Parasympathetic neurons derived from human pluripotent stem cells model human diseases and development. Wu et al.

Parasympathetic neurons (parasymNs) belong to the autonomic nervous system (ANS) and are critical for unconscious body responses, including rest-and-digest and calming the body. ParasymN innervation is important for organ development; and ParasymN dysfunction is a hallmark of neural diseases such as autonomic neuropathy and neurological autoimmune disease. However, human parasymN function and dysfunction is vastly understudied, due to the lack of a model system. Human pluripotent stem cell (hPSC)-derived neurons can fill this void and serve as a platform for disease modeling, drug screening, and transplantation therapy. Here, we developed a differentiation paradigm detailing, the derivation of functional human parasymNs from Schwann cell progenitors (SCP). We employ these neurons (i) to assess human ANS developmental paradigms, (ii) to model neuropathy in the genetic disorder Familial Dysautonomia (FD), (iii) to show parasymN dysfunction during SARS-CoV-2 infection, (iv) to model the autoimmune disease Sjögren’s syndrome and, (v) to show that parasymN innervation of white adipocytes during development and help mature the tissue. Our model system could become instrumental for future disease modeling and drug discovery studies as well as for human developmental studies.