Majd Homa, Samuel Ryan M, Cesiulis Andrius, Ramirez Jonathan T, Kalantari Ali, Barber Kevin, Farahvashi Sina, Ghazizadeh Zaniar, Majd Alireza, Chemel Angeline K, Richter Mikayla N, Das Subhamoy, Bendrick Jacqueline L, Keefe Matthew G, Wang Jeffrey, Shiv Rahul K, Bhat Samyukta, Khoroshkin Matvei, Yu Johnny, Nowakowski Tomasz J, Wen Kwun Wah, Goodarzi Hani, Thapar Nikhil, Kaltschmidt Julia A, McCann Conor J, Fattahi Faranak
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Nature. 2025 Jun 25. doi: 10.1038/s41586-025-09208-3.
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. 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.
胃肠（GI）动力障碍是一项重大的医学挑战，可用的有效治疗方法很少。这些疾病通常是由肠神经系统中产生抑制性一氧化氮（NO）的运动神经元功能障碍引起的，这些神经元对调节肠道动力至关重要。NO神经元的丧失或功能障碍与严重疾病有关，包括贲门失弛缓症、胃轻瘫、肠道假性梗阻和慢性便秘。在这里，我们介绍了一个基于人类多能干细胞（hPSC）的平台，用于针对胃肠动力障碍的治疗开发。通过无偏见筛选，我们确定了能够调节NO神经元活性并增强离体小鼠结肠组织动力的候选药物。我们建立了一种高通量策略来定义驱动NO神经元特化的发育程序，并发现抑制血小板衍生生长因子受体（PDGFR）可促进其从肠神经系统前体分化而来。将这些神经元移植到缺乏NO神经元的小鼠体内可导致强大的植入并改善胃肠动力，为神经退行性胃肠疾病提供了一种有前景的基于细胞的治疗方法。这些研究为理解和治疗肠道神经病变提供了一个新框架。
