Postnatal human enteric neuronal progenitors can migrate, differentiate, and proliferate in embryonic and postnatal aganglionic gut environments

Abstract

BACKGROUNDEnteric neural stem/progenitor cells (ENSCs) offer an innovative approach to treating Hirschsprung disease (HSCR) and other enteric neuropathies. However, postnatal-derived human ENSCs have not been thoroughly characterized and their behavior in the embryonic and postnatal intestinal environment is unknown.METHODSENSCs were isolated from the intestines of 25 patients undergoing bowel resection, including 7 children with HSCR. Neuronal differentiation and proliferation of ENSCs from submucosal and myenteric plexuses from patients with and without HSCR were characterized. ENSC migration and differentiation were studied following transplantation into embryonic chick neural crest, embryonic chick hindgut, and postnatal mouse aganglionic colon.RESULTSThe proliferative and neurogenic potential of ENSCs from HSCR intestine is equivalent to that of non-HSCR controls. Similarly, no difference was observed between myenteric- and submucosal-derived ENSCs. Postnatal ENSCs transplanted to embryonic neural crest pathways and to aneural hindgut migrate normally and differentiate into appropriate neural crest-derived cell types. ENSCs in postnatal mouse aganglionic colon differentiate into neurons and glia both ex vivo and in vivo.CONCLUSIONSENSCs isolated from the postnatal intestine of patients with and without HSCR can behave like embryonic neural crest-derived cells. These results support the feasibility of cell-based therapy for future treatment of neurointestinal disease.

Enteric neural stem cell therapies for enteric neuropathies

“…After cell culture, lentiviral labeling and transplantation to the distal colon, these cells were found to retain their capacity for self renewal and could be observed proliferating and differentiating into neurons within the aganglionic colon after 2 weeks in vivo. Indeed, the same research group has recently demonstrated that unsorted human ENSC harvested from postnatal ganglionated HSCR bowel resections can colonize both aneural chick gut and Ednrb −/− aganglionic colon both in ex vivo organotypic cultures and in vivo . Human ENSC were observed within the gut wall, close to the site of transplantation and gave rise to both neurons and glia.…”

“…Indeed, the same research group has recently demonstrated that unsorted human ENSC harvested from postnatal ganglionated HSCR bowel resections can colonize both aneural chick gut and Ednrb −/− aganglionic colon both in ex vivo organotypic cultures and in vivo. 49 Human ENSC were observed within the gut wall, close to the site of transplantation and gave rise to both neurons and glia. These studies taken together provide further evidence for potential autologous treatment of human neuropathologies.…”

Postnatal human enteric neurospheres show a remarkable molecular complexity

“…In cell culture experiments, both cell types form enteric neurospheres, which are also composed of neuronal, glial, fibroblast, immune, and smooth muscle cells in undefined combinations . However, so far little is known about the detailed cellular composition, the proportional distribution, and the interplay of the different cell types in enteric neurospheres …”

“…In addition, the stem cell therapy field may highly benefit from this approach. In previous studies, enteric neurospheres have been used to investigate their ENS restoration capacity for the development of novel stem cell therapies without addressing this aspect in detail …”

“…14 In cell culture experiments, both cell types form enteric neurospheres, which are also composed of neuronal, glial, fibroblast, immune, and smooth muscle cells in undefined combinations. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] However, so far little is known about the detailed cellular composition, the proportional distribution, and the interplay of the different cell types in enteric neurospheres. 13 We envision to take advantage of this auspicious cell resource to unravel underlying ENS-relevant pathomechanisms in neurogastrointestinal disorders like Hirschsprung's disease, IBS, or IBD.…”