Reprogramming in vivo produces teratomas and iPS cells with totipotency features
Reprogramming in vivo produces teratomas and iPS cells with totipotency features
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DOI：
10.1038/nature12586
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发表时间：
2013-10-17
期刊：
影响因子：
64.8
通讯作者：
Serrano, Manuel
中科院分区：
文献类型：
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作者：
Abad, Maria;Mosteiro, Lluc;Serrano, Manuel
成年细胞重编程产生诱导多能干细胞（iPS细胞）开辟了新的治疗机会;然而，对组织内体内重编程的可能性知之甚少。在这里，我们表明，在小鼠中的四个因素Oct 4，Sox 2，Klf 4和c-Myc的短暂诱导导致畸胎瘤出现从多个器官，这意味着完全重编程可以在体内发生。对胃、肠、胰腺和肾脏的分析揭示了表达多能性标志物NANOG的去分化细胞组，其指示原位重编程。通过骨髓移植，我们证明了造血细胞也可以在体内重编程。值得注意的是，可重编程小鼠在血液中存在循环iPS细胞，并且在转录组水平上，这些体内产生的iPS细胞比标准的体外产生的iPS细胞更接近胚胎干细胞（ES细胞）。此外，在体内iPS细胞有效地有助于滋养外胚层谱系，这表明它们实现了比ES细胞更可塑或原始的状态。最后，腹膜内注射体内iPS细胞产生表达胚胎和胚外标记的胚胎样结构。我们的结论是，在体内重编程是可行的，并赋予全能性功能，缺乏标准的iPS或ES细胞。这些发现可能与再生医学中重编程的未来应用有关。
Reprogramming of adult cells to generate induced pluripotent stem cells (iPS cells) has opened new therapeutic opportunities; however, little is known about the possibility of in vivo reprogramming within tissues. Here we show that transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice results in teratomas emerging from multiple organs, implying that full reprogramming can occur in vivo. Analyses of the stomach, intestine, pancreas and kidney reveal groups of dedifferentiated cells that express the pluripotency marker NANOG, indicative of in situ reprogramming. By bone marrow transplantation, we demonstrate that haematopoietic cells can also be reprogrammed in vivo. Notably, reprogrammable mice present circulating iPS cells in the blood and, at the transcriptome level, these in vivo generated iPS cells are closer to embryonic stem cells (ES cells) than standard in vitro generated iPS cells. Moreover, in vivo iPS cells efficiently contribute to the trophectoderm lineage, suggesting that they achieve a more plastic or primitive state than ES cells. Finally, intraperitoneal injection of in vivo iPS cells generates embryo-like structures that express embryonic and extraembryonic markers. We conclude that reprogramming in vivo is feasible and confers totipotency features absent in standard iPS or ES cells. These discoveries could be relevant for future applications of reprogramming in regenerative medicine.