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

Yue Ji,Paul Kwong-Hang Tam,Clara Sze-Man Tang

doi:10.3390/ijms22189659

Yue Ji, Paul Kwong-Hang Tam + Show 1 more

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https://doi.org/10.3390/ijms22189659

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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.

Highlights

Even along the Hirschsprung disease (HSCR) colon, abnormal distribution of fibronectin and collagens (I and III) was reported, with higher expression detected in the aganglionic segment, but the level decreased in the transitional zone and normoganglionic bowel [61,62,63]
Bulk RNA sequencing of enteric neural crest cells (ENCCs) derived from patient-specific induced pluripotent stem cells (iPSCs) showed perturbation of pathways related to morphogenesis of the epithelium and extracellular matrix (ECM) organization, calling into question whether the observed ECM aberrations are non-cell autonomous or cell autonomous effects of the ENCCs [31]
The importance of cell-ECM interaction was further demonstrated in a β1-integrin–/– mouse model in which the conditional ablation of Itgb1 in ENCCs resulted in impaired adhesion on ECM, migratory defects, and colonic aganglionosis [66]

Summary

Introduction

The ENS is a major division of the autonomic nervous system [1]. It is a complex network of interconnected neurons and glia arranged in the myenteric and submucosal plexuses within the gut wall. ENS is known as the “second brain” for its extent, diversity, and complexity in neuronal cell types, as well as the importance in regulating autonomous intestinal functions. Majority of the ENS is derived from the vagal neural crest cells (NCCs) which migrate rostro-caudally from the neural tube to the foregut, proliferate, and differentiate into neurons and glia to colonize the whole intestine [3]. The sacral NCCs, originating from the second, caudal region of the neuraxis, contribute in a smaller extent to the ENS, mainly at the hindgut.

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