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Amino acid intake strategies define pluripotent cell states

Mammalian pre-implantation development is associated with striking metabolic robustness, as embryos can develop in a wide variety of nutrient conditions including even the complete absence of soluble amino acids. Here, we show that mouse embryonic stem cells (ESCs) capture the unique metabolic state of pre-implantation embryos and proliferate in the absence of several essential amino acids. Amino acid independence is enabled by constitutive uptake of exogenous protein through macropinocytosis alongside a robust lysosomal digestive system. Upon transition to more committed states, ESCs reduce digestion of extracellular protein and instead become reliant upon exogenous amino acids. Accordingly, amino acid withdrawal selects for ESCs that mimic the pre-implantation epiblast. More broadly, we find that all lineages of the pre-implantation blastocysts exhibit constitutive macropinocytotic protein uptake and digestion. Together, these results highlight exogenous protein uptake and digestion as an intrinsic feature of pre-implantation development and provide insight into the catabolic strategies that enable embryos to sustain viability prior to implantation.