. Brachial plexus injury induced 90% loss of spinal motoneurons and 70% decrease in biceps muscle weight at 28 days after injury. Retrograde degeneration in spinal cord was associated with decreased density of dendritic branches and presynaptic boutons and increased density of astrocytes and macrophages/microglial cells. Early repair of the injured brachial plexus significantly delayed retrograde degeneration of spinal motoneurons and reduced the degree of macrophage/microglial reaction but had no effect on muscle atrophy. The results demonstrate that early nerve repair of neonatal brachial plexus injury could promote survival of injured motoneurons and attenuate neuroinflammation in spinal cord.

Place, publisher, year, edition, pages
Sage Publications, 2018
Keywords
Brachial plexus injury, neonatal rat, spinal cord, motor neuron, cell death
National Category
Orthopaedics Surgery
Identifiers
urn:nbn:se:umu:diva-147362 (URN)10.1177/1753193417732696 (DOI)000429871600005 ()28950736 (PubMedID)
Available from: 2018-05-03 Created: 2018-05-03 Last updated: 2018-06-09Bibliographically approved
McGrath, A. M., Brohlin, M., Wiberg, R., Kingham, P. J., Novikov, L. N., Wiberg, M. & Novikova, L. N. (2018). Long-Term Effects of Fibrin Conduit with Human Mesenchymal Stem Cells and Immunosuppression after Peripheral Nerve Repair in a Xenogenic Model. Cell Medicine, 10, 1-13
Open this publication in new window or tab >>Long-Term Effects of Fibrin Conduit with Human Mesenchymal Stem Cells and Immunosuppression after Peripheral Nerve Repair in a Xenogenic Model
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2018 (English)In: Cell Medicine, ISSN 2155-1790, Vol. 10, p. 1-13Article in journal (Refereed) Published
Abstract [en]

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

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-60908 (URN)10.1177/2155179018760327 (DOI)000433910200001 ()
Available from: 2012-11-02 Created: 2012-11-01 Last updated: 2018-09-10Bibliographically approved
Jones, I., Novikova, L. N., Novikov, L. N., Renardy, M., Ullrich, A., Wiberg, M., . . . Kingham, P. J. (2018). Regenerative effects of human embryonic stem cell-derived neural crest cells for treatment of peripheral nerve injury. Journal of Tissue Engineering and Regenerative Medicine, 12(4), E2099-E2109
Open this publication in new window or tab >>Regenerative effects of human embryonic stem cell-derived neural crest cells for treatment of peripheral nerve injury
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2018 (English)In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 12, no 4, p. E2099-E2109Article in journal (Refereed) Published
Abstract [en]

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

Keywords
artificial nerve graft, human embryonic stem cells, neural crest cells, peripheral nerve injuries, ripheral nervous system, VELOPMENTAL EVOLUTION, V314B, P95 e Gabsang, 2007, NATURE BIOTECHNOLOGY, V25, P1468
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-147466 (URN)10.1002/term.2642 (DOI)000430395400024 ()29327452 (PubMedID)
Funder
Swedish Research Council, 2014-2306
Available from: 2018-05-28 Created: 2018-05-28 Last updated: 2018-06-09Bibliographically approved
Ching, R. C., Wiberg, M. & Kingham, P. J. (2018). Schwann cell-like differentiated adipose stem cells promote neurite outgrowth via secreted exosomes and RNA transfer. Stem Cell Research & Therapy, 9, Article ID 266.
Open this publication in new window or tab >>Schwann cell-like differentiated adipose stem cells promote neurite outgrowth via secreted exosomes and RNA transfer
2018 (English)In: Stem Cell Research & Therapy, E-ISSN 1757-6512, Vol. 9, article id 266Article in journal (Refereed) Published
Abstract [en]

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

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

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

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

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Exosomes, Extracellular vesicles, Peripheral nerves, Regeneration, Schwann cells, Stem cells
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-153126 (URN)10.1186/s13287-018-1017-8 (DOI)000447275400002 ()30309388 (PubMedID)2-s2.0-85054757041 (Scopus ID)
Available from: 2018-11-09 Created: 2018-11-09 Last updated: 2018-11-09Bibliographically approved
Novikova, L. N., Kolar, M. K., Kingham, P. J., Ullrich, A., Oberhoffner, S., Renardy, M., . . . Novikov, L. N. (2018). Trimethylene carbonate-caprolactone conduit with poly-p-dioxanone microfilaments to promote regeneration after spinal cord injury. Acta Biomaterialia, 66, 177-191
Open this publication in new window or tab >>Trimethylene carbonate-caprolactone conduit with poly-p-dioxanone microfilaments to promote regeneration after spinal cord injury
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2018 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 66, p. 177-191Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Synthetic conduit, Tissue engineering, Biomaterials, Spinal cord injury, Regeneration
National Category
Biomaterials Science
Identifiers
urn:nbn:se:umu:diva-145385 (URN)10.1016/j.actbio.2017.11.028 (DOI)000424309200013 ()29174588 (PubMedID)
Available from: 2018-03-01 Created: 2018-03-01 Last updated: 2018-06-09Bibliographically approved
Lauvrud, A. T., Kelk, P., Wiberg, M. & Kingham, P. J. (2017). Characterization of human adipose tissue-derived stem cells with enhanced angiogenic and adipogenic properties. Journal of Tissue Engineering and Regenerative Medicine, 11(9), 2490-2502
Open this publication in new window or tab >>Characterization of human adipose tissue-derived stem cells with enhanced angiogenic and adipogenic properties
2017 (English)In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 11, no 9, p. 2490-2502Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
Adipogenesis, adult stem cell, angiogenesis, fat grafting, pericyte, regeneration
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-133355 (URN)10.1002/term.2147 (DOI)000411481600006 ()26833948 (PubMedID)
Available from: 2017-04-06 Created: 2017-04-06 Last updated: 2018-06-09Bibliographically approved
Brohlin, M., Kelk, P., Wiberg, M. & Kingham, P. J. (2017). Effects of a defined xeno-free medium on the growth and neurotrophic and angiogenic properties of human adult stem cells. Cytotherapy, 19(5), 629-639
Open this publication in new window or tab >>Effects of a defined xeno-free medium on the growth and neurotrophic and angiogenic properties of human adult stem cells
2017 (English)In: Cytotherapy, ISSN 1465-3249, E-ISSN 1477-2566, Vol. 19, no 5, p. 629-639Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2017
Keywords
adipose, bone marrow, clinical cell culture, mesenchymal stromal cells, neurotrophic factors
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-134811 (URN)10.1016/j.jcyt.2017.02.360 (DOI)000399265300007 ()28366194 (PubMedID)
Available from: 2017-05-30 Created: 2017-05-30 Last updated: 2018-06-09Bibliographically approved
Pettersson, L. F., Kingham, P. J., Wiberg, M. & Kelk, P. (2017). In Vitro Osteogenic Differentiation of Human Mesenchymal Stem Cells from Jawbone Compared with Dental Tissue. Tissue Engineering and Regenerative Medicine, 14(6), 763-774
Open this publication in new window or tab >>In Vitro Osteogenic Differentiation of Human Mesenchymal Stem Cells from Jawbone Compared with Dental Tissue
2017 (English)In: Tissue Engineering and Regenerative Medicine, ISSN 1738-2696, Vol. 14, no 6, p. 763-774Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Korean Tissue Engineering and Regenerative Medicine, 2017
Keywords
Stem cells from apical papilla, Dental pulp stem cells, Periodontal ligament stem cells, Stem cells from jawbone, Osteogenic differentiation
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-143573 (URN)10.1007/s13770-017-0071-0 (DOI)000417074300011 ()
Available from: 2018-01-04 Created: 2018-01-04 Last updated: 2018-06-09Bibliographically approved
Dahlin, L. B. & Wiberg, M. (2017). Nerve injuries of the upper extremity and hand. EFORT OPEN REVIEWS, 2(5), 158-170
Open this publication in new window or tab >>Nerve injuries of the upper extremity and hand
2017 (English)In: EFORT OPEN REVIEWS, ISSN 2058-5241, Vol. 2, no 5, p. 158-170Article in journal (Refereed) Published
Abstract [en]

A nerve injury has a profound impact on the patient's daily life due to the impaired sensory and motor function, impaired dexterity, sensitivity to cold as well as eventual pain problems. To perform an appropriate treatment of nerve injuries, a correct diagnosis must be made, where the injury is properly classified, leading to an optimal surgical approach and technique, where timing of surgery is also important for the outcome. Knowledge about the nerve regeneration process, where delicate processes occur in neurons, non-neuronal cells (i. e. Schwann cells) and other cells in the peripheral as well as the central nervous systems, is crucial for the treating surgeon. The surgical decision to perform nerve repair and/or reconstruction depends on the type of injury, the condition of the wound as well as the vascularity of the wound. To reconnect injured nerve ends, various techniques can be used, which include both epineurial and fascicular nerve repair, and if a nerve defect is caused by the injury, a nerve reconstruction procedure has to be performed, including bridging the defect using nerve-grafts or nerve transfer techniques. The patients must be evaluated properly and regularly after the surgical procedure and appropriate rehabilitation programmes are useful to improve the final outcome.

Place, publisher, year, edition, pages
BRITISH EDITORIAL SOC BONE & JOINT SURGERY, 2017
Keywords
nerve injury, nerve repair, nerve reconstruction, nerve transfer, nerve regeneration, neuroma, LLON AL, 1974, PLASTIC AND RECONSTRUCTIVE SURGERY, V53, P297 hlin LB, 2001, NEUROSURGERY CLINICS OF NORTH AMERICA, V12, P341 rnebo S, 2012, Hand Surgery (A volume in the Plastic Surgery 6-Volume Set: Expert Consult Premium), orsen Frida, 2012, JOURNAL OF PLASTIC SURGERY AND HAND SURGERY, V46, P184
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-144366 (URN)10.1302/2058-5241.2.160071 (DOI)000419975400007 ()28630754 (PubMedID)
Available from: 2018-02-02 Created: 2018-02-02 Last updated: 2018-06-09Bibliographically approved
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