Glial differentiation of human adipose-derived stem cells: implications for cell-based transplantation therapy.
Increasing evidence has shown that adipose-derived stem cells (ASCs) could transdifferentiate into Schwann cell (SC)-like cells to enhance nerve regeneration, suggesting potential new cell-based transplantation therapy for peripheral nerve injuries and neurodegenerative disorders. For the implementation of these results to the clinical setting, it is of great importance to establish the differentiation of human ASCs (hASCs) into a SC phenotype. In this study, we studied hASCs obtained from subcutaneous fat tissue of healthy donors. By a mixture of glial growth factors we differentiated them into Schwann cell-like cells (dhASCs). We then assessed their ability to act as Schwann cells in vitro and in vivo and also compared them with primary human Schwann cells (hSCs). Enzyme-linked immunosorbent assay showed that dhASCs secreted brain-derived neurotrophic factor (BDNF)/nerve growth factor (NGF) at a comparable level, and glial cell-derived neurotrophic factor (GDNF) at a level even higher than hSCs, whereas undifferentiated hASCs (uhASCs) secreted low levels of these neurotrophic factors. In co-culture with NG108-15 neuronal cells we found that both dhASCs and hSCs significantly increased the percentage of cells with neurites, the neurite length, and the number of neurites per neuron, whereas uhASCs increased only the percentage of cells with neurites. Finally, we transplanted green fluorescent protein (GFP)-labeled hASCs into the crushed tibial nerve of athymic nude rats. The transplanted hASCs showed a close association with PGP9.5-positive axons and myelin basic protein (MBP)-positive myelin at 8weeks after transplantation. Quantitative analysis revealed that dhASCs transplantation resulted in significantly improved survival and myelin formation rates (a 7-fold and a 10-fold increase, respectively) as compared with uhASCs transplantation. These findings suggest that hASCs took part in supporting and myelinating regenerating axons, and thus have achieved full glial differentiation in vivo. In conclusion, hASCs can differentiate into SC-like cells that possess a potent capacity to secrete neurotrophic factors as well as to form myelin in vivo. These findings make hASCs an interesting prospect for cell-based transplantation therapy for various peripheral nerve disorders.
Department of Plastic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan. ktomita9@hotmail.co.jp
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K
Tomita
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T
Madura
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Sakai
K
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Yano
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Terenghi
K
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Hosokawa
D017667:Adipocytes / Q000166:cytology*; D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D002454:Cell Differentiation / Q000502:physiology*; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D020932:Nerve Growth Factor / Q000096:biosynthesis; D012583:Schwann Cells / Q000166:cytology* / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*
D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D020932:Nerve Growth Factor