Recapitulating hypoxic metabolism in cartilaginous organoids via adaptive cell-matrix interactions enhances histone lactylation and cartilage regeneration
Boguang Yang, Zhuo Li, Zhengmeng Yang, Pengchao Zhao, Sien Lin, Jiahao Wu, Wei Liu, Xuefeng Yang, Xian Xie, Zhixian Zong, Yuanning Lyu, Zhinan Yang, Gang Li, To Ngai, Kunyu Zhang, Liming Bian
Abstract
Mesenchymal condensation, characterized by rapid proliferation and aggregation of precursor cells within a restructured mesodermal extracellular matrix, is critical for skeletal tissue development, including articular cartilage. This process establishes a hypoxic microenvironment that drives metabolic shifts and epigenetic modifications essential for cartilage development. To replicate this, we engineer a cell-adaptable supramolecular hydrogel that accommodates the extensive volumetric and morphological changes of encapsulated mesenchymal stromal cells, facilitating the rapid formation of large multicellular cartilaginous organoids. This adaptation fosters a hypoxic environment and induces metabolic shifts toward glycolysis, increasing lactate accumulation and histone lysine lactylation. Enhanced lactylation on Lysine 18 of Histone H3 promotes chondrogenesis and cartilage matrix deposition by improving the accessibility of chondrogenic genes, while the inhibition of histone lactylation disrupts these processes. Implantation of the ultradynamic hydrogel in large animal cartilage defects results in superior repair compared to less dynamic alternatives, providing insights for effective biomaterial delivery in cell therapies. Our findings reveal how matrix biophysical cues influence cellular development, metabolic reprogramming, and epigenetic modifications. Mesenchymal condensation is essential for cartilage development. Here, the authors report on a cell-adaptable supramolecular hydrogel to replicate the hypoxic environment and structural support needed for cartilage organoid formation and study the metabolic reprogramming involved.