Schwann Cell Precursors from Human Pluripotent Stem Cells as a Potential Therapeutic Target for Myelin Repair

Abstract

SummarySchwann cells play a crucial role in successful nerve repair and regeneration by supporting both axonal growth and myelination. However, the sources of human Schwann cells are limited both for studies of Schwann cell development and biology and for the development of treatments for Schwann cell-associated diseases. Here, we provide a rapid and scalable method to produce self-renewing Schwann cell precursors (SCPs) from human pluripotent stem cells (hPSCs), using combined sequential treatment with inhibitors of the TGF-β and GSK-3 signaling pathways, and with neuregulin-1 for 18 days under chemically defined conditions. Within 1 week, hPSC-derived SCPs could be differentiated into immature Schwann cells that were functionally confirmed by their secretion of neurotrophic factors and their myelination capacity in vitro and in vivo. We propose that hPSC-derived SCPs are a promising, unlimited source of functional Schwann cells for treating demyelination disorders and injuries to the peripheral nervous system.

Cell transplantation strategies for acquired and inherited disorders of peripheral myelin

“…Further studies will be required to investigate alternative methods for generating iPSC-derived Schwann cells, including directed differentiation using transcription factors, or bypassing the need for hNCSCs as was recently demonstrated. 48 Taken together, our data support the feasibility of surgical delivery of Schwann cells for inherited disorders of peripheral myelin, demonstrating good survival, migration, and myelination of chronically amyelinated axons. Further studies are needed to address whether cell therapy for peripheral nerves can mitigate secondary axon loss which leads to disability in Charcot-Marie-Tooth disease and to identify appropriate cell sources for transplantation therapy.…”

“…iPSCs are a highly attractive source for cell therapy because they are easy to generate, are infinitely expandable, and can be readily manipulated using genome‐editing techniques to correct disease gene defects 46. Several groups have reported differentiating Schwann‐like cells from iPSCs 29, 47, 48. Characterization of iPSC‐derived Schwann cells from these protocols varied widely, in most cases being limited to expression of a few markers such as S100b or GFAP (reviewed in37).…”

“…46 Several groups have reported differentiating Schwann-like cells from iPSCs. 29,47,48 Characterization of iPSC-derived Schwann cells from these protocols varied widely, in most cases being limited to expression of a few markers such as S100b or GFAP (reviewed in 37 ). We attempted to reproduce a protocol previously reported to generate primarily Schwann cell precursors with the capacity to myelinate axons in vitro; 29 however, we found placing NCSCs into MesenPRO with heregulin-b1-generated cells most closely resembling mesenchymal precursor cells that did not have the capacity to form myelin after in vivo transplantation.…”

Modeling Human Peripheral Myelin Fully from Pluripotent Stem Cells and Immune-mediated NeuropathyIn Vitrousing ZIKA Virus

“…We established a robust method for the isolation, expansion, co-culture 361 and transplantation of a new population of hPSC derived myelinating SCp. To our knowledge, 362 this is the first myelination system with SCs and peripheral neurons derived from hPSCs, 363 amenable to disease modeling and drug tests (Clark et al, 2017;Kim et al, 2017). 364…”

“…All available cellular models are based on interspecies 39 models using rodent dorsal root ganglia (DRG) neurons or rodent SCs to co-culture with human 40 pluripotent stem cell (hPSC) derived neurons or hPSC-Schwann cells (SCs). There is no 41 analogous model available for human Myelination due to inability of hPSC-SCs to myelinate 42 hPSC-neurons (Clark et al, 2017;Kim et al, 2017). 43…”