Childs Charlie J, Poling Holly M, Chen Kevin, Tsai Yu-Hwai, Wu Angeline, Vallie Abigail, Eiken Madeline K, Huang Sha, Sweet Caden W, Schreiner Ryan, Xiao Zhiwei, Spencer Ryan C, Paris Samantha A, Conchola Ansley S, Villanueva Jonathan W, Anderman Meghan F, Holloway Emily M, Singh Akaljot, Giger Roman J, Mahe Maxime M, Loebel Claudia, Helmrath Michael A, Walton Katherine D, Rafii Shahin, Spence Jason R
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Biomedical Engineering, University of Cincinnati College of Engineering and Applied Science, Cincinnati, OH, USA.
Cell Stem Cell. 2025 Apr 3;32(4):640-651.e9. doi: 10.1016/j.stem.2025.02.007. Epub 2025 Mar 4.
Human intestinal organoids (HIOs) derived from human pluripotent stem cells co-differentiate both epithelial and mesenchymal lineages in vitro but lack important cell types such as neurons, endothelial cells, and smooth muscle, which limits translational potential. Here, we demonstrate that the intestinal stem cell niche factor, EPIREGULIN (EREG), enhances HIO differentiation with epithelium, mesenchyme, enteric neuroglial populations, endothelial cells, and organized smooth muscle in a single differentiation, without the need for co-culture. When transplanted into a murine host, HIOs mature and demonstrate enteric nervous system function, undergoing peristaltic-like contractions indicative of a functional neuromuscular unit. HIOs also form functional vasculature, demonstrated in vitro using microfluidic devices and in vivo following transplantation, where HIO endothelial cells anastomose with host vasculature. These complex HIOs represent a transformative tool for translational research in the human gut and can be used to interrogate complex diseases as well as for testing therapeutic interventions with high fidelity to human pathophysiology.
源自人多能干细胞的人肠道类器官（HIOs）在体外可共同分化上皮和间充质谱系，但缺乏神经元、内皮细胞和平滑肌等重要细胞类型，这限制了其转化应用潜力。在此，我们证明肠道干细胞龛因子表皮调节素（EREG）可在单一分化过程中增强HIO向上皮、间充质、肠神经胶质细胞群体、内皮细胞和有组织的平滑肌的分化，而无需共培养。当移植到小鼠宿主中时，HIOs会成熟并表现出肠神经系统功能，经历类似蠕动的收缩，表明存在功能性神经肌肉单元。HIOs还形成功能性脉管系统，这在体外使用微流控装置得以证明，在移植后的体内也得到证实，其中HIO内皮细胞与宿主脉管系统吻合。这些复杂的HIOs代表了人类肠道转化研究的一种变革性工具，可用于研究复杂疾病以及以高度忠实于人类病理生理学的方式测试治疗干预措施。
