(F1315) DERIVATION OF ENTERIC NEURAL PROGENITORS FROM HUMAN INDUCED PLURIPOTENT STEM CELL AND EVALUATION OF THERAPEUTIC POTENTIAL AS A SOURCE FOR CELL-BASED THERAPY OF HIRSCHSPRUNG’S DISEASE
Associate Director Takeda Pharmaceutical Company Fujisawa, Kanagawa, Japan
Abstract: Dysfunction of enteric nervous system (ENS) leads to severe motility disorder of gastrointestinal tract including rare diseases such as Hirschsprung’s disease (HSCR). To date, no cell-based treatment has yet been developed to fully restore its function. Here, we introduce our novel culture condition that enables efficient induction and expansion of enteric neural progenitors (ENPs) from human induced pluripotent stem cells (hiPSCs) via neural crest cell (NCC) lineage. Induced ENPs (iENPs) co-expressed key progenitor genes SOX10 and PHOX2B and showed high differentiation potential into subtypes of enteric neurons and glial cells in vitro. The single cell RNA sequencing revealed that iENPs followed trajectory of ENS development and their similarity of iENP-derived enteric neurons to those from human fetal colon. Expanded iENPs could be engrafted into intestinal muscle layer of immune deficient mice and showed differentiation into neural and glial lineage. Potential of iENPs to recover motility function in the HSCR gut environment was demonstrated using two different HSCR-relevant models. We developed immune deficient HSCR disease model mice (B6RGs-Retwt/S811F) which showed reduced gut motility due to aganglionosis at the distal end of the colon. Four months after transplantation of iENPs into aganglionic region of the B6RGs-Retwt/S811F mice, statistically significant recovery of electrical field stimulation-induced gut contraction was detected by organ bath assay. Also, efficacy of iENP transplantation was confirmed in the human intestinal gut organoid-based model derived from hiPSCs harboring HSCR-related point mutation. These data suggest that iENPs are a desirable source for cell-based therapy of HSCR.
