Friday, May 9, 2025
5/9/2025
Human pluripotent stem cells for the study of gastrointestinal dysmotility - Abstract The enteric nervous system (ENS) accomplishes a broad range of activities that rely on a remarkably diverse population of neuronal and glial subtypes. Loss of specific cell types, such as nitric oxide (NO) producing neurons (nitrergic neurons) leads to enteric neuropathies associated with dysmotility disorders including esophageal achalasia, gastroparesis and infantile hypertrophic pyloric stenosis. The underlying pathophysiology of these disorders have remained largely unknown due to limitations of currently available cellular models. We have recently reported a new alternative approach for differentiation of ENS lineages from human pluripotent stem cells under fully defined conditions, providing a unique and reliable framework for ENS disease modeling and drug discovery. Taking advantage of high content chemical compound screening in combination with fate map reconstruction guided by single cell transcriptomics, here we propose a new strategy for efficient derivation and prospective isolation of enteric nitrergic neurons. This system will provide a unique in vitro model for identification of pharmacological regulator of these neurons and dissection of cellular mechanisms that underlie GI dysmotilty. We will further evaluate the potential of these neurons in transplantation studies aimed at the ultimate development of cell-based treatment of enteric neuropathies related to the loss of nitrergic neurons.
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