Spatial heterogeneity of lactylation: insights into gene expression, metabolism, and lactate transport in human embryonic stem cells

Low reprogramming efficiency and high phenotypic variability hinder the regenerative medicine applications of human pluripotent stem cells. Understanding the mechanisms that regulate pluripotency is crucial to overcoming these challenges. This study investigated the relationship between lactylation, a newly identified regulator of gene expression, pluripotency, metabolism, and lactate transport in human embryonic stem cells (hESCs). Histone lactylation levels were significantly higher in hESCs than in differentiated cells. Further, exogenous lactate increased histone lactylation and acetylation levels and altered pluripotency gene expression, notably increasing KLF4, KLF5, GBX2, and DMNT3L in hESCs. Finally, naïve-like hESC colonies exhibited higher lactylation levels peripherally, coinciding with elevated peripheral SOX2 levels. Conversely, lactate transport and production protein levels were higher centrally. This study suggests that elevated histone lysine lactylation levels are a newly identified characteristic of human pluripotency. The spatial distribution findings are consistent with a positive relationship between histone lactylation and SOX2 expression in naïve-like hESCs.