mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells

doi:10.1073/pnas.0901854106

mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells

^aDepartment of Cell and Developmental Biology and
^bInstitute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
^cDepartment of Pharmacology, College of Medicine, The University of Iowa, Iowa City, IA 52242;
^dDepartment of Cell and Tissue Biology, University of California, San Francisco, CA 94143;
^eDepartment of Pathology, New York University School of Medicine, New York, NY 10016;
^fDepartment of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
^gState Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; and
^hDepartment of Bioengineering, University of California, Riverside, CA 92521

Edited by R. Michael Roberts, University of Missouri, Columbia, MO, and approved March 24, 2009 (received for review February 20, 2009)

Abstract

Despite the recent identification of the transcriptional regulatory circuitry involving SOX2, NANOG, and OCT-4, the intracellular signaling networks that control pluripotency of human embryonic stem cells (hESCs) remain largely undefined. Here, we demonstrate an essential role for the serine/threonine protein kinase mammalian target of rapamycin (mTOR) in regulating hESC long-term undifferentiated growth. Inhibition of mTOR impairs pluripotency, prevents cell proliferation, and enhances mesoderm and endoderm activities in hESCs. At the molecular level, mTOR integrates signals from extrinsic pluripotency-supporting factors and represses the transcriptional activities of a subset of developmental and growth-inhibitory genes, as revealed by genome-wide microarray analyses. Repression of the developmental genes by mTOR is necessary for the maintenance of hESC pluripotency. These results uncover a novel signaling mechanism by which mTOR controls fate decisions in hESCs. Our findings may contribute to effective strategies for tissue repair and regeneration.

Footnotes

¹To whom correspondence should be addressed. E-mail: feiwang{at}life.uiuc.edu
Author contributions: J.Z. and F.W. designed research; J.Z., P.S., L.W., and Joanna Chen performed research; M.Z., O.G., O.A., M.C.H., T.T., E.D., S.J.F., J.L., and Jie Chen contributed new reagents/analytic tools; J.Z. and F.W. analyzed data; and J.Z. and F.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0901854106/DCSupplemental.