mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells.
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.
Department of Cell and Developmental Biology and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Jiaxi
J
Zhou
Pei
P
Su
Lu
L
Wang
Joanna
J
Chen
Maike
M
Zimmermann
Olga
O
Genbacev
Olubunmi
O
Afonja
Mary C
MC
Horne
Tetsuya
T
Tanaka
Enkui
E
Duan
Susan J
SJ
Fisher
Jiayu
J
Liao
Jie
J
Chen
Fei
F
Wang
D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004707:Endoderm / Q000378:metabolism*; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D008648:Mesoderm / Q000378:metabolism*; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D011494:Protein Kinases / Q000378:metabolism* / Q000502:physiology*; D012038:Regeneration; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases