Cytoskeletal prestress: The cellular hallmark in mechanobiology and mechanomedicine

Abstract

Increasing evidence demonstrates that mechanical forces, in addition to soluble molecules, impact cell and tissue functions in physiology and diseases. How living cells integrate mechanical signals to perform appropriate biological functions is an area of intense investigation. Here, we review the evidence of the central role of cytoskeletal prestress in mechanotransduction and mechanobiology. Elevating cytoskeletal prestress increases cell stiffness and reinforces cell stiffening, facilitates long-range cytoplasmic mechanotransduction via integrins, enables direct chromatin stretching and rapid gene expression, spurs embryonic development and stem cell differentiation, and boosts immune cell activation and killing of tumor cells whereas lowering cytoskeletal prestress maintains embryonic stem cell pluripotency, promotes tumorigenesis and metastasis of stem cell-like malignant tumor-repopulating cells, and elevates drug delivery efficiency of soft-tumor-cell-derived microparticles. The overwhelming evidence suggests that the cytoskeletal prestress is the governing principle and the cellular hallmark in mechanobiology. The application of mechanobiology to medicine (mechanomedicine) is rapidly emerging and may help advance human health and improve diagnostics, treatment, and therapeutics of diseases.

Keywords: cell softness; extracellular vesicles; immune cells; stem cells; substrate stiffness; tumor metastasis.

FIGURE 1

The heterodimeric integrin superfamily and their corresponding ligand binding components. In mammals, 18 α and 8 β subunits give rise to 24 different αβ integrin receptor combinations. β1 subunits are the most commonly found. Integrin activation leads to the accumulation of cytoplasmic FA (focal adhesion) proteins connecting to actomyosin (myosin II and filamentous actin) and elevation of the cytoskeletal prestress that all living cells generate. The cytoskeletal prestress is balanced at other anchoring sites. FAK: Focal adhesion kinase

FIGURE 2

Cytoskeletal prestress is the cellular hallmark in mechanobiology. As one of the primary mechanosensors on the cell surface, integrins mediate cell adhesion and increase actomyosin‐dependent cytoskeletal prestress. Control of cytoskeletal prestress regulates a myriad of cellular functions in addition to embryonic development and cell fate determination. The cytoskeletal prestress is the governing principle and the cellular hallmark. For brevity, a single integrin heterodimer is drawn to illustrate clustered integrins and an actomyosin filament represