1. Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
2. Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Kyoto 606-8501, Japan
3. Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan
4. Center of Regenerative Medicine in Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain
5. Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluis Companys 23, 08010 Barcelona, Spain
6. Networking Center of Biomedical Research in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Dr. Aiguader 88, 08003 Barcelona, Spain
7. These authors contributed equally to this work.

Correspondence to: Geoffrey M. Wahl¹Juan Carlos Izpisúa Belmonte^1,4 Correspondence and requests for materials should be addressed to J.C.I.B. (Email: belmonte@salk.edu) or G.M.W. (Email: wahl@salk.edu).

Abstract

Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes^{1, 2, 3, 4, 5, 6, 7, 8}, but the low frequency and tendency to induce malignant transformation⁹ compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. Here we show that reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing reprogramming-induced apoptosis in mouse fibroblasts increases reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the reprogramming efficiency of human somatic cells. These results provide insights into reprogramming mechanisms and suggest new routes to more efficient reprogramming while minimizing the use of oncogenes.

1. Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
2. Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Kyoto 606-8501, Japan
3. Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan
4. Center of Regenerative Medicine in Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain
5. Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluis Companys 23, 08010 Barcelona, Spain
6. Networking Center of Biomedical Research in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Dr. Aiguader 88, 08003 Barcelona, Spain
7. These authors contributed equally to this work.

Correspondence to: Geoffrey M. Wahl¹Juan Carlos Izpisúa Belmonte^1,4 Correspondence and requests for materials should be addressed to J.C.I.B. (Email: belmonte@salk.edu) or G.M.W. (Email: wahl@salk.edu).

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