Lactate Accelerates Mouse ES Cell Differentiation Towards the XEN Lineage

Metabolism plays a crucial role for cell survival and function; however, recent evidence has implicated it in regulating embryonic development. The inner cell mass undergoes orchestrated cellular divisions resulting in the formation of embryonic stem cells and extraembryonic endoderm (XEN) cells. Concomitantly, changes in the metabolic profile occurs during development and are well-documented in the embryonic lineages. However, a comprehensive multi-omics analysis of these features in XEN cells remains lacking. We observed that feeder-free XEN cells exhibited high sensitivity to glycolytic inhibition in addition to maintaining elevated intra- and extracellular lactate levels. XEN cells maintain high lactate levels by increased LDHA activity and re-routing pyruvate away from the mitochondria. Importantly, exogenous lactate supplementation or promoting intracellular lactate accumulation enhances XEN differentiationin vitro. Our results highlight how lactate contributes to XEN differentiation in the mammalian embryo and may serve to enhance reprogramming efficiency of cells used for regenerative medicine.