While the preimplantation embryo possesses a degree of developmental plasticity in response to changes in the extracellular nutrient environment, enabling short term adaptation, this plasticity comes at a cost to embryo viability and subsequent long-term offspring health. However, the mechanisms by which the extracellular environment elicits persistent changes have remained unclear.
Beyond their role in generating ATP, metabolites and cofactors have recently been shown to induce long-term cellular changes through the regulation of the epigenome, a phenomenon referred to as metaboloepigenetics. Using Pluripotent Stem Cells (PSC), as an in vitro representative of the blastocyst stage inner cell mass, our data reveal links between metabolic activity and stem cell health, differentiation kinetics, maintenance of pluripotency and reprogramming of adult cells to induced Pluripotent Stem Cells (iPSC).
Cell culture conditions can elicit permanent changes that perturb embryonic stem cell responses to physiological stimuli and interfere with differentiation timing, and highlight the significance of assessing cell physiology in in vitro culture models. The relative availability of several key metabolites alters not only stem cell physiology but also the epigenetic landscape and impacts subsequent differentiation. Furthermore, we have identified the retention of somatic metabolic memory in iPSC, which can be modulated by altered nutrient availability during the reprogramming process to affect cell physiology, cell integrity and genetic stability.
Metabolic regulation of the epigenome is therefore a plausible mechanism underpinning how the extracellular microenvironment induces persistent modifications during early embryonic programing.