Mechanical Forces Matter in Health and Disease: From Cancer to Tissue Engineering

Abstract

Abstract Cellular microenvironments control many aspects of cell behavior, differentiation and wound healing. When cells are in an inappropriate environment, they often stop growth or enter an apoptotic pathway. Environment is defined by the biological or engineered matrix, soluble molecules, adjacent cells and physical factors of force and geometry that all act at the nanometer (protein) level. The development of nanotechnology tools has provided new ways to measure the forces and control the geometry spatial in which ligands are presented. In this chapter, we focus on reviewing the effects of mechanical force on cellular functions because it is a critical intensive parameter that dynamically affects cell functions in health and disease. For force transmission, cell adhesion sites must be linked mechanically to the cell cytoskeleton and force‐generating machinery within the cell, as well as to the extracellular matrix (ECM). Forces are processed by specialized adhesive structures that are dynamic as the cells actively bind, stretch and remodel their surroundings. Once formed, the early contacts either mature rapidly or break. We will discuss how forces upregulate the maturation of early cell–matrix junctions and regulate the dynamic interplay between the assembly and disassembly of adhesion sites. Once sufficiently stabilized through recruitment of additional focal adhesion proteins, intracellular traction can generate large forces on the adhesive junctions – forces which are easily visualized as strain applied by cells to flexible substrates. Protein stretching and unfolding plays a central role in the recruitment of proteins to an adhesion site, and in regulating intracellular signaling events, including stretch‐dependent tyrosine phosphorylation. The nanoscale machinery of an adhesion site enables the cell to sense and respond to the spatial patterns of its environment, as well as to its rigidity. In response, cells change their protein expression pattern and assemble and remodel the ECM. This in turn regulates cell motility and many other cellular functions. We will then discuss that many diseases have a mechanical origin or show abnormalities in cellular mechanoresponses, from cancer to cardiovascular disorders, from osteoporosis to other aging‐related diseases. Ultimately, mechanotransduction processes regulate tissue formation, remodeling and healing in native wound sites of tissue engineered scaffolds, as well as how stem cells differentiate and whether cells derail and evolve into cancer cells or other disease conditions.