Reprogramming in vivo produces teratomas and iPS cells with totipotency features

Abstract

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.

Heat-induced masculinization in domesticated zebrafish is family-specific and yields a set of different gonadal transcriptomes

“…Although targeting the stem cell microenvironment is believed to be important for proper tissue reprogramming (reviewed in ref. 58), earlier attempts at induced in vivo reprogramming in rodent models have resulted in the appearance of teratomas in multiple tissues (59). Our observation may be linked to the extraordinary plasticity of fish gonads compared with most other vertebrate tissues (60,61), and constitutes an aspect that deserves further study.…”

The molecular underpinnings of totipotency

“…Recently, it was observed that the in vivo induction of OSKM in adult mice generated iPS cells that could differentiate towards embryonic and extraembryonic lineages both in vitro and in vivo [37]. These iPS cells have a transcriptional profile that correlates more strongly with ES cells than iPS cells generated by standard in vitro induction of the four transcription factors.…”

Induced pluripotent stem cell (iPSCs) and their application in immunotherapy

“…Recently, Abad et al 12 achieved this difficult task. In this striking study, the authors generated reprogrammable mice carrying a doxycycline-inducible cassette encoding the four reprogramming factors and demonstrated that the reprogrammed iPSCs acquired totipotent characteristics that were passed on by the zygote and its immediate daughter cells, which in vitro-generated ESCs and iPSCs could not accomplish.…”