Enteric Neural Stem Cells Expressing Insulin-Like Growth Factor 1: A Novel Cellular Therapy for Hirschsprung's Disease in Mouse Model.

Transplanting enteric neural stem cells (ENSCs) is an innovative approach for replacing enteric neurons in Hirschsprung's disease (HSCR). However, posttransplantation cell survival and differentiation limit efficacy. We aimed to investigate whether transplantation of ENSCs engineered with insulin-like growth factor 1 (IGF-1) could improve survival and differentiation of the engrafted cells and promote functional recovery of the aganglionic colon. ENSCs were isolated from the intestine of neonatal mice and genetically modified to express IGF-1. After implantation into the mice aganglionic colon induced by benzalkonium chloride, survival and differentiation of engrafted cells were assessed by immunohistochemistry for GFP, neuronal, and glial cell markers. Colonic motility was quantified by colonic bead expulsion time and response to electrical field stimulation (EFS). Expression of the neural marker nNOS and the glial cell marker (glial fibrillary acidic protein [GFAP]) was increased in IGF-1-ENSCs. IGF-1 had also improved neuroglial differentiation of ENSCs following transplantation in vivo. Colonic motility was significantly improved after IGF-1-ENSC transplantation, as demonstrated by reduction of colonic bead expulsion time and recovery of EFS-induced relaxation. IGF-1 has enhanced neurogenesis and function of ENSCs upon transplantation for enteric nervous system replacement, which may provide a potential novel therapy for the treatment of HSCR.