Mechanotransduction and extracellular matrix homeostasis

Abstract

Soft connective tissues at steady state are dynamic; resident cells continually read environmental cues and respond to them to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix (ECM) that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the ECM by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechanoregulation process, which includes the deposition, rearrangement or removal of the ECM to maintain overall form and function. Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research.

Fig. 1. Key components in soft connective tissue mechanical homeostasis

Schematic drawing depicting a fibroblast embedded in extracellular matrix (ECM) consisting primarily of collagen, fibronectin, and glycosaminoglycans, with an expanded view showing cell-matrix interactions and associated intracellular structures. In particular, cells interact mechanically with the ECM via heterodimeric transmembrane receptors called integrins, which in turn interact with intracellular signaling molecules (including focal adhesion kinase (FAK) and Src) and physically connect to cytoskeletal actin via a host of linker proteins (including talin, vinculin, filamin, the ILK-PINCH-parvin complex, and α-actinin). Key signaling pathways associated with integrin activation include the Rho-Rho kinase and mitogen-activated protein kinase (MAPK) pathways. The mechano-stimulation of cells is complemented in most situations by chemo-stimulation via soluble ligands.

Fig. 2. Feedback loops regulate extracellular matrix structure and function

Flow chart of the effects of increased mechanical loading or matrix stiffness on the cellular responses that lead either to a homeostatic regulation of matrix properties (negative feedback loop) or fibrotic conditions (positive feedback loop). In both cases, stabilized focal adhesions of greater number or size and increased actomyosin contractility, often via the Rho–Rho kinase pathway, play central roles. The precise molecular mechanisms responsible for these feedback loops remain unknown, particularly for the negative feedback that is required, by definition, for homeostasis.

Fig. 3. Cell-matrix interactions in health and disease

Schematic drawing of a normal cell and its mechanical interaction with extant matrix that is stressed or strained due to native applied forces (indicated by the grey arrows) (top row, center). Shown, too, is both a cell ensuring homeostatic maintenance of matrix under constant forces, despite the continual degradation of stressed matrix (top row, left) and a homeostatic remodeling in response to increased applied forces, that is, overloading (black arrows; bottom row, left). In contrast, loss of signaling via the matrix can lead to a special form of apoptosis called anoikis (top row, right) whereas pathologic signaling in response to overloading can lead to a fibrotic response (bottom row, right). Note, in particular, that homeostasis ultimately requires the balanced production and removal of constituents, with the new constituents having the same mechanical properties as the old. These properties include stiffness, orientation, and prestress.

Fig. 4. Force-mediated regulation of integrin adhesions

a| Schematic drawing of the “focal adhesion clutch”. The immobile integrins are coupled to the filamentous actin (F-actin) via linker proteins (for example, talin and vinculin) that can move (as indicated by the small arrows) as the F-actin moves rearward under pushing forces from actin polymerization or pulling forces from myosin II activity. A stiff matrix resists this force. b| A compliant matrix deforms under the force of F-actin flow (as indicated by the compressed actin fibers), which reduces the net loading rate on intracellular components and results in an altered cellular response.