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The use of adipose derived stem cells in spinal cord and peripheral nerve repair
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.
2014 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Clinically, injuries affecting the spinal cord or peripheral nerves can leave those affected with severe disability and, at present, there are limited options for treatment. Peripheral nerve injury with a significant gap between the proximal and distal stumps is currently treated with autologous nerve grafting but this is limited by availability of donor nerve and has associated morbidities. In contrast, injuries to the spinal cord lead to an inhibitory environment caused by the glial cells and thereby, limit potential axonal regeneration. This thesis investigates the effects of human adipose derived stem cells (ASC) on regeneration after peripheral nerve and spinal cord injury in adult rats.

Human ASC expressed various neurotrophic molecules and growth factor stimulation of the cells in vitro resulted in increased secretion of BDNF, GDNF, VEGF-A and angiopoietin-1 proteins. Stimulated ASC also showed an enhanced ability to induce capillary-like tube formation in an in vitro angiogenesis assay. In contrast to Schwann cells, ASC did not induce activation of astrocytes and supported neurite outgrowth from the adult rat sensory DRG neurons in culture.

In a peripheral nerve injury model, ASC were seeded into a fibrin conduit, which was used to bridge a 10 mm rat sciatic nerve gap. After 2 weeks, ASC enhanced GAP-43 and ATF-3 expression in the spinal cord, reduced c-jun expression in the DRG and increased the vascularity of the fibrin nerve conduits. The animals treated with stimulated ASC showed an enhanced axon regeneration and reduced caspase-3 expression in the DRG.

After transplantation into the injured C3-C4 cervical spinal cord. ASC continued to express neurotrophic factors and laminin and stimulated extensive ingrowths of 5HT-positive raphaespinal axons into the trauma zone. 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 and the density of the astroglial scar. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the reactivity of OX42-positive microglial cells was markedly reduced.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2014. , 54 p.
Keyword [en]
spinal cord injury, peripheral nerve injury, adipose derived stem cells, regeneration, neurotrophic factor, angiogenic factor
National Category
Surgery
Identifiers
URN: urn:nbn:se:umu:diva-89445ISBN: 978-91-7601-007-5 (print)OAI: oai:DiVA.org:umu-89445DiVA: diva2:721167
Available from: 2014-06-03 Created: 2014-06-03 Last updated: 2014-06-05Bibliographically approved
List of papers
1. Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair
Open this publication in new window or tab >>Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair
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2014 (English)In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 23, no 7, 741-754 p.Article in journal (Refereed) Published
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.

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-83708 (URN)10.1089/scd.2013.0396 (DOI)000333613700007 ()24124760 (PubMedID)
Available from: 2013-12-05 Created: 2013-12-05 Last updated: 2017-12-06Bibliographically approved
2. The therapeutic effects of human adipose derived stem cells in a rat cervical spinal cord injury model
Open this publication in new window or tab >>The therapeutic effects of human adipose derived stem cells in a rat cervical spinal cord injury model
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2014 (English)In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 23, no 14, 1659-1674 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2014
National Category
Neurosciences Cell and Molecular Biology Hematology
Identifiers
urn:nbn:se:umu:diva-88637 (URN)10.1089/scd.2013.0416 (DOI)000339315000009 ()24803143 (PubMedID)
Note

Included in thesis in manuscript form.

Available from: 2014-05-12 Created: 2014-05-12 Last updated: 2017-12-05Bibliographically approved

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