PR001636 (Project)

Description:Schwann cells (SCs) are the major glia of the peripheral nervous system (PNS) and are essential for its function. Defects in SCs are associated with many PNS disorders including diabetic peripheral neuropathy (DPN), a condition affecting millions of patients. We have developed a strategy for deriving SCs from human pluripotent stem cells (hPSCs) which recapitulate the molecular features of primary SCs and are capable of engrafting efficiently and producing myelin in vitro and in injured sciatic nerves in rats. We further established an hPSC-based model of DPN that revealed the selective vulnerability of human SCs to hyperglycemia-induced cytotoxicity. By high-throughput screening we found bupropion counteracts glucose-mediated cytotoxicity in SCs and normalizes glucose-induced transcriptional and metabolic abnormalities in SCs. Treatment of hyperglycemic mice with bupropion rescued sensory function, prevented SC death, and counteracted myelin damage in sciatic nerves. Our retrospective analysis of patient health records revealed that bupropion treatment was associated with a lower incidence of neuropathy among diabetic patients that receive antidepressant medications.