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Cell transplantation strategies for acquired and inherited disorders of peripheral myelin

ABSTRACT: Objective: To investigate transplantation of rat Schwann cells or human iPSC-derived neural crest cells and derivatives into models of acquired and inherited peripheral myelin damage. Methods: Primary cultured rat Schwann cells labeled with a fluorescent protein for monitoring at various times after transplantation. Human induced pluripotent stem cells (iPSCs) were differentiated into neural crest stem cells (NCSC), and subsequently toward a Schwann cell lineage via two different protocols. Protocol 1 = treated with MesenPRO with Heregulin. Protocol 2 = coculture with iPSC-derived Motor Neurons. Cell types were characterized using flow cytometry, immunocytochemistry and transcriptomics. Rat Schwann cells and human iPSC-derivatives were transplanted into (i) nude rats pretreated with lysolecithin to induce demyelination or (ii) a transgenic rat model of dysmyelination due to PMP22 overexpression. Results: Rat Schwann cells transplanted into sciatic nerves with either toxic demyelination or genetic dysmyelination engrafted successfully, and migrated longitudinally for relatively long distances, with more limited axial migration. Transplanted Schwann cells engaged existing axons and displaced dysfunctional Schwann cells to form normal appearing myelin. Human iPSC-derived neural crest stem cells and their derivatives shared similar engraftment and migration characteristics to rat Schwann cells after transplantation, but did not further differentiate into Schwann cells or form myelin. Interpretation: These results indicate that cultured Schwann cells surgically delivered to peripheral nerve can engraft and form myelin in either acquired or inherited myelin injury, as proof of concept for pursuing cell therapy for diseases of peripheral nerve. However, lack of reliable technology for generating human iPSC-derived Schwann cells for transplantation therapy remains a barrier in the field.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109686 | GEO | 2018/01/26

REPOSITORIES: GEO

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Project description:The current understanding is that Schwann cell transplantation is ideal strategy for peripheral nerve regeneration instead of autograft. It is difficult to obtain the required amount of Schwann cells which are best transplant condition, and central nervous cells have been gained attention in recent years, but its regenerative mechanism remain unknown. Neural stem/progenitor cells (NSPC) can generate various type of neural lineage cells (NLCs), and NSPCs derived from pluripotent stem cells are promising cells for cell therapy for neurodegenerative diseases. However, more safe and accessible cell source of NSPCs are required. In this study, we aim to provide NLCs derived from human dental pulp stem cells (DPSCs), and reveal the mechanism involved in regeneration after NLCs transplantation into peripheral nerve defect. Here, characterization of NLCs, paracrine effects for endothelial cells and Schwann cells, in xenotransplant for rat 10mm sciatic nerve defect, the differentiation, the survival, and outcome of nerve regeneration were investigated. Induced NLCs consisted of neuronal lineage cells, astrocyte lineage cells, oligodendrocyte lineage cells, and neural crest lineage cells. Considering retrospectively, NLCs were possible derived from NSPCs. Microarray analysis revealed neural markers of primary embryological development were up-regulated in induced NLCs compared to DPSCs. Moreover, NLCs enhanced the activity of endothelial cells and Schwann cells by paracrine effects in vitro. Two weeks after transplantation, many transplanted NLCs differentiated into platelet-derived growth factor receptor alpha (PDGFRa) + oligodendrocyte progenitor cells (OPCs), and PDGFRa+/p75 neurotrophin receptor + Schwann cells derived from OPCs were observed. Twelve weeks after transplantation, NLCs promoted functional repair of peripheral nerve. A few human Schwann cells survived, but did not myelinate axon. These findings suggest that some of mechanism promoting for peripheral nerve regeneration by transplanted NLCs. Transplantation of NLCs derived from DPSCs into partial peripheral nerve defect may be widely used for further experiments.

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Cell transplantation strategies for acquired and inherited disorders of peripheral myelin

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