Hypoxia Promotes Wound Healing via Dynamical-Mechanical Balance and Adhesion Remodeling

Wound healing is a tightly orchestrated physiological process governed by dynamic cell–cell and cell–matrix interactions, yet how hypoxic microenvironments regulate migratory behavior in cells with latent lineage plasticity remains fully elucidated. Here, utilizing human embryonic kidney (HEK293T) and Madin-Darby Canine Kidney (MDCK) cells as a genetically tractable model, we investigate the cellular and molecular mechanisms driving hypoxia-accelerated collective wound repair. Time-lapse live-cell imaging and morphometric analyses reveal that hypoxic exposure significantly accelerates migration, shifts cell cycle dynamics toward the S/G2/M proliferative phases, and induces pronounced morphological spreading. Mechanistically, hypoxia induces a persistent, time-dependent downregulation of the desmosomal cadherin desmoglein-2 (DSG2), thereby weakening intercellular cohesion. Concurrently, the cell-matrix adhesion molecule integrin β3 (ITGB3) exhibits a distinctive biphasic kinetic response—an initial sharp upregulation followed by a sustained decline-which serves to optimize focal adhesion traction and subsequent trailing-edge detachment. Transcriptomic profiling further corroborates these phenotypic transitions, demonstrating a global enrichment of gene networks associated with plasma-membrane adhesion organization, receptor activity, and ion homeostasis that independently mirrors the altered junctional dynamics and accelerated cellular responses. Collectively, our findings uncover a novel cooperative mechanism by which hypoxic stress coordinates cell-cell and cell-matrix adhesion remodeling to facilitate efficient tissue repair, highlighting the valuable utility of plastic cellular models in decoding microenvironmental stress responses.