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.
Zhou
Jiaxi
J
Department of Cell and Developmental Biology and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Su
Pei
P
Wang
Lu
L
Chen
Joanna
J
Zimmermann
Maike
M
Genbacev
Olga
O
Afonja
Olubunmi
O
Horne
Mary C
MC
Tanaka
Tetsuya
T
Duan
Enkui
E
Fisher
Susan J
SJ
Liao
Jiayu
J
Chen
Jie
J
Wang
Fei
F
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