Novel insights into tissue mechano-adaptation through extracellular matrix sensing

Tissues must continuously adapt to mechanical constraints imposed by their extracellular environment. How cells interpret extracellular architecture and translate this information into coordinated changes in cell behavior and matrix turnover remains incompletely understood. Our recent findings identify Capillary Morphogenesis Gene 2 (CMG2) as a key molecular interpreter of extracellular composition and organization that instructs cells. In lymphatic capillaries, CMG2 regulates VEGFR3 signalling and actin-dependent junctional architecture required for fluid uptake. Loss of CMG2 disrupts button junction organization and impairing interstitial fluid clearance, demonstrating how cytoskeletal state transitions can directly control organ-level function. These in vivo observations provide a unifying mechanistic model for several previously unexplained molecular properties of CMG2: CMG2 is a receptor that “reads” extracellular ligands reflecting matrix composition and architecture. Ligand engagement instructs distinct cellular responses – actin cytoskeleton reorganization, receptor trafficking, lysosomal degradation of extracellular components. This determines junction organization, tissue permeability, and mechanical resilience. CMG2 emerges as a key component of tissue mechano-adaptation. This integrated view reconciles observations from genetic models, patient mutations, and biochemical studies, and identifies Hyaline Fibromatosis Syndrome, caused by mutations in cmg2, as a disorder of impaired tissue mechano-adaptation.