Myofibroblast Mechanobiology in Tissue Repair

Myofibroblasts are specialised contractile cells that emerge during wound healing to mediate tissue contraction and extracellular matrix remodelling. They derive from resident fibroblasts and other progenitors under the combined influence of biochemical signals—most notably transforming growth factor-β—and mechanical cues such as matrix stiffness, cell tension and cell shape. Mechanical forces are sensed at focal adhesions through integrin receptors and transmitted via Rho/ROCK, focal adhesion kinase–PI3K/Akt and downstream nuclear effectors including myocardin-related transcription factors. Emerging evidence highlights roles for mechanosensitive ion channels, cytoskeletal tension and liquid–liquid phase separation in the control of collagen synthesis and α-smooth muscle actin expression. Dysregulated mechanobiology underlies pathological fibrosis across organs from heart to lung and skin, making these signalling pathways attractive targets for therapies aimed at promoting regenerative repair while minimising scar formation.

Research from Nature Portfolio

Recent studies have uncovered a mechanosensitive cofactor that controls collagen production in cardiac myofibroblasts by translocating into the nucleus in response to substrate stiffness. Once inside, it undergoes liquid–liquid phase separation and assembles with nuclear condensates to suppress microRNA targeting of collagen mRNA, thereby driving fibrotic matrix accumulation in the post-infarction heart. Another line of work has identified an elastic-fibre component at the interface of tissue stiffness and inflammation in cutaneous fibrosis, demonstrating that modulating extracellular elasticity can short-circuit a profibrotic feedback loop, reduce inflammatory signalling and restore tissue homeostasis.

Myofibroblast Mechanobiology in Tissue Repair publication trend

The graph below shows the total number of articles in myofibroblast mechanobiology in tissue repair across all publications each year (not limited to Nature Index journals).

Technical terms

Mechanotransduction: Conversion of mechanical stimuli into intracellular biochemical signals.

Extracellular matrix (ECM): Network of proteins and polysaccharides that provides structural support and biochemical cues to cells.

Fibroblast-to-myofibroblast transition (FMT): Process by which quiescent fibroblasts acquire contractile features and enhanced matrix-secreting capacity.

α-Smooth muscle actin (α-SMA): Actin isoform whose incorporation into stress fibres endows myofibroblasts with contractile force.

Liquid–liquid phase separation: Self-organisation of proteins into membrane-less condensates that compartmentalise nuclear functions.

References

1. VGLL3 is a mechanosensitive protein that promotes cardiac fibrosis through liquid–liquid phase separation. Nature Communications (2023).
2. Actomyosin Activity and Piezo1 Activity Synergistically Drive Urinary System Fibroblast Activation. Advanced Science (2023).
3. Mechanical and Physical Regulation of Fibroblast–Myofibroblast Transition: From Cellular Mechanoresponse to Tissue Pathology. Frontiers in Bioengineering and Biotechnology (2020).
4. The matrix protein Fibulin-5 is at the interface of tissue stiffness and inflammation in fibrosis. Nature Communications (2015).
5. Engineered Biomaterial Platforms to Study Fibrosis. Advanced Healthcare Materials (2020).
6. Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis. Biomolecules (2021).