Generation of Mouse and Human Organoid-Forming Intestinal Progenitor Cells by Direct Lineage Reprogramming
Generation of Mouse and Human Organoid-Forming Intestinal Progenitor Cells by Direct Lineage Reprogramming
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DOI：
10.1016/j.stem.2017.08.020
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发表时间：
2017-10-05
期刊：
影响因子：
23.9
通讯作者：
Suzuki, Atsushi
中科院分区：
文献类型：
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作者：
Miura, Shizuka;Suzuki, Atsushi
肠道有机化合物作为研究和治疗肠道疾病的一种有价值的工具，前景广阔。目前可用的人类肠道器官、组织碎片或多能干细胞的来源分别涉及侵入性程序或复杂的分化方案。在这里，我们展示了一组四个转录因子，Hnf4α，Foxa3，GATA6和CDX2，可以直接重新编程小鼠成纤维细胞，以获得胎儿肠源性祖细胞(FIPC)的身份。这些诱导的FIPC(IFIPC)形成球形类器官，这些类器官发育成成体类型的萌芽类器官，含有具有肠道干细胞特性的细胞。由此产生的干细胞产生所有的肠道上皮细胞系，并经历自我更新的细胞分裂。移植后，诱导的球形类器官和萌芽类器官可分别重建结肠和肠上皮。四种已定义的转录因子的相同组合也可以诱导人的iFIPC。这种生产肠道有机化合物的替代方法可以很好地促进疾病分析和治疗开发的应用。
Intestinal organoids hold great promise as a valuable tool for studying and treating intestinal diseases. The currently available sources of human intestinal organoids, tissue fragments or pluripotent stem cells, involve invasive procedures or complex differentiation protocols, respectively. Here, we show that a set of four transcription factors, Hnf4 alpha, Foxa3, Gata6, and Cdx2, can directly reprogram mouse fibroblasts to acquire the identity of fetal intestine-derived progenitor cells (FIPCs). These induced FIPCs (iFIPCs) form spherical organoids that develop into adult-type budding organoids containing cells with intestinal stem cell properties. The resulting stem cells produce all intestinal epithelial cell lineages and undergo self-renewing cell divisions. After transplantation, the induced spherical and budding organoids can reconstitute colonic and intestinal epithelia, respectively. The same combination of four defined transcription factors can also induce human iFIPCs. This alternative approach for producing intestinal organoids may well facilitate application for disease analysis and therapy development.