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Schwann cells (SCs) are the primary glia of the peripheral nervous system. SCs are involved in many debilitating disorders, including diabetic peripheral neuropathy (DPN). Here, we present a strategy for deriving SCs from human pluripotent stem cells (hPSCs) that enables comprehensive studies of SC development, physiology, and disease. hPSC-derived SCs recapitulate the molecular features of primary SCs and are capable of in vitro and in vivo myelination. We established a model of DPN that revealed the selective vulnerability of SCs to high glucose. We performed a high-throughput screen and found that an antidepressant drug, bupropion, counteracts glucotoxicity in SCs. Treatment of hyperglycemic mice with bupropion prevents their sensory dysfunction, SC death, and myelin damage. Further, our retrospective analysis of health records revealed that bupropion treatment is associated with a lower incidence of neuropathy among diabetic patients. These results highlight the power of this approach for identifying therapeutic candidates for DPN., Competing Interests: Declaration of interests F.F., L.S., S.C., and Z.G. are inventors on several patent applications owned by UCSF, MSKCC, and Weill Cornell Medicine related to hPSC differentiation technologies including the technologies reported in this manuscript. L.S. is a scientific co-founder and paid consultant of BlueRock Therapeutics and DaCapo BrainScience., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Myelin provides physical, neurotrophic, and metabolic support for axonal integrity. The thickness of CNS (central nervous system) myelin sheath is usually < one micrometer, which is under or near the detection threshold of the conventional light microscopy. Here, we present a high-resolution transmission electron microscopy-based protocol to assess myelination at the ultrastructural level. We describe sample preparation from mouse tissue, followed by electron microscopic imaging and CNS myelination analysis. This protocol is also useful for analyzing murine PNS myelination. For complete details on the use and execution of this protocol, please refer to Wang et al. (2021)., Competing Interests: The authors declare no competing interest., (© 2022 The Author(s).)