Extracellular matrix mechanics as a master regulator of mechanotransduction in tissue homeostasis and disease

Integrin-mediated adhesions and focal adhesion maturation

Cells sense ECM mechanics largely through integrins, which bind ECM ligands such as fibronectin, collagen, laminin, and vitronectin, and organize into focal adhesions (FAs), multi-protein complexes containing talin, vinculin, paxillin, FAK, Src-family kinases, and scaffolding molecules.^1–4,22,23 Force-dependent unfolding of talin and recruitment of vinculin link integrins to actomyosin stress fibers, enabling cells to apply contractile forces and “probe” ECM stiffness.^5,24,25

On stiff substrates, resistance to cell-generated forces promotes FA growth and stabilization, leading to enhanced FAK/Src signaling, RhoA activation, elevated actomyosin contractility, and reinforcement of stress fibers; on soft matrices, limited resistance leads to smaller, more transient adhesions and diminished mechanotransductive signaling.^4,5,8,16 In 3D interstitial and basement membrane–like matrices, integrins assemble distinct adhesion structures (e.g., fibrillar adhesions, 3D matrix adhesions, invadopodia-like protrusions) whose composition and lifetime depend on local ECM type, fiber orientation, and degradability (Figure 1).^26–28OPEN IN VIEWER

Cytoskeleton dynamics and mechano-sensitive machineries

The actin cytoskeleton, intermediate filaments, and microtubules form integrated networks that transmit mechanical forces from the plasma membrane to the nucleus.^5,29,30 Myosin II–driven contractility generates tensile forces in actin stress fibers; cross-talk with microtubules and intermediate filaments such as vimentin and cytokeratins stabilizes cell shape and modulates load-bearing capacity.

Mechanosensitive machineries include stretch-activated ion channels (e.g., Piezo1), mechano-regulated small GTPases (RhoA, Rac1, Cdc42), and conformationally responsive cytoskeletal proteins that change binding affinities or enzymatic activity under force.^5,6,8,31,32 The relative contributions of these systems depend on ECM type: cells embedded in viscoelastic, fibrillar interstitial matrices rely heavily on actomyosin contractility and proteolysis to create migration tracks, whereas cells on basement membranes or in pericellular matrices may be more sensitive to local tension, shear, and glycocalyx-mediated force filtering. Forces sensed at adhesions are distributed through actin, microtubules, and intermediate filaments and relayed to the nuclear envelope via the LINC complex, enabling mechanical regulation of nuclear shape and chromatin organization.^33,34

YAP/TAZ and other transcriptional mechanotransducers

The transcriptional co-activators YAP and TAZ are central hubs converting mechanical cues into gene expression programs. ECM stiffness, cell spreading, and cytoskeletal tension promote nuclear localization and activation of YAP/TAZ, whereas soft matrices, reduced actomyosin contractility, or cell confinement drive their cytoplasmic retention.^6,7,35–37 Multiple pathways couple ECM mechanics to YAP/TAZ, including integrin–FAK/Src–RhoA–ROCK–actomyosin signaling, interactions with the Hippo kinase cascade, and nuclear mechanics that influence nuclear pore transport.^{6,11,30,35,36,38–40}

Computational and experimental studies have revealed that YAP/TAZ responses depend on cell shape, nuclear shape, ECM type (basement membrane vs interstitial vs 3D hydrogels), and dimensionality (2D vs 3D), and that nuclear deformation serves as a key integrator of mechanical cues upstream of YAP/TAZ activation.^{11,36,37,39,42,43} In fibroblasts, matrix stiffness–driven YAP/TAZ activation coordinates a positive feedback loop that sustains matrix deposition and fibrogenesis.^7–9

ECM mechanics and cellular metabolism

Matrix stiffness and architecture modulate cellular metabolism, including glycolysis, oxidative phosphorylation, and biosynthetic pathways. ECM-induced cytoskeletal tension and YAP/TAZ activity intersect with metabolic regulators (e.g., mTOR, AMPK) and influence mitochondrial dynamics and reactive oxygen species, linking mechanical cues to metabolic reprogramming in development, regeneration, and disease.^8,41,42 Recent work suggests that stiffness- and viscoelasticity-dependent metabolic states may help define “mechanotypes” of cells that predict their behavior in homeostasis and pathology.^41,42 Tissue-specific ECM types impose distinct metabolic demands—for example, cells in highly crosslinked, stiff interstitial matrices versus cells on compliant basement membranes or within soft pericellular matrices—further diversifying mechano-metabolic coupling.

Force transmission to the nucleus via the LINC complex

The nucleus is coupled to the cytoskeleton through the LINC (linker of nucleoskeleton and cytoskeleton) complex, allowing external forces to deform nuclear shape, strain the nuclear lamina, and reorganize chromatin.^29,30,33,34 Lamin A/C and B-type lamins form the nuclear lamina, which provides mechanical stability and participates in gene regulation through lamina-associated domains. Nuclear deformation alters the spatial organization of chromatin and nuclear bodies, thereby influencing transcriptional programs.^{29,30,43–46} These nuclear mechanotransduction pathways and associated epigenetic outcomes are discussed in Sections 3.^2–4,47

Lamin a scaling with tissue stiffness

Landmark work demonstrated that lamin A levels scale with tissue stiffness: nuclei in cells derived from stiff tissues (e.g., bone, muscle) are lamin A–rich and mechanically robust, whereas those from soft tissues (e.g., brain, fat) are lamin A–poor and more deformable. ⁴⁵ Matrix elasticity can upregulate lamin A levels and turnover, tuning nuclear mechanics to match the mechanical environment and contributing to lineage specification.^30,45,46

More recent studies have shown coordinated increases in nuclear tension and lamin A with ECM stiffness and cytoskeletal prestress, providing a mechanistic basis for long-term nuclear adaptation to mechanical microenvironments, as well as protective roles of lamin A/C against mechanical damage.^18,29,46 These adaptations occur in parallel with ECM remodeling, linking organ-specific ECM types and mechanics to nucleus-scale structural changes (Figure 2).OPEN IN VIEWER

Nuclear deformation and gene regulation

ECM stiffening and cell-generated traction forces can flatten or elongate nuclei, leading to redistribution of nuclear stresses and nuclear lamina “unwrinkling.” Once the lamina becomes taut, further deformation can trigger changes in chromatin organization and gene expression.^30,43,44

3D matrix confinement and anisotropic ECM architectures—such as aligned collagen fibers in interstitial tumor stroma or dense provisional matrices in wounds—can induce nuclear envelope folding, chromatin condensation or decondensation, and changes in accessibility of mechano-sensitive loci, thereby reprogramming gene expression patterns associated with lineage specification, migration, and invasion.^{30,38,43,44,48} Recent models describe nuclei as “drops” with surface tension regulated by lamin A/C, linking nuclear shape changes to YAP/TAZ nuclear localization and mechanosensitive transcription.^11,38,43

Matrix stiffness and epigenetic reprogramming

Mechanical cues from the ECM modulate epigenetic states, including DNA methylation, histone modifications, and chromatin accessibility. Matrix stiffness can act as a biphasic regulator of epigenetic reprogramming efficiency and has been shown to influence chromatin-modifying enzymes and the accessibility of lineage-specific gene loci.^41,48

In cancer and fibrosis, increased matrix stiffness and altered ECM type (e.g., replacement of compliant basement membranes with stiff, collagen-rich interstitial or provisional matrices) can epigenetically regulate oncogenic or pro-fibrotic programs (including YAP/TAZ target genes), and softening or “normalization” of the ECM can partially reverse such epigenetic changes, highlighting direct links between mechanical microenvironments and gene regulation.^{9,13,41,42,48}

Fibrosis and wound healing

Fibrosis is characterized by excessive deposition and crosslinking of ECM, leading to progressive tissue stiffening, architectural distortion, and loss of organ function. Activated fibroblasts and myofibroblasts are central effectors that both sense and remodel matrix mechanics, integrating pro-fibrotic cytokines and growth factors with changes in stiffness, viscoelasticity, and topography.^{4,7–11,13,14,19,38,41,49} Fibrotic matrices typically show expansion of fibrillar collagens I and III, accumulation of fibronectin (including EDA-containing isoforms), periostin, thrombospondins, and other matricellular proteins, along with altered proteoglycan and glycosaminoglycan content that modify interstitial fluid flow and tissue swelling.^{4,8–11,13,14,19,21,49} Beyond bulk stiffening, changes in stress relaxation and plasticity create mechanical “memory” that stabilizes myofibroblast phenotypes even after the initial injury subsides, helping to explain why late-stage fibrosis is often refractory to therapy.^{7–9,14,38,41,49,50}

