On March 19, 2025, Nature Communications published online a groundbreaking study entitled "Recapitulating Hypoxic Metabolism in Cartilaginous Organoids via Adaptive Cell-Matrix Interactions Enhances Histone Lactylation and Cartilage Regeneration" from Professor Liming Bian's research team. The study features Dr. Boguang Yang, Dr. Zhuo Li, and Dr. Zhengmeng Yang from The Chinese University of Hong Kong as co-first authors, with Professors Liming Bian, Kunyu Zhang (South China University of Technology), and Tao Wei (The Chinese University of Hong Kong) serving as corresponding authors.

Hydrogels have been widely investigated as artificial extracellular matrix (ECM) mimics that recapitulate native biophysical properties, serving as effective delivery vehicles for therapeutic cells to repair damaged soft tissues including articular cartilage. Nevertheless, traditional covalently crosslinked hydrogels generally possess restricted network dynamics that cannot accommodate the substantial volumetric changes during rapid proliferation and dense aggregation of encapsulated cells, thereby limiting cartilage organoid formation and subsequent regenerative outcomes.Mesenchymal stromal/stem cells (MSCs), considered an optimal cell source for cartilage repair, require precisely orchestrated biophysical cues from the surrounding matrix to guide their chondrogenic differentiation. Of importance is mesenchymal condensation - a critical morphogenetic event during early cartilage development wherein dispersed progenitor cells rapidly reorganize the surrounding mesodermal ECM and form high-density cellular aggregates, thereby establishing the hypoxic microenvironment essential for chondrogenesis. To address these challenges, the development of ultra-dynamic cell-adaptive hydrogels (HA-TP) capable of supporting MSC-mediated mesenchymal condensation and hypoxia-driven metabolism represents a promising strategy for engineering functional cartilage organoids and achieving effective cartilage regeneration.

Building upon this foundation, the research team developed an ultra-dynamic hydrogel crosslinked through host-guest complexation. By recapitulating the mesenchymal condensation process during cartilage development, the HA-TP hydrogel significantly enhances cell-derived organoid formation, thereby establishing localized hypoxic microenvironments that drive metabolic reprogramming. This process ultimately leads to increased lactate accumulation and enhanced histone lactylation in encapsulated hMSCs. Notably, the augmented histone lactylation modification promotes chondrogenic differentiation of hMSCs encapsulated within the ultra-dynamic hydrogel system.

Schematic illustration of how the cell-adaptive dynamic hydrogel network facilitates encapsulated cells to complete developmentally essential condensation processes and metabolic reprogramming, thereby enhancing cartilage organ formation.

This study reveals the crucial importance of designing cell-adaptive dynamic hydrogel networks–such networks enable encapsulated cells to achieve developmentally essential condensation processes and metabolic reprogramming, thereby enhancing cartilage organ formation and promoting in situ tissue regeneration.

Article link：

https://www.nature.com/articles/s41467-025-57779-6#Abs1