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.
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Gene Expression Omnibus
The primary RNA-seq data has been deposited in the GEO repository under accession number GSE48364.
We are grateful to M.Torres for advice, and to K. Hochedlinger and R. Jaenisch for reagents. We also thank F. Beier, R. Serrano and N. Soberón for technical support. Work in the laboratory of M.S. is funded by the CNIO and by grants from the Spanish Ministry of Economy (MINECO, SAF), the Regional Government of Madrid (ReCaRe), the European Union (RISK-IR), the European Research Council (ERC Advanced Grant), the Botin Foundation, the Ramon Areces Foundation and the AXA Foundation. Work in the laboratory of M.M. is funded by grants from the MINECO (BFU), the Regional Government of Madrid (Cell-DD) and the ProCNIC Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Extended data figures
This table shows differentially expressed genes in in vivo iPS cells vs in vitro iPS cells.
This table shows differentially expressed genes in in vivo iPS cells vs ES cells.
This table shows differentially expressed genes in ES cells vs in vitro iPS cells.
This table shows upregulated and downregulated genes in in vivo iPS cells and ES cells (vs in vitro iPS cells).
This table shows upregulated and downregulated genes in in vivo iPS cells (vs in vitro iPS cells and ES cells).
About this article
In Vivo Transient and Partial Cell Reprogramming to Pluripotency as a Therapeutic Tool for Neurodegenerative Diseases
Molecular Neurobiology (2018)