FGF, BMP, and TGFβ signaling together control human embryonic stem cell fates.

Although both mouse and human embryonic stem cells (hESCs) can be maintained on fibroblast feeder cells, extrinsic cues identified to sustain their self-renewal are different. Leukemia inhibitory factor and bone morphogenetic proteins (BMPs), members of the TGFβ super-family, are sufficient to maintain self-renewal of mouse, but not human, ES cells. Instead, we and others have found that self-renewal of hESCs is promoted by FGF and TGFβ/Activin signaling, and their differentiation is promoted by BMP signaling. Using a defined medium, we have further shown that both TGFβ and FGF signals synergize to inhibit BMP signaling, sustain expression of pluripotency-associated genes, and promote long-term undifferentiated proliferation of hESCs. We further characterized the molecular mechanisms that link these signaling pathways with maintenance of pluripotency in the cells. Together we demonstrate that FGF, BMP, and TGFβ signaling are three driving forces that control the hESC fates. [ABSTRACT FROM AUTHOR]