Reprogramming in vivo produces teratomas and iPS cells with totipotency features

María Abad, Lluc Mosteiro, Cristina Pantoja, Marta Cañamero, Teresa Rayon, Inmaculada Ors, Osvaldo Graña, Diego Megías, Orlando Domínguez, Dolores Martínez, Miguel Manzanares, Sagrario Ortega and Manuel Serrano ()
Additional contact information
María Abad: Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
Lluc Mosteiro: Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
Cristina Pantoja: Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
Marta Cañamero: Histopathology Unit, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
Teresa Rayon: Spanish National Cardiovascular Research Centre (CNIC), Madrid E-28029, Spain
Inmaculada Ors: Spanish National Cardiovascular Research Centre (CNIC), Madrid E-28029, Spain
Osvaldo Graña: Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
Diego Megías: Confocal Microscopy Unit, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
Orlando Domínguez: Genomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
Dolores Martínez: Flow Cytometry Unit, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
Miguel Manzanares: Spanish National Cardiovascular Research Centre (CNIC), Madrid E-28029, Spain
Sagrario Ortega: Transgenic Mice Unit, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
Manuel Serrano: Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain

Nature, 2013, vol. 502, issue 7471, 340-345

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature12586

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