Recapitulating cartilaginous organoids and hypoxic metabolic switching via adaptive stem cell-matrix interactions promotes histone lactylation and cartilage regeneration

The formation of cartilaginous organoids fostered by the cell–hydrogel adaptation creates a hypoxic microenvironment and induces metabolic switching to favor glycolysis and the accumulation of lactate in the MSC spheroids, leading to significantly elevated histone lysine lactylation (Kla). We further show that the increased H3K18la enhances chondrogenesis and cartilaginous matrix deposition by regulating the transcriptional accessibility of chondrogenic genes. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for histone modification H3K18la in hMSCs encapsulated in the hydrogels with different dynamic properties.