Metabolic regulation in pluripotent stem cells.

Pluripotent stem cells (PSCs) have the capacity to give rise to all cell types of the adult body and to expand rapidly while retaining genome integrity, representing a perfect tool for regenerative medicine. PSCs are obtained from preimplantation embryos as embryonic stem cells (ESCs), or by reprogramming of somatic cells as induced pluripotent stem cells (iPSCs). Understanding the metabolic requirements of PSCs is instrumental for their efficient generation, expansion and differentiation. PSCs reshape their metabolic profile during developmental progression. Fatty acid oxidation is strictly required for energy production in naive PSCs, but becomes dispensable in more advanced, or primed, PSCs. Other metabolites directly affect proliferation, differentiation or the epigenetic profile of PSCs, showing how metabolism plays an instructive role on PSC behaviour. Developmental progression of pluripotent cells can be paused, both in vitro and in vivo, in response to hormonal and metabolic alterations. Such reversible pausing has been recently linked to mammalian target of rapamycin activity, lipid metabolism and mitochondrial activity. Finally, metabolism is not simply regulated by exogenous stimuli or nutrient availability in PSCs, as key pluripotency regulators, such as Oct4, Stat3 and Tfcp2l1, actively shape the metabolic profile of PSCs.

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