美国密歇根大学医学院Jason R. Spence课题组取得一项新突破。他们提出了具有功能性肠神经元和血管的人肠道类器官的协调分化。这一研究成果于2025年3月4日发表在国际顶尖学术期刊《细胞—干细胞》上。

该课题组证明肠干细胞生态位因子EPIREGULIN （EREG）可以在一次分化中增强HIO与上皮细胞、间质细胞、肠神经胶质细胞群、内皮细胞和有组织的平滑细胞的分化，而无需共培养。当移植到小鼠宿主中时，HIOs成熟并表现出肠神经系统功能，经历蠕动样收缩，表明功能性神经细胞单位。HIO也能形成功能性的脉管系统，这在体外微流控装置和体内移植中得到了证明，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变革性工具，可以以询问复杂疾病为主题，也可以用于测试具有高保真度的人类病理生理学的治疗干预措施。

据了解，来源于人多能干细胞的人类肠道类器官（HIOs）在体外可分化上皮细胞和间充质细胞谱系，但缺乏重要的细胞类型，如神经元、内皮细胞和平滑肌，这限制了转化潜力。

附：英文原文

Title: Coordinated differentiation of human intestinal organoids with functional enteric neurons and vasculature

Author: Charlie J. Childs, Holly M. Poling, Kevin Chen, Yu-Hwai Tsai, Angeline Wu, Abigail Vallie, Madeline K. Eiken, Sha Huang, Caden W. Sweet, Ryan Schreiner, Zhiwei Xiao, Ryan C. Spencer, Samantha A. Paris, Ansley S. Conchola, Jonathan W. Villanueva, Meghan F. Anderman, Emily M. Holloway, Akaljot Singh, Roman J. Giger, Maxime M. Mahe, Claudia Loebel, Michael A. Helmrath, Katherine D. Walton, Shahin Rafii, Jason R. Spence

Issue&Volume: 2025-03-04

Abstract: 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.

DOI: 10.1016/j.stem.2025.02.007

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00046-3