Reprogramming in vivo produces teratomas and iPS cells with totipotency features

摘要

Manuel Serrano及同事首次发现，体细胞被经典"Yamanaka因子"Oct4、 So×2、 Klf4和 c-Myc重新编程为具有多能性的过程可以在活体中实现。对从小鼠的胃、小肠、胰腺和肾脏细胞在活体中诱导生成的"诱导多能干"(iPS)细胞所做分析显示，它们比在体外生成的iPS细胞更接近胚胎干细胞。这些活体iPS细胞还具有生成表达胚胎标记和胚胎外标记的胚胎样结构的潜力，这说明它们具有传统iPS细胞或胚胎干细胞所没有的全能特征。%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, mtestine, 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.