Rapamycin Promotes the Osteoblastic Differentiation of Human Embryonic Stem Cells by Blocking the mTOR Pathway and Stimulating the BMP/Smad Pathway

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Studies revealed that PI3K/AKT/mTOR signaling is important in the regulation of human embryonic stem cell (hESC) self-renewal and differentiation. However, its action on osteogenic differentiation of hESCs is poorly understood. We tested the effects of pharmacological PI3K/AKT/mTOR inhibitors on their potential to induce osteogenic differentiation of hESCs. Under feeder-free culture conditions, rapamycin (an mTOR inhibitor) potently inhibited the activities of mTOR and p70S6K in undifferentiated hESCs; however, LY294002 (a PI3K inhibitor) and an AKT inhibitor had no effects. Treatment with any of these inhibitors down-regulated the hESC markers Oct4 and Nanog, but only rapamycin induced the up-regulation of the early osteogenic markers BMP2 and Runx2. We also observed that hESCs differentiated when treated with FK506, a structural analog of rapamycin, but did not exhibit an osteogenic phenotype. Increases in Smad1/5/8 phosphorylation and Id1-4 mRNA expression indicated that rapamycin significantly stimulated BMP/Smad signaling. After inducing both hESCs and human embryoid bodies (hEBs) for 2-3 weeks with rapamycin, osteoblastic differentiation was further characterized by the expression of osteoblastic marker mRNAs and/or proteins (osterix, osteocalcin, osteoprotegerin, osteonectin, and bone sialoprotein), alkaline phosphatase activity, and alizarin red S staining for mineralized bone nodule formation. No significant differences in the osteogenic phenotypes of rapamycin-differentiated hESCs and hEBs were detected. Our results suggest that, among these 3 inhibitors, only rapamycin functions as a potent stimulator of osteoblastic differentiation of hESCs, and it does so by modulating rapamycin-sensitive mTOR and BMP/Smad signaling.
Publisher
MARY ANN LIEBERT INC
Issue Date
2010-04
Language
English
Article Type
Article
Keywords

GROWTH-FACTOR-BETA; IN-VITRO DIFFERENTIATION; OSTEOGENIC DIFFERENTIATION; ES CELLS; ENHANCES OSTEOGENESIS; 3-KINASE PATHWAY; MOUSE; LINEAGE; PROLIFERATION; PLURIPOTENCY

Citation

STEM CELLS AND DEVELOPMENT, v.19, no.4, pp.557 - 568

ISSN
1547-3287
URI
http://hdl.handle.net/10203/97362
Appears in Collection
BS-Journal Papers(저널논문)
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