Múnera Jorge O, Sundaram Nambirajan, Rankin Scott A, Hill David, Watson Carey, Mahe Maxime, Vallance Jefferson E, Shroyer Noah F, Sinagoga Katie L, Zarzoso-Lacoste Adrian, Hudson Jonathan R, Howell Jonathan C, Chatuvedi Praneet, Spence Jason R, Shannon John M, Zorn Aaron M, Helmrath Michael A, Wells James M
Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
Cell Stem Cell. 2017 Jul 6;21(1):51-64.e6. doi: 10.1016/j.stem.2017.05.020. Epub 2017 Jun 22.
Gastric and small intestinal organoids differentiated from human pluripotent stem cells (hPSCs) have revolutionized the study of gastrointestinal development and disease. Distal gut tissues such as cecum and colon, however, have proved considerably more challenging to derive in vitro. Here we report the differentiation of human colonic organoids (HCOs) from hPSCs. We found that BMP signaling is required to establish a posterior SATB2+ domain in developing and postnatal intestinal epithelium. Brief activation of BMP signaling is sufficient to activate a posterior HOX code and direct hPSC-derived gut tube cultures into HCOs. In vitro, HCOs express colonic markers and contained colon-specific cell populations. Following transplantation into mice, HCOs undergo morphogenesis and maturation to form tissue that exhibits molecular, cellular, and morphologic properties of human colon. Together these data show BMP-dependent patterning of human hindgut into HCOs, which will be valuable for studying diseases including colitis and colon cancer.
从人多能干细胞（hPSC）分化而来的胃和小肠类器官彻底改变了胃肠道发育和疾病的研究。然而，诸如盲肠和结肠等远端肠道组织在体外培养中被证明具有更大的挑战性。在此，我们报告了从hPSC分化出人结肠类器官（HCO）的过程。我们发现，BMP信号通路对于在发育中的和出生后的肠上皮中建立一个后部SATB2+区域是必需的。短暂激活BMP信号通路足以激活后部HOX编码，并将hPSC来源的肠管培养物引导分化为HCO。在体外，HCO表达结肠标志物并包含结肠特异性细胞群体。移植到小鼠体内后，HCO经历形态发生和成熟，形成具有人类结肠分子、细胞和形态学特性的组织。这些数据共同表明，人后肠通过BMP依赖性模式形成HCO，这对于研究包括结肠炎和结肠癌在内的疾病将具有重要价值。
