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

Abstract

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 {beta}3 (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.