Format

Send to

Choose Destination
Cell Stem Cell. 2015 May 7;16(5):547-55. doi: 10.1016/j.stem.2015.03.001. Epub 2015 Apr 9.

ERRs Mediate a Metabolic Switch Required for Somatic Cell Reprogramming to Pluripotency.

Author information

1
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology, Central 4, 1-1-4 Higashi, Tsukuba 305-8562, Japan.
2
Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Kyoto 606-8501, Japan; Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Shiga 525-8577, Japan.
3
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
4
Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Kyoto 606-8501, Japan.
5
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology, Central 4, 1-1-4 Higashi, Tsukuba 305-8562, Japan.
6
Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
7
Genomic Analysis Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
8
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: evans@salk.edu.

Abstract

Cell metabolism is adaptive to extrinsic demands; however, the intrinsic metabolic demands that drive the induced pluripotent stem cell (iPSC) program remain unclear. Although glycolysis increases throughout the reprogramming process, we show that the estrogen-related nuclear receptors (ERRα and ERRγ) and their partnered co-factors PGC-1α and PGC-1β are transiently induced at an early stage, resulting in a burst of oxidative phosphorylation (OXPHOS) activity. Upregulation of ERRα or ERRγ is required for the OXPHOS burst in both human and mouse cells, respectively, as well as iPSC generation itself. Failure to induce this metabolic switch collapses the reprogramming process. Furthermore, we identify a rare pool of Sca1(-)/CD34(-) sortable cells that is highly enriched in bona fide reprogramming progenitors. Transcriptional profiling confirmed that these progenitors are ERRγ and PGC-1β positive and have undergone extensive metabolic reprogramming. These studies characterize a previously unrecognized, ERR-dependent metabolic gate prior to establishment of induced pluripotency.

PMID:
25865501
PMCID:
PMC4427539
DOI:
10.1016/j.stem.2015.03.001
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center