American Society for Peripheral Nerve

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Deriving Schwann Cells from iPSCs through a Melanocytic Intermediate
Abdel Armaiz Flores, MS; Mayo Clinic, Rochester, MN; Robert J Spinner, MD; Department of Neurological Surgery, Mayo Clinic, Rochester, MN; Anthony J. Windebank, MD; Neurology, Mayo Clinic, Rochester, MN; Huan Wang, MD, PhD; Neurologic Surgery, Mayo Clinic, Rochester, MN

Schwann cells (SCs) play a critical role in the peripheral nervous system by promoting various aspects of nerve regeneration. Autologous transplanted SCs have shown to assist regeneration following nerve injury, leading to interest in their use alongside biomaterials to improve recovery and regeneration. However, a disadvantage of autologous SCs is their limited source and the morbidity associated with their harvest. Deriving Schwann cells from induced pluripotent stem cells (iPSCs) has the advantages of obtaining cells from a minimally invasive skin biopsy and potential for large scale iPSC expansion prior to differentiation. Current methods for generating iPSC-derived SCs can take up from 50 to 80 days and may require additional intermediate sorting steps. These methods rely on differentiating cells from iPSCs to neural crest and finally SCs. In order to improve feasibility of these protocols, increases in efficiency and quickness are needed, necessitating novel approaches.

Peripheral glial cells and melanocytes are intimately related from a developmental standpoint. Furthermore, evidence points to a common glial/melanocytic progenitor that gives rise to both types of cells in the body, as is seen with quail studies that differentiate melanocytes to Schwann cells and vice versa. This close relationship can be used to develop a new protocol to generate iPSC-derived SCs. In this study, iPSCs were differentiated to a neural crest fate using small molecules and growth factors. These newly generated neural crest cells were guided to a melanocytic fate using a combination of melanocytic and SC growth factors. The resulting protocol generated cells that expressed SOX-10, S100b and MITF-M, with purities exceeding 80%. This protocol accomplished this in approximately 34 days, with no cell sorting steps or generation of embryoid bodies needed.

The next crucial step in developing this novel SC differentiation protocol involves transdifferentiation of these immature melanocytic cells to a multipotent precursor state that allows them to take a SC fate, thus taking advantage of the speed and purity at which melanocytic cells can be generated. In order to accomplish this, these newly generated melanocytic cells will be cultured in the presence of endothelin-3, a growth factor previously shown to induce melanocytes to adopt a multipotent state, along with the presence of SC growth factors to generate a population of iPSC-derived SCs through the melanocytic intermediate.

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