Mechanosensing via cell-matrix adhesions in 3D microenvironments

Abstract

The extracellular matrix (ECM) microenvironment plays a central role in cell migration by providing physiochemical information that influences overall cell behavior. Much of this external information is accessed by direct interaction of the cell with ECM ligands and structures via integrin-based adhesions that are hypothesized to act as mechanosensors for testing the surrounding microenvironment. Our current understanding of these mechanical complexes is derived primarily from studies of cellular adhesions formed on two-dimensional (2D) substrates in vitro. Yet the rules of cell/ECM engagement and mechanosensing in three-dimensional (3D) microenvironments are invariably more complex under both in vitro and in vivo conditions. Here we review the current understanding of how cellular mechanosensing occurs through adhesion complexes within 3D microenvironments and discuss how these mechanisms can vary and differ from interactions on 2D substrates.

A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance

“…Because cells are less able to form cell-matrix adhesions on soft versus stiff 2D substrates, and in 3D versus 2D environments 54 , genes associated with integrin-mediated adhesion and cell-surface receptor linked signal transduction are varied across our biomaterials (Figure 2b–d). Matrix adhesion via integrins mediates survival and drug resistance through activation of survival signaling, such as FAK, Src, and ERK 55–57 .…”

Collagen: a network for regenerative medicine

“…73,74 Thus the regulation of integrin binding is extremely important. Regulation can occur by affinities between the ligand and receptor, integrin clustering, and intracellular movement of the integrin receptors.…”

“…20 Even shifting from two-dimensional to three-dimensional culture systems can affect the expression of alpha subunits in vitro . 74 Regardless of the type of signal, the downstream effects of integrin binding are mediated by a host of other molecules and proteins, known collectively as the adhesome. 20 …”

Molecular mechanisms of mechanotransduction in integrin-mediated cell-matrix adhesion

“…This has been accompanied by the development of microfluidic-based cell culture systems [70] and 3D ECM-mimicking scaffolds [69]. Although 3D matrix adhesions are comprised of many of the same molecules of 2D cell-matrix adhesions, cell adhesions and behaviors are distinguished from the interactions on the 2D substrates due to inherent complexity of 3D matrices.…”