Roles of Enteric Neural Stem Cell Niche and Enteric Nervous System Development in Hirschsprung Disease

Abstract

The development of the enteric nervous system (ENS) is highly modulated by the synchronized interaction between the enteric neural crest cells (ENCCs) and the neural stem cell niche comprising the gut microenvironment. Genetic defects dysregulating the cellular behaviour(s) of the ENCCs result in incomplete innervation and hence ENS dysfunction. Hirschsprung disease (HSCR) is a rare complex neurocristopathy in which the enteric neural crest-derived cells fail to colonize the distal colon. In addition to ENS defects, increasing evidence suggests that HSCR patients may have intrinsic defects in the niche impairing the extracellular matrix (ECM)-cell interaction and/or dysregulating the cellular niche factors necessary for controlling stem cell behaviour. The niche defects in patients may compromise the regenerative capacity of the stem cell-based therapy and advocate for drug- and niche-based therapies as complementary therapeutic strategies to alleviate/enhance niche-cell interaction. Here, we provide a summary of the current understandings of the role of the enteric neural stem cell niche in modulating the development of the ENS and in the pathogenesis of HSCR. Deciphering the contribution of the niche to HSCR may provide important implications to the development of regenerative medicine for HSCR.

Genetic Background Influences Severity of Colonic Aganglionosis and Response to GDNF Enemas in the Holstein Mouse Model of Hirschsprung Disease

“…Although the impact on GDNF diffusion in the colon is currently unknown, we do know that GDNF-induced migration of ENS progenitors from gut explants is more efficient when collagen VI levels are reduced [ 33 ]. Our data thus add credence to the growing belief that modulation of the extracellular matrix around ENS progenitors might have therapeutic value for enteric neuropathies [ 2 , 47 ].…”

Fecal microbiota transplantation enhances cell therapy in a rat model of hypoganglionosis by SCFA‐induced MEK1/2 signaling pathway

“…Based on these results and given the proximity of the intestinal microbiota to the ENS, these mutually beneficial interactions could influence ENCC transplantation methods and be considered when optimizing the cell therapy for hypoganglionosis. Moreover, interactions between intestinal microbiota and the ENS before, during, and after ENCC transplantation could create a better microenvironment for repairing ENS injuries (Ji et al , 2021). Indeed, the SCFA‐producing Bacteroides and Clostridium were missing in the hypoganglionosis model and were reestablished after FMT, which was consistent with improved ENCC transplantation, further indicating a positive role of FMT in ENCC transplantation in HSCR therapies (Morrison & Preston, 2016; Zhao et al , 2018).…”

Susceptibility of ECE1 polymorphisms to Hirschsprung's disease in southern Chinese children

“…The incidence of HSCR is 4 to 1 between males and females ( 6 ). Clinicians have classified HSCR into short-segment HSCR (S-HSCR), long-segment HSCR (L-HSCR) and total colonic aganglionosis (TCA), accounting for about 60%–80%, 10%–15% and 5% of HSCR cases, respectively ( 7 ). From a genetic perspective, only 10%–15% of HSCR patients have familial inheritance, while more than 70% are sporadic cases ( 8 ).…”