美国科学家首次在实验室中将多功能干细胞变成了功能性的人体肠道组织。
辛辛那提儿童医院医学中心的科学家在12日出版的《自然》杂志在线版上表示，最新突破为人体肠道的发育、功能和有关疾病的研究打开了一扇大门，并有望研制出用于移植的肠道组织。
该研究主要负责人、辛辛那提儿童医院发育生物学分部高级研究员詹姆斯·威尔斯表示，这是科学家首次证明，皮氏培养皿（用作细菌培养的有盖玻璃碟）中人体多功能干细胞能转变为具有三维架构、细胞组成成分同人体肠组织非常类似的人体组织。将干细胞变成肠道组织最终会让罹患坏死性小肠结肠炎、炎性肠病、短肠综合征的病人大大受益。
威尔斯团队在研究中使用了两类多功能干细胞：来自于几个月大的人体胚胎干细胞（hESCs）和基于人体皮肤细胞的诱导多能干细胞（iPSCs）。hESCs能变为人体内200多种细胞类型中的任何一种，因此也被称为多功能干细胞。iPSCs可以使用病人的细胞来获得，因拥有该病人的遗传成分而不会发生排斥反应。威尔斯解释到，因为iPSCs技术非常新颖，其是否具有hESCs所拥有的全部潜能还是未解之谜，因此，研究人员在本次实验中使用了这两种干细胞，以进一步测试和比较这两种干细胞转化为其他细胞的能力。
为了将多功能干细胞变成肠道组织，科学家使用化学物质和生长因子蛋白进行了一系列细胞操作，在实验室中模拟出了胚胎肠的发育过程。
科学家首先将多功能干细胞变成名为定型内胚层（其会产生食道、胃、肠、肺、胰脏和肝脏的内衬）的胚胎细胞，接着将胚胎细胞变成了名为“后肠定向祖细胞”的胚胎肠细胞。随后，他们将胚胎肠细胞提交给促进肠发育的“亲肠”细胞培养装置。
28天后，科学家获得了类似于胎儿肠的成型三维组织，这种组织包含肠道所有的主要细胞，包括肠上皮细胞、帕内特细胞（一种分布于肠腺底部的肠黏膜分化上皮细胞）、肠内分泌细胞。这个组织会持续成熟，获得正常人体肠组织拥有的吸收和分泌功能，并会形成肠特异性干细胞。
威尔斯表示，这个过程可以作为人体肠发育的研究工具，也可帮助科学家了解人体肠道在生病后的变化。由于大部分口服药都通过肠道吸收发挥作用，该突破还将有助于科学家设计出更好的、更容易吸收的口服药物。
研究人员接下来将进行动物实验，验证该肠组织是否可以有效地用于移植手术中，并最终用来治疗罹患肠道疾病的病人。（生物谷Bioon.com）
生物谷推荐原文出处：
Nature doi:10.1038/nature09691
Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro
Jason R. Spence,Christopher N. Mayhew,Scott A. Rankin,Matthew F. Kuhar,Jefferson E. Vallance,Kathryn Tolle,Elizabeth E. Hoskins,Vladimir V. Kalinichenko,Susanne I. Wells,Aaron M. Zorn,Noah F. Shroyer& James M. Wells
Studies in embryonic development have guided successful efforts to direct the differentiation of human embryonic and induced pluripotent stem cells (PSCs) into specific organ cell types in vitro1, 2. For example, human PSCs have been differentiated into monolayer cultures of liver hepatocytes and pancreatic endocrine cells3, 4, 5, 6 that have therapeutic efficacy in animal models of liver disease7, 8 and diabetes9, respectively. However, the generation of complex three-dimensional organ tissues in vitro remains a major challenge for translational studies. Here we establish a robust and efficient process to direct the differentiation of human PSCs into intestinal tissue in vitro using a temporal series of growth factor manipulations to mimic embryonic intestinal development10. This involved activin-induced definitive endoderm formation11, FGF/Wnt-induced posterior endoderm pattering, hindgut specification and morphogenesis12, 13, 14, and a pro-intestinal culture system15, 16 to promote intestinal growth, morphogenesis and cytodifferentiation. The resulting three-dimensional intestinal ‘organoids’ consisted of a polarized, columnar epithelium that was patterned into villus-like structures and crypt-like proliferative zones that expressed intestinal stem cell markers17. The epithelium contained functional enterocytes, as well as goblet, Paneth and enteroendocrine cells. Using this culture system as a model to study human intestinal development, we identified that the combined activity of WNT3A and FGF4 is required for hindgut specification whereas FGF4 alone is sufficient to promote hindgut morphogenesis. Our data indicate that human intestinal stem cells form de novo during development. We also determined that NEUROG3, a pro-endocrine transcription factor that is mutated in enteric anendocrinosis18, is both necessary and sufficient for human enteroendocrine cell development in vitro. PSC-derived human intestinal tissue should allow for unprecedented studies of human intestinal development and disease.
