Tissue stiffness dictates development, homeostasis, and disease progression

Abstract

Tissue development is orchestrated by the coordinated activities of both chemical and physical regulators. While much attention has been given to the role that chemical regulators play in driving development, researchers have recently begun to elucidate the important role that the mechanical properties of the extracellular environment play. For instance, the stiffness of the extracellular environment has a role in orienting cell division, maintaining tissue boundaries, directing cell migration, and driving differentiation. In addition, extracellular matrix stiffness is important for maintaining normal tissue homeostasis, and when matrix mechanics become imbalanced, disease progression may ensue. In this article, we will review the important role that matrix stiffness plays in dictating cell behavior during development, tissue homeostasis, and disease progression.

Keywords: ECM, Extracellular matrix; EPC, Endothelial progenitor cell; FA, Focal adhesion; FAK, Focal adhesion kinase; LOX, Lysyl oxidase; MKL1, Megakaryoblastic leukemia factor-1; MMP, Matrix metalloproteinase; MSC, Mesenchymal stem cell; ROCK, Rho-associated protein kinase; VSMC, Vascular smooth muscle cell.; cancer; extracellular matrix; fibrosis; stiffness; tissue development; tissue homeostasis.

Figure 1.

Distinct modulus of human tissues suggesting tissue-specific stiffness. Different tissues with their specific elastic modulus in the body are correlated with their functions (adapted from Cox et al.).

Figure 2.

Molecular regulation by ECM stiffness. Integrins respond to ECM stiffness by clustering together to activate adaptor proteins of focal adhesion and downstream signaling molecules to regulate cell behavior. Previous findings of the regulatory pathways underlying the molecular mechanism induced by ECM stiffness are illustrated as representative examples.