Search

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.)

SARS-CoV-2 infection has led to a global health crisis, and yet our understanding of the disease and potential treatment options remains limited. The infection occurs through binding of the virus with angiotensin converting enzyme 2 (ACE2) on the cell membrane. Here, we established a screening strategy to identify drugs that reduce ACE2 levels in human embryonic stem cell (hESC)-derived cardiac cells and lung organoids. Target analysis of hit compounds revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression and protected hESC-derived lung organoids against SARS-CoV-2 infection. Finally, clinical data on COVID-19 patients demonstrated that prostate diseases, which are linked to elevated androgen, are significant risk factors and that genetic variants that increase androgen levels are associated with higher disease severity. These findings offer insights on the mechanism of disproportionate disease susceptibility in men and identify antiandrogenic drugs as candidate therapeutics for COVID-19., Competing Interests: Declaration of Interests P.N. receives grants from Apple, Amgen, and Boston Scientific, and personal fees from Apple and Blackstone Life Sciences, all outside the submitted work. F.F. receives grants from Takeda Pharmaceuticals on projects outside of the submitted work., (Copyright © 2020 Elsevier Inc. All rights reserved.)