Jevans, Benjamin;
Cooper, Fay;
Fatieieva, Yuliia;
Gogolou, Antigoni;
Kang, Yi-Ning;
Restuadi, Restuadi;
Moulding, Dale;
... McCann, Conor J; + view all
(2024)
Human enteric nervous system progenitor transplantation improves functional responses in Hirschsprung disease patient-derived tissue.
Gut
10.1136/gutjnl-2023-331532.
(In press).
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Abstract
OBJECTIVE: Hirschsprung disease (HSCR) is a severe congenital disorder affecting 1:5000 live births. HSCR results from the failure of enteric nervous system (ENS) progenitors to fully colonise the gastrointestinal tract during embryonic development. This leads to aganglionosis in the distal bowel, resulting in disrupted motor activity and impaired peristalsis. Currently, the only viable treatment option is surgical resection of the aganglionic bowel. However, patients frequently suffer debilitating, lifelong symptoms, with multiple surgical procedures often necessary. Hence, alternative treatment options are crucial. An attractive strategy involves the transplantation of ENS progenitors generated from human pluripotent stem cells (hPSCs). DESIGN: ENS progenitors were generated from hPSCs using an accelerated protocol and characterised, in detail, through a combination of single-cell RNA sequencing, protein expression analysis and calcium imaging. We tested ENS progenitors' capacity to integrate and affect functional responses in HSCR colon, after ex vivo transplantation to organotypically cultured patient-derived colonic tissue, using organ bath contractility. RESULTS: We found that our protocol consistently gives rise to high yields of a cell population exhibiting transcriptional and functional hallmarks of early ENS progenitors. Following transplantation, hPSC-derived ENS progenitors integrate, migrate and form neurons/glia within explanted human HSCR colon samples. Importantly, the transplanted HSCR tissue displayed significantly increased basal contractile activity and increased responses to electrical stimulation compared with control tissue. CONCLUSION: Our findings demonstrate, for the first time, the potential of hPSC-derived ENS progenitors to repopulate and increase functional responses in human HSCR patient colonic tissue.
| Type: | Article |
|---|---|
| Title: | Human enteric nervous system progenitor transplantation improves functional responses in Hirschsprung disease patient-derived tissue |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1136/gutjnl-2023-331532 |
| Publisher version: | http://dx.doi.org/10.1136/gutjnl-2023-331532 |
| Language: | English |
| Additional information: | © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. |
| Keywords: | ENTERIC NERVOUS SYSTEM, GASTROINTESTINAL SURGERY, HIRSCHSPRUNG'S DISEASE, STEM CELLS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10193097 |
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