Parasympathetic Neurons Derived From Human Pluripotent Stem Cells Model Human Diseases and Development

Parasympathetic neurons (parasymNs) are critical for unconscious body responses, including rest-and-digest and calming the body. ParasymN dysfunction plays important roles in diseases such as autonomic neuropathy; autoimmune disease may attack parasymNs; and parasymN innervation is important for organ development. 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 for disease modeling, drug screening, and transplantation therapy. Here, we developed a differentiation paradigm detailing for the first time, the derivation of functional human parasymNs from Schwann cell progenitors (SCP). We employ these neurons (i) to model neuropathy in the genetic disorder Familial Dysautonomia, (ii) to show parasymN dysfunction during SARS-CoV-2 infection, (iii) to model the autoimmune disease Sjörgen’s syndrome and, (iv) to show that parasymNs innervation of white adipocytes during development and helps mature the tissue.  Our model system will become instrumental for future disease mechanistic and drug discovery studies as well as for human developmental studies.