Majd, Homa;
Samuel, Ryan M;
Cesiulis, Andrius;
Ramirez, Jonathan T;
Kalantari, Ali;
Barber, Kevin;
Farahvashi, Sina;
... Fattahi, Faranak; + view all
(2025)
Engrafted nitrergic neurons derived from hPSCs improve gut dysmotility in mice.
Nature
10.1038/s41586-025-09208-3.
(In press).
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Abstract
Gastrointestinal (GI) motility disorders represent a major medical challenge, with few effective therapies available. These disorders often result from dysfunction of inhibitory nitric oxide (NO)-producing motor neurons in the enteric nervous system, which are essential for regulating gut motility. Loss or dysfunction of NO neurons is linked to severe conditions, including achalasia, gastroparesis, intestinal pseudo-obstruction and chronic constipation<sup>1,2</sup>. Here we introduce a platform based on human pluripotent stem cells (hPSCs) for therapeutic development targeting GI motility disorders. Using an unbiased screen, we identified drug candidates that modulate NO neuron activity and enhance motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define developmental programs driving the specification of NO neurons and found that inhibition of platelet-derived growth factor receptors (PDGFRs) promotes their differentiation from precursors of the enteric nervous system. Transplantation of these neurons into NO-neuron-deficient mice led to robust engraftment and improved GI motility, offering a promising cell-based therapy for neurodegenerative GI disorders. These studies provide a new framework for understanding and treating enteric neuropathies.
| Type: | Article |
|---|---|
| Title: | Engrafted nitrergic neurons derived from hPSCs improve gut dysmotility in mice |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41586-025-09208-3 |
| Publisher version: | https://doi.org/10.1038/s41586-025-09208-3 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Differentiation, Regeneration, Regeneration and repair in the nervous system, Stem-cell differentiation |
| 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/10212568 |
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