Cell therapy for GI motility disorders: comparison of cell sources and proposed steps for treating Hirschsprung disease

Abstract

Cell therapeutic approaches to treat a range of congenital and degenerative neuropathies are under intense investigation. There have been recent significant advancements in the development of cell therapy to treat disorders of the enteric nervous system (ENS), enteric neuropathies. These advances include the efficient generation of enteric neural progenitors from pluripotent stem cells and the rescue of a Hirschsprung disease model mouse following their transplantation into the bowel. Furthermore, a recent study provides evidence of functional innervation of the bowel muscle by neurons derived from transplanted ENS-derived neural progenitors. This mini-review discusses these recent findings, compares endogenous ENS-derived progenitors and pluripotent stem cell-derived progenitors as a cell source for therapy, and proposes the key steps for cell therapy to treat Hirschsprung disease.

Enteric neuronal cell therapy reverses architectural changes in a novel diphtheria toxin-mediated model of colonic aganglionosis

“…Abnormalities of the ENS comprise a group of GI motility disorders that include HSCR, esophageal achalasia, intestinal pseudo-obstruction, and gastroparesis. Developing neuronal stem cell-based therapies to replace missing or abnormal enteric neurons has gained momentum recently, especially for the treatment of HSCR 3,6,27–29 . However, the utility of genetic rodent models of HSCR for long-term studies is hindered by their short lifespan, typically 4 weeks.…”

“…Current treatment for HSCR involves surgical removal of the aganglionic segment, but the functional outcome is variable and often accompanied by long-term GI problems, including enterocolitis, constipation, fecal incontinence, and reduced quality of life. New and more effective therapies for the treatment of HSCR are needed 3,6,7 .…”

Derivation of enteric neuron lineages from human pluripotent stem cells

“…The protocol described here presents the evolution of our previously published work and stands amid a limited set of previously reported methods for the derivation of enteric neural progenitors from pluripotent stem cells 22 . Many labs in the stem cell field no longer rely on the support of feeder cells and have adopted the use of defined basal media, such as mTeSR™1 (Stemcell Tech, 85850) or Essential 8 (Life Technologies, A2858501) for the maintenance of hPSC lines.…”

Wnt Receptor Frizzled-4 as a Marker for Isolation of Enteric Neural Progenitors in Human Children

“…In search of new treatments for such enteric neuropathies, the characterization of neural stem or progenitor cells from the postnatal ENS, as a potential source for future cell replacement therapies, made a lot of progress during the last two decades [5,6]. After initial reports of proliferative neural cells in the postnatal intestine of rats by Kruger et al [7], ENS progenitors were isolated from mice [8,9] and human gut samples [10], even from elderly patients [11].…”