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Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration
Blond McIndoe Research Laboratories, University of Manchester, Manchester, UK.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
2004 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 362, no 3, 200-203 p.Article in journal (Refereed) Published
Abstract [en]

Bone marrow mesenchymal stem cells can trans-differentiate into neuronal phenotypes. We examined the differentiation of marrow stromal cells (MSCs) in culture and during nerve regeneration. MSCs from adult rats were exposed to glial growth factor (GGF) to stimulate glial differentiation. Subsequently differentiated MSCs were retrovirally labelled with green fluorescent protein and transplanted into 1 cm nerve conduits in the rat sciatic nerve. Fifteen days post-operatively the conduits were examined for axonal and Schwann cell regeneration and MSC integration. In vitro, MSCs exposed to GGF expressed S100 and glial fibrillary acidic protein. Following transplantation, MSCs maintained S100 expression and enhanced nerve regeneration, with significant Schwann cell regeneration compared to control (2.7 +/- 0.21 vs. 2.05 +/- .21 mm; P < 0.05). MSCs not exposed to GGF prior to transplantation expressed S100 in vivo indicating glial differentiation in response to local cytokines and growth factors.

Place, publisher, year, edition, pages
Elsevier , 2004. Vol. 362, no 3, 200-203 p.
Keyword [en]
Animals, Bone Marrow Cells/cytology/drug effects/metabolism/*physiology, Bone Marrow Transplantation/methods, Cell Count/methods, Cell Differentiation/drug effects/*physiology, Gene Expression Regulation, Glial Fibrillary Acidic Protein/*metabolism, Green Fluorescent Proteins, Immunohistochemistry/methods, Luminescent Proteins/metabolism, Nerve Regeneration/*physiology, Neuregulin-1/metabolism, Rats, Rats; Sprague-Dawley, Retroviridae/metabolism, S100 Proteins/*metabolism, Sciatic Nerve/transplantation, Stromal Cells/drug effects/metabolism
National Category
Medical and Health Sciences
URN: urn:nbn:se:umu:diva-12711DOI: 10.1016/j.neulet.2004.03.077PubMedID: 15158014OAI: diva2:152382
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2011-11-03Bibliographically approved
In thesis
1. Schwann cells and mesenchymal stem cells as promoter of peripheral nerve regeneration
Open this publication in new window or tab >>Schwann cells and mesenchymal stem cells as promoter of peripheral nerve regeneration
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The transplantation of primary Schwann cells (SC) has been shown to improve nerve regeneration. However, to monitor the survival of transplanted cells within the host, a stable labelling method is required. The in vitro characteristics of green fluorescent protein labelled SC (GFP SC) and their effects in an in vivo peripheral nerve injury model were investigated.   The GFP-SC were readily visualised ex vivo and stimulated significantly better axonal regeneration compared to controls. Clinical use of autologous SC for the treatment of nerve injuries is of limited use due to difficulty in obtaining clinically useful numbers. However, bone marrow mesenchymal stem cells (MSC) can trans-differentiate into SC like cells (dMSC). The in vitro and in vivo differentiation of MSC was explored, and the study extended to include the easily-accessible adipose stem cells (ASC).  In vitro, glial growth factor stimulated MSC express S100, a SC marker, and its expression is maintained following in vivo transplantation.  Similarly, untreated MSC transplanted in vivo also expressed S100, which indicates glial differentiation in response to local cytokines and growth factors. Using an in vitro model, comprising dMSC or dASC co-cultured with adult dorsal root ganglia (DRG) neurons, the capacity of the dMSC and SC like differentiated ASC (dASC) to promote axon myelination was verified: both cell types expressed transcripts for protein zero, peripheral myelin protein-22 and myelin basic protein.

The potential of stem cells in nerve repair may be limited by innate cellular senescence or donor age affecting cell functionality thus it was essential to determine the effects of donor age on morphology and functionality of stem cells.  The proliferation rates, expression of senescence markers (p38 and p53) and the stimulation of neurite outgrowth from DRG neurons by stem cells isolated from neonatal, young or old rats were very similar. However, the distribution and ultrastructure of mitochondria in dMSC and dASC from young and old rats were quite different, and seem to indicate physiological senescence of the aged cells.  Given the wide-ranging influence of Notch signalling in cell differentiation, including the neural crest to a glial cell type switch, and self-renewal in mammals, its role in the differentiation of stem cells to SC was investigated. The mRNA for notch-1 and -2 receptors were expressed in the dASC, blockage of notch signaling did not affect the neurotrophic and myelination potential of dASC. 

In conclusion, these findings show that GFP labelling has no deleterious effect on SC survival and function. MSC and ASC differentiated into glial-type cells acquire SC morphology, and express characteristic SC markers, and the differentiation process was independent of the Notch signaling pathway. Also, following transplantation into a nerve gap injury dMSC improve regeneration. This study established that following co-culture with DRG neurons, dMSC and dASC were able to express peripheral myelin proteins.  Also, the functional bioactivity of these cells is independent of the donor animal age. Finally, although the glial lineage differentiated aged cells characterized in this study expressed markers typical of senescence they retained the potential to support axon regeneration.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2011. 92 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1434
peripheral nerve regeneration, Schwann cell, adult stem cell, myelin, senescence
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
urn:nbn:se:umu:diva-48413 (URN)978-91-7459-277-1 (ISBN)
Public defence
2011-11-24, sal BiA201, Biologihuset, Umeå universitet, Umeå, 09:00 (English)
Available from: 2011-11-03 Created: 2011-10-19 Last updated: 2012-11-09Bibliographically approved

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