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Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
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.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
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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.

Place, publisher, year, edition, pages
2014. Vol. 23, no 7, 741-754 p.
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-83708DOI: 10.1089/scd.2013.0396ISI: 000333613700007PubMedID: 24124760OAI: oai:DiVA.org:umu-83708DiVA: diva2:675971
Available from: 2013-12-05 Created: 2013-12-05 Last updated: 2017-12-06Bibliographically approved
In thesis
1. The use of adipose derived stem cells in spinal cord and peripheral nerve repair
Open this publication in new window or tab >>The use of adipose derived stem cells in spinal cord and peripheral nerve repair
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
spinal cord injury, peripheral nerve injury, adipose derived stem cells, regeneration, neurotrophic factor, angiogenic factor
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-89445 (URN)978-91-7601-007-5 (ISBN)
Available from: 2014-06-03 Created: 2014-06-03 Last updated: 2014-06-05Bibliographically approved
2. Transplantation of mesenchymal stem cells and injections of microRNA as therapeutics for nervous system repair
Open this publication in new window or tab >>Transplantation of mesenchymal stem cells and injections of microRNA as therapeutics for nervous system repair
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic injuries to the spinal cord (SCI) and peripheral nerve (PNI) affect several thousand people worldwide every year. At present, there is no effective treatment for SCI and despite continuous improvements in microsurgical reconstructive techniques for PNI, many patients are still left with permanent, devastating neurological dysfunction. This thesis investigates the effects of mesenchymal stem cells (MSC) derived from adipose (ASC) and dental (DSC) tissue and chitosan/microRNA-124 polyplex particles on regeneration after spinal cord and peripheral nerve injury in adult rats. Dental stem cells were obtained from apical papilla, dental pulp, and periodontal ligament. ASC and DSC expressed MSC surface markers (CD73, CD90, CD105 and CD146) and various neurotrophic molecules including BDNF, GDNF, NGF, VEGF-A and angiopoietin-1. Growth factor stimulation of the stem cells resulted in increased secretion of these proteins. Both ASC and DSC supported in vitro neurite outgrowth and in contrast to Schwann cells, ASC did not induce activation of astrocytes. Stimulated ASC also showed an enhanced ability to induce capillary-like tube formation in an in vitro angiogenesis assay. In a peripheral nerve injury model, ASC and DSC were seeded into a fibrin conduit, which was used to bridge a 10 mm rat sciatic nerve gap. After 2 weeks, both ASC and DSC promoted axonal regeneration in the conduit and reduced caspase-3 expression in the dorsal root ganglion (DRG). ASC also enhanced GAP-43 and ATF-3 expression in the spinal cord, reduced c-jun expression in the DRG and increased the vascularity of the implant. After transplantation into injured C3-C4 cervical spinal cord, ASC continued to express neurotrophic factors and laminin and stimulated extensive ingrowth 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. However, ASC did not enhance recovery of forelimb function. In order to reduce activation of microglia/macrophages and the secondary tissue damage after SCI, the role of microRNA-124 was investigated. In vitro transfection of chitosan/microRNA-124 polyplex particles into rat microglia resulted in the reduction of reactive oxygen species and TNF-α levels and lowered 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. Alternatively, particles injected in the peritoneum were transported by macrophages to the site of spinal cord injury. Microinjections of chitosan/microRNA-124 particles significantly reduced the number of ED-1 positive macrophages after SCI. In summary, these results show that human MSC produce functional neurotrophic and angiogenic factors, creating a more desirable microenvironment for neural regeneration after spinal cord and peripheral nerve injury. The data also suggests that chitosan/microRNA-124 particles could be potential treatment technique to reduce neuroinflammation.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2016. 97 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1802
Keyword
spinal cord injury, peripheral nerve injury, mesenchymal stem cells, regeneration, neurotrophic factor, angiogenic factor
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-119437 (URN)978-91-7601-465-3 (ISBN)
Public defence
2016-05-13, N360, Naturvetarhuset, Umeå universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 2014-2306EU, European Research Council
Available from: 2016-04-22 Created: 2016-04-19 Last updated: 2016-05-26Bibliographically approved

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