The (dys)functional extracellular matrix

Abstract

The extracellular matrix (ECM) is a major component of the biomechanical environment with which cells interact, and it plays important roles in both normal development and disease progression. Mechanical and biochemical factors alter the biomechanical properties of tissues by driving cellular remodeling of the ECM. This review provides an overview of the structural, compositional, and mechanical properties of the ECM that instruct cell behaviors. Case studies are reviewed that highlight mechanotransduction in the context of two distinct tissues: tendons and the heart. Although these two tissues demonstrate differences in relative cell-ECM composition and mechanical environment, they share similar mechanisms underlying ECM dysfunction and cell mechanotransduction. Together, these topics provide a framework for a fundamental understanding of the ECM and how it may vary across normal and diseased tissues in response to mechanical and biochemical cues. This article is part of a Special Issue entitled: Mechanobiology.

Keywords: Biomechanics; Cell mechanics; Cytoskeleton; Diastolic dysfunction; Mechanotransduction; Tendinopathy.

Conflict of interest statement

Conflicts of interest

The authors have no conflicts of interest to report.

Copyright © 2015. Published by Elsevier B.V.

Figures

Fig. 1

Model of cell–ECM and cell-cell mechanotransduction. Cells sense ECM stiffness and external loading by balancing the force between the actomyosin machinery and integrin adhesions. Important molecules involved in the generation of cytoskeletal tension include F-actin, myosin, and the Rho signaling cascade. It is noted that this illustration highlights only the basic subunits of these adhesion complexes, and that these components come together into higher order assemblies in vivo.

Fig. 2

Tissue stiffness and its relationship to collagen content. (A) Tissues exhibit a wide range of stiffnesses as measured by the elastic modulus. (B) Tissue stiffness relates to the quantity of type I collagen. As the most prevalent protein in many tissues, collagen modulates mechanical properties of tissue. (C) Hematoxylin and eosin staining shows increasing severity of cardiac fibrosis with elevated collagen content (arrows) between muscle fibers (red), leading to tissue stiffening. Panel A: Reproduced with permission from Janmey and Miller [11]. Panel B: Reproduced with permission from Swift and Discher [10]. Panel C: Reproduced with permission from Weidemann et al. [44].

Fig. 3

Tendon hierarchical structure and a typical stress-strain curve. (A) Tendons contain tenocytes (tendon fibroblasts) embedded in a hierarchical matrix of collagenous and noncollagenous components. Tendons are composed of fascicles, fibers, and fibrils that form from collagen molecules. (B) During mechanical loading, tendons exhibit nonlinearity in their stress strain curve, containing a toe region prior to a transition to a linear region. With increases in stress and strain, collagen fibers uncrimp and re-align. Panels A and B: Reproduced with permission from Connizzo et al. [201].

Fig. 4

Various pathways that may result following mechanical loading in tendon. Low loading decreased tensile strength [80,82,110], collagen organization [80,110], and tenocyte markers [135]; net collagen degradation and inflammatory cytokines increased [82,135], and GAG content was unchanged [109]. Moderate loading increased tensile strength [84], net collagen synthesis [83,84,86,109,111], tenogenic differentiation [89], and cross-sectional area [84,85]. Knowledge regarding collagen organization, vascularization, GAG production, and inflammatory cytokines with moderate loading remains limited. Excessive loading decreased tensile strength [77,115] and collagen organization [91,95], and increased net collagen degradation [78,90], aberrant differentiation [,–94,118,119], cross-sectional area [73], vascularization [73,91,115], GAG production [114], and inflammatory cytokines [79,115].

Fig. 5

Feedback mechanisms of loading on cell–ECM, cell–cell, and intracellular proteins that regulate cytoskeletal architecture, remodeling, and functional response. Myocardial remodeling represents changes in the cell (fibroblasts and cardiomyocyte) and ECM compartments of the heart in response to physiologic (e.g., endurance exercise) and pathologic (e.g., ischemia, infarction, infection, infiltration, and hypertension) stimuli. This leads to changes in cardiac biomechanics (stiffness), electrophysiology, and function (systole and diastole). Adverse myocardial remodeling represents a major mechanism and endpoint leading to the development of HF. HFrEF — Heart Failure with Reduced Ejection Fraction, HFpEF — Heart Failure with Preserved Ejection Fraction.