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Notch independent signalling mediates Schwann cell-like differentiation of adipose derived stem cells
Blond McIndoe Laboratories, Tissue Injury & Repair Research Group, School of Clinical and Laboratory Sciences, The University of Manchester, Manchester, UK.
Blond McIndoe Laboratories, Tissue Injury & Repair Research Group, School of Clinical and Laboratory Sciences, The University of Manchester, Manchester, UK.
Blond McIndoe Laboratories, Tissue Injury & Repair Research Group, School of Clinical and Laboratory Sciences, The University of Manchester, Manchester, UK.
2009 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 467, no 2, 164-168 p.Article in journal (Refereed) Published
Abstract [en]

Adipose derived stem cells (ASC) differentiate into a Schwann cell (SC)-like phenotype but the signalling pathways mediating this are unknown. We hypothesised that notch might be involved, given its important role in regulating SC development. Rat ASC were differentiated using bFGF, PDGF, GGF-2 and forskolin. RT-PCR analysis showed that mRNA for notch-1 and notch-2 receptors and the notch responsive gene, hes-1, were expressed throughout the differentiation process whereas jagged-1 a notch ligand, and the hey-1 gene were markedly down-regulated. In contrast delta-1 was up-regulated with differentiation and was strongly expressed by rat primary SC. Treatment of ASC with N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor which blocks notch signalling, had no effect on up-regulation of SC proteins S100 or GFAP during differentiation. Furthermore, when co-cultured with NG108-15 neurons, differentiated ASC cultures treated in the absence or presence of DAPT enhanced neurite outgrowth to similar levels. Differentiated ASC expressed PMP-22 but P0 was only present when co-cultured with dorsal root ganglia neurons. DAPT did not affect the expression of these myelin proteins. Thus, ASC express components of the notch signalling pathway but our studies suggest notch is unlikely to play a role in the neurotrophic activity and myelination capability of ASC differentiated into SC-like cells.

Place, publisher, year, edition, pages
Elsevier , 2009. Vol. 467, no 2, 164-168 p.
Keyword [en]
Glia, Myelination, Neurotrophic, Peripheral nerve
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:umu:diva-48410DOI: 10.1016/j.neulet.2009.10.030OAI: oai:DiVA.org:umu-48410DiVA: diva2:449087
Available from: 2011-10-27 Created: 2011-10-19 Last updated: 2017-12-08Bibliographically 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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1434
Keyword
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)
Identifiers
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)
Opponent
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Available from: 2011-11-03 Created: 2011-10-19 Last updated: 2012-11-09Bibliographically approved

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Kingham, Paul JMantovani, Maria Cristina
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