Engrafted nitrergic neurons derived from hPSCs improve gut dysmotility in mice

Homa Majd, Ryan M. Samuel, Andrius Cesiulis, Jonathan T. Ramirez, Ali Kalantari, Kevin Barber, Sina Farahvashi, Zaniar Ghazizadeh, Alireza Majd, Angeline K. Chemel, Mikayla N. Richter, Subhamoy Das, Jacqueline L. Bendrick, Matthew G. Keefe, Jeffrey Wang, Rahul K. Shiv, Samyukta Bhat, Matvei Khoroshkin, Johnny Yu, Tomasz J. Nowakowski, Kwun Wah Wen, Hani Goodarzi, Nikhil Thapar, Julia A. Kaltschmidt, Conor J. McCann and Faranak Fattahi ()
Additional contact information
Homa Majd: University of California, San Francisco
Ryan M. Samuel: University of California, San Francisco
Andrius Cesiulis: University of California, San Francisco
Jonathan T. Ramirez: University of California, San Francisco
Ali Kalantari: University of California, San Francisco
Kevin Barber: University of California, San Francisco
Sina Farahvashi: University of California, San Francisco
Zaniar Ghazizadeh: School of Medicine, Stanford University
Alireza Majd: University of California, San Francisco
Angeline K. Chemel: University of California, San Francisco
Mikayla N. Richter: University of California, San Francisco
Subhamoy Das: School of Medicine, Stanford University
Jacqueline L. Bendrick: Stanford University
Matthew G. Keefe: University of California, San Francisco
Jeffrey Wang: University of California, San Francisco
Rahul K. Shiv: Stanford University
Samyukta Bhat: University of California, San Francisco
Matvei Khoroshkin: University of California, San Francisco
Johnny Yu: University of California, San Francisco
Tomasz J. Nowakowski: University of California, San Francisco
Kwun Wah Wen: University of California, San Francisco
Hani Goodarzi: University of California, San Francisco
Nikhil Thapar: UCL Great Ormond Street Institute of Child Health
Julia A. Kaltschmidt: School of Medicine, Stanford University
Conor J. McCann: UCL Great Ormond Street Institute of Child Health
Faranak Fattahi: University of California, San Francisco

Nature, 2025, vol. 645, issue 8079, 158-167

Abstract: 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 constipation1,2. 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.

Date: 2025
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DOI: 10.1038/s41586-025-09208-3

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