Chen L, Khillan JS
A Novel Signaling by Vitamin A/Retinol Promotes Self Renewal of Mouse ES Cells by Activating PI3K/Akt Signaling Pathway Via IGF-1 Receptor. [JOURNAL ARTICLE]
Stem Cells 2009 Nov 4.
Pluripotent embryonic stem (ES) are potential source of all types of cells for regenerative medicine. ES cells maintain pluripotency through a complex interplay of different signaling pathways and transcription factors including leukemia inhibitory factor (LIF), Nanog, Sox2 and Oct3/4. Nanog however, plays a key role in maintaining the pluripotency of mouse and human ESCs. Phosphoinositde 3-kinase (PI3K) signaling pathway that is activated in response to growth factors and cytokines also plays a critical role in promoting the survival and proliferation of ES cells. Our earlier studies have revealed that retinol the alcohol form of vitamin A enhances expression of Nanog and prevents differentiation of ES cells in long term cultures. Normally vitamin A/retinol is associated with cell differentiation via its potent metabolite retinoic acid. Thus far, no direct function has been ascribed to retinol itself. In these studies we demonstrate for the first time that retinol directly activates phosphoinositide 3 (PI3) kinase signaling pathway through IGF-1 receptor/insulin receptor substrate 1 (IRS-1) by engaging Akt/PKB-mTORC1 and mTORC2 complexes indicating a growth factor like function of vitamin A. Further, ES cells do not express enzymes to metabolize retinol into retinoic acid and lack receptors for retinol transport into the cytoplasm indicating that retinol signaling is independent of retinoic acid. The studies present a novel system to investigate how extracellular signals control the self renewal of ES cells which will be important for high quality ES cells for regenerative medicine.
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