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In vivo reprogramming in living mice

A recent paper in Nature1 from Spanish scientists at the Spanish National Cancer Research Center (CNIO) reports the reprogramming of cells to generate induced pluripotent stem cells (iPSCs)in adult mice in vivo. This work, led by Manuel Serrano who heads the Tumour suppression Group at CNIO, advances the current knowledge of iPSCs by showing that there may be no need to remove somatic tissues from an organism for reprogramming to occur inside a petri dish in a laboratory incubator, but that reprogramming can be achieved inside a living organism. The authors performed their work in reprogrammable mice, turning on the 4 classic Yamanaka pluripotency factors (Oct4, Klf4, Sox2 and c-Myc/OKSM) via a lentiviral dox-inducible system. In their paper, Abad et al. describe that inducing too much expression of OKSM was catastrophic, causing fatal teratoma formation, however by determining the right dosage they were able to achieve teratoma formation in situ in multiple organs in live mice that could be studied. Across multiple organs the authors also found in situ dedifferentiated somatic cells which lost the expression of mature markers and gained expression of the pluripotency marker NANOG. Termed ‘in vivo iPSCs’, these were found in highest frequency in abdominal organs, but were also found circulating within the bloodstream, and were easily obtainable from the blood of induced mice. Intriguingly, in vivo iPSCs were more similar to embryonic stem cells (ECSs) than in vitro-generated iPSCs, with in vivo iPSCs demonstrating totipotency by forming extra-somatic cell types, indicating greater plasticity than ESCs which are pluripotent in nature.

This provocative study pushes the boundary of iPSC technology and raises some interesting questions, such as why some organs were more easily reprogrammable than others. The significant number of malignant tumours caused by this technique causes major hurdles for its direct clinical relevance at this stage. Nonetheless, the ability to induce adult cells to pluripotency without removing them from the body paves the way for the next generation of iPSC research and, if controllable, could abate the requirement for ex vivo GMP requirements and the race to find the best defined animal-free matrix and media formulations for iPSC maintenance. If in vivo reprogramming can indeed be stringently controlled and coupled with methods to enable the specific differentiation and functional integration of de novo cells, are we at the cusp of a previously unimaginable Wolverine-esque era of in vivo regenerative medicine?


Original Article

1 . Abad, M. et al. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature (2013).

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Stem Cell Correspondent Carla Mellough reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.