Understanding Hirschsprung disease using hPSC-derived models of the enteric nervous system

Abstract Hirschsprung Disease (HSCR) is a severe congenital anomaly within the gastrointestinal (GI) tract, resulting from the absence of intrinsic nerves in the distal bowel, a condition medically termed as aganglionosis. HSCR arises from mutations in numerous genes that lead to defects in the enteric nervous system (ENS)—an intricate network of neurons and glial cells that governs the GI motility and secretory functions. While surgical resection remains the primary treatment, it often fails to rectify persistent GI dysfunctions, underscoring the need for a comprehensive understanding of the disease pathogenesis beyond the current insights provided by animal models. Building upon established protocols for differentiating human pluripotent stem cells (hPSCs) into enteric neurons and glial cells, this research aims to systematically explore the impacts of known HSCR mutations on ENS development, from cell fate specification to migration and neuronal maturation. Employing single-cell transcriptomics, functional assays and transplantation experiments in mouse models, the study seeks to unravel mutation-specific effects on ENS function and identify therapeutic targets capable of ameliorating the cellular phenotypes associated with HSCR. The anticipated outcomes promise to drive the inception of broad-spectrum therapeutic strategies, enabling the development of personalized treatment modalities based on the unique genotypic and phenotypic presentations of HSCR, potentially improving quality of life and outcomes for affected individuals.