During physiological wound healing, transient increases in ECM stiffness and tension within fibrin- and fibronectin-rich provisional matrices are required for clot retraction, wound closure, and subsequent remodeling. Failure to resolve these mechanical cues, to re-establish compliant basement membranes, or to downregulate matrix crosslinking locks fibroblasts into persistently activated states and redirects repair programs from regeneration toward scarring.^{9–14,19,49,50} Recent work in skin, lung, liver, and kidney has emphasized that fibrosis arises from coupled stromal–immune mechanotransduction networks, in which matrix stiffness, tensile strain, and altered ECM composition potentiate profibrotic signaling in fibroblasts while simultaneously reprogramming macrophages, T cells, and other immune populations toward inflammatory and pro-fibrogenic states.^{9–13,19,49,50} The mechanotransduction–immune axis in organ fibrosis has therefore emerged as a dual regulatory system that coordinates chronic ECM deposition, immune activation, and aberrant tissue repair, and is increasingly viewed as a targetable bottleneck for anti-fibrotic interventions.^19,41,49,50 Recent work has further defined fibrotic ECM as a driver of organ-level dysfunction by showing that stiff, confining matrices corrupt actomyosin-dependent tension to distort organelles such as the nucleus, endoplasmic reticulum, Golgi apparatus, endolysosomal system, biomolecular condensates, and mitochondria, thereby sustaining organelle stress and pro-fibrotic signaling. ⁵¹ In parallel, studies in hepatic fibrosis demonstrate that hepatic stellate cells can be pharmacologically reprogrammed to degrade collagen-rich ECM, in which inhibition of acid ceramidase activates a PKCα–ERK1/2–AP1–MMP-1 pathway that enhances collagen clearance and promotes regression of established liver fibrosis. ⁵² Representative disease contexts in which ECM mechanics actively drive pathogenesis are summarized in Table 2.

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Table 2.

Representative disease contexts in which ECM mechanics actively drive pathogenesis.

Disease area/context	Dominant ECM mechanical changes	Key mechanobiological consequences
Fibrosis and chronic wound remodeling	Progressive stiffening of interstitial and provisional matrices; increased collagen content and crosslinking; loss of normal compliance	Persistent myofibroblast activation and contractility; transition from provisional to scar matrix; impaired resolution and regeneration7–14,19,49
Solid tumors and tumor microenvironment	Collagen densification and alignment; LOX-mediated crosslinking; disruption of basement membrane; elevated tissue stiffness	Enhanced proliferation, epithelial–mesenchymal transition, invasion, and metastatic potential; immune exclusion; therapy resistance17,18,42,51,52
Vascular and cardiovascular disease	Arterial ECM stiffening due to elastin fragmentation, collagen accumulation, and calcification; altered basement membrane elasticity	Endothelial dysfunction and barrier disruption; smooth muscle phenotypic switching; hypertension and atherosclerotic plaque progression19,57,58
Pulmonary fibrosis and fibrotic lung diseases	Alveolar matrix stiffening and distortion; fibroblast foci with dense collagen; loss of compliant elastin-rich architecture	Sustained profibrotic signaling; impaired gas exchange and tissue compliance; progressive decline in lung function10–13,49

Cancer progression and metastasis

Tumors often exhibit pronounced stiffening and reorganization of the ECM due to collagen accumulation, lysyl oxidase (LOX)-mediated crosslinking, and fiber alignment, as well as basement membrane disruption and replacement by desmoplastic interstitial matrix.^{1,2,8,17,18,42,53–56} This altered mechanical landscape is highly heterogeneous: dense, aligned collagen tracks provide low-resistance paths that guide collective invasion of tumor cells and cancer-associated fibroblasts (CAFs), whereas softer, proteoglycan- and hyaluronan-rich niches can shelter stem-like, slow-cycling, or therapy-tolerant tumor cell populations.^{17,18,42,53,54,56} CAFs themselves behave as mechano-responsive stromal hubs that integrate stiffness, strain, and confinement cues, and in turn deposit, remodel, and crosslink ECM, thereby amplifying local stiffness gradients and generating physical barriers to drug penetration and immune cell entry.^{17,18,42,53,54,56}

At the cellular level, stiff tumor ECM promotes malignant behaviors including enhanced proliferation, epithelial–mesenchymal transition, invasion, and metastasis, in part through integrin–FAK/Src–RhoA–ROCK signaling, YAP/TAZ activation, and mechanosensitive changes in chromatin organization and metabolism.^{6,8,17–19,41,48,53–56} Mechanotransductive signaling intersects with oncogenic and metabolic pathways to reprogram tumor cells and stromal cells, while epigenetic changes driven by ECM mechanics can sustain oncogenic programs even after removal from the stiff microenvironment.^{6,8,17–19,41,48,53–55} In parallel, tumor mechanobiology exerts profound effects on anti-tumor immunity: elevated matrix stiffness and aberrant topography impede cytotoxic T-cell and NK-cell infiltration, impair immune synapse formation, and skew myeloid cells toward immunosuppressive phenotypes, contributing to resistance to immune checkpoint blockade and other immunotherapies.^{17,42,53,54,56,57}

These insights have motivated a new generation of mechano-focused therapeutic strategies. Targeting tumor ECM mechanics—by inhibiting crosslinking enzymes such as LOX, degrading specific matrix components, modulating tumor-associated basement membranes and interstitial matrices, or blocking mechanosensing pathways in tumor and stromal cells—is under active investigation as a strategy to normalize the tumor microenvironment and improve responses to therapy.^{17,18,42,53–56,58} In preclinical models, pharmacologic or biomaterial-based softening of the tumor stroma can enhance perfusion, facilitate drug delivery, and increase T-cell infiltration and effector function, thereby boosting responses to chemo-, radio-, and immunotherapies.^{17,18,42,53–58} Conceptually, these approaches shift the focus from treating tumors solely as biochemical entities to explicitly targeting the abnormal mechanical context in which malignant and immune cells reside.

Vascular and cardiovascular diseases

In the vasculature, ECM mechanics regulate endothelial and smooth muscle cell behavior, vascular development, and tone by distributing pressure, flow-derived shear, and cyclic stretch across the arterial wall.^{19,32,59–62} Arterial ECM comprises elastic lamellae rich in elastin and fibrillin, interspersed with collagen- and proteoglycan-rich interstitial matrices and endothelial basement membranes; together, these structures define arterial stiffness, compliance, and the pattern of wall strain.^{19,32,59–62} With aging and cardiometabolic disease, fragmentation of elastin, accumulation and crosslinking of collagen, proteoglycan deposition, and focal calcification progressively stiffen the arterial wall, alter pulse wave velocity, and modify the transmission of cyclic strain to endothelial and smooth muscle cells, contributing to atherosclerosis, vascular calcification, aneurysm formation, and pulmonary hypertension.^{11,14,19,32,59–62}

Stiffened arterial ECM enhances smooth muscle cell contractility, promotes pro-inflammatory and synthetic phenotypes, and alters endothelial barrier function, while changes in basement membrane composition and elasticity impact angiogenesis, leukocyte trafficking, and vascular remodeling.^{19,32,59–62} Beyond static stiffness, complex combinations of pressure, shear stress, and cyclic stretch converge with ECM composition to regulate vascular mechanotransduction across arterial beds; regions of disturbed flow and locally stiffened matrix at branch points augment pro-atherogenic signaling, whereas compliant segments experiencing unidirectional shear promote anti-inflammatory, atheroprotective endothelial phenotypes.^{19,32,59–62} Mechanistic studies and comprehensive reviews of vascular mechanotransduction have begun to map how mechanosensitive ion channels, glycocalyx structures, and adhesion complexes integrate these forces to control vascular tone, permeability, and remodeling, and emphasize that strategies aimed at restoring physiological ECM mechanics may complement traditional blood pressure– and lipid-lowering therapies in preventing cardiovascular disease progression (Figure 3).^{19,32,59–62}OPEN IN VIEWER