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Fibrin conduit supplemented with human mesenchymal stem cells supports regeneration after peripheral nerve injury   
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. (Neurogruppen)
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. (Neurogruppen)
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. (Neurogruppen)
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(English)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.

Keyword [en]
Peripheral nerve injury, Nerve conduit, Bone marrow, Mesenchymal stem cells, Regeneration
National Category
Neurosciences
Research subject
Human Anatomy; cellforskning
Identifiers
URN: urn:nbn:se:umu:diva-47756OAI: oai:DiVA.org:umu-47756DiVA: diva2:444340
Available from: 2011-09-28 Created: 2011-09-28 Last updated: 2011-09-29Bibliographically approved
In thesis
1. Mesenchymal stem cells for repair of the peripheral and central nervous system
Open this publication in new window or tab >>Mesenchymal stem cells for repair of the peripheral and central nervous system
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Odlade mesenkymala stamcellers användning vid skador på perifera och centrala nervsystemet
Abstract [en]

Bone marrow-derived mesenchymal stem cells (MSC) have been shown to provide neuroprotection after transplantation into the injured nervous system. The present thesis investigates whether adult human and rat MSC differentiated along a Schwann cell lineage could increase their expression of neurotrophic factors and promote regeneration after transplantation into the injured peripheral nerve and spinal cord.

Human and rat mesenchymal stem cells (hMSC and rMSC) expressed characteristic stem cell surface markers, mRNA transcripts for different neurotrophic factors and demonstrated multi-lineage differentiation potential. Following treatment with a cocktail of growth factors, the hMSC and rMSC expressed typical Schwann cells markers at both the transcriptional and translational level and significantly increased production of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF).

Age and time in culture are of relevance for clinical settings and growth-promoting effects of hMSC from young donors (16-18 years) and old donors (67-75 years) were compared. Undifferentiated hMSC from both young and old donors increased total neurite length of cultured dorsal root ganglion (DRG) neurons. Differentiation of hMSC from the young donors, but not the eldery donors, further enhanced the neurite outgrowth. Undifferentiated hMSC were cultured for eleven weeks in order to examine the effect of in vitro expansion time on neurite outgrowth. hMSC from the young donors maintained their proliferation rate and their ability to enhance neurite outgrowth from DRG neurons.

Using a sciatic nerve injury model, a 10mm gap was bridged with either an empty tubular fibrin glue conduit, or conduits containing hMSC, with and without cyclosporine treatment. Cells were labeled with PKH26 prior to transplantation. At 3 weeks after injury the conduits with cells and immunosuppression increased regeneration compared with an empty conduit. PKH26 labeled human cells survived in the rat model and the inflammatory reaction could be suppressed by cyclosporine.

After cervical C4 hemisection, BrdU/GFP-labeled rMSC were injected into the lateral funiculus rostral and caudal to the spinal cord lesion site. Spinal cords were analyzed 2-8 weeks after transplantation. Transplanted MSC remained at the injection sites and in the trauma zone for several weeks and were often associated with numerous neurofilament-positive axons. Transplanted rMSC induced up-regulation of vascular endothelial growth factor in spinal cord tissue rostral to the injury site, but did not affect expression of brain-derived neurotrophic factor. Although rMSC provided neuroprotection for rubrospinal neurons and significantly attenuated astroglial and microglial reaction, cell transplantation caused aberrant sprouting of calcitonin gene-related peptide immunostained sensory axons in the dorsal horn.

In summary these results demonstrate that both rat and human MSC can be differentiated towards the glial cell lineage, and show functional characteristics similar to Schwann cells. hMSC from the young donors represent a more favorable source for neurotransplantation since they maintain proliferation rate and preserve their growth-promoting effects in long-term cultures. The data also suggest that differentiated MSC increase expression of neurotrophic factors and support regeneration after peripheral nerve and spinal cord injury.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2011. 59 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1433
Keyword
Bone marrow-derived stromal cells, Schwann cells, Peripheral nerve injury, Spinal cord injury, Neurotransplantation
National Category
Neurosciences
Research subject
Human Anatomy; cellforskning
Identifiers
urn:nbn:se:umu:diva-47746 (URN)978-91-7459-240-5 (ISBN)
Public defence
2011-10-20, BiA201, Biologihuset, Umeå universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2011-09-29 Created: 2011-09-28 Last updated: 2011-09-29Bibliographically approved

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