Parasympathetic neurons derived from human pluripotent stem cells model human diseases and development

Area of Science:

• Neuroscience
• Stem Cell Biology
• Developmental Biology

Background:

• Autonomic parasympathetic neurons (parasymNs) regulate vital "rest-and-digest" functions and are crucial for organ development.
• ParasymN dysfunction is implicated in autonomic neuropathies, but human studies are limited by the lack of suitable model systems.
• Human pluripotent stem cells (hPSCs) provide a versatile platform for generating specific neuronal subtypes for research.

Purpose of the Study:

• To develop a differentiation method for deriving functional human parasymNs from Schwann cell progenitors.
• To utilize these hPSC-derived parasymNs to model human autonomic nervous system (ANS) development and various neuropathies.
• To investigate parasymN roles in disease and development, including genetic disorders, viral infections, autoimmune conditions, and adipocyte maturation.

Main Methods:

• Established a differentiation paradigm to derive human parasymNs from hPSC-derived Schwann cell progenitors.
• Utilized the derived parasymNs to model familial dysautonomia (FD), Sjögren's syndrome (SS), and SARS-CoV-2 infection effects.
• Investigated parasymN innervation and its role in white adipocyte (WAT) development and maturation.

Main Results:

• Successfully derived functional human parasymNs from Schwann cell progenitors using a novel differentiation strategy.
• Demonstrated the utility of this model system for studying human ANS development and modeling FD, SS, and SARS-CoV-2-induced parasymN dysfunction.
• Showed that parasymNs innervate WATs and promote their maturation, highlighting a novel developmental interaction.

Conclusions:

• A new model system using hPSC-derived parasymNs has been established for studying human autonomic nervous system development.
• This model enables the investigation of parasymN dysfunction in various human diseases, including genetic, autoimmune, and infectious conditions.
• The developed platform holds significant potential for future disease modeling, drug discovery, and advancing our understanding of human neurodevelopment.