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 () and Liming Bian ()
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Boguang Yang: The Chinese University of Hong Kong
Zhuo Li: The Chinese University of Hong Kong
Zhengmeng Yang: The Chinese University of Hong Kong
Pengchao Zhao: South China University of Technology
Sien Lin: The Chinese University of Hong Kong
Jiahao Wu: The Chinese University of Hong Kong
Wei Liu: The Chinese University of Hong Kong
Xuefeng Yang: The Chinese University of Hong Kong
Xian Xie: The Chinese University of Hong Kong
Zhixian Zong: The Chinese University of Hong Kong
Yuanning Lyu: South China University of Technology
Zhinan Yang: The Chinese University of Hong Kong
Gang Li: The Chinese University of Hong Kong
To Ngai: The Chinese University of Hong Kong
Kunyu Zhang: South China University of Technology
Liming Bian: South China University of Technology

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57779-6

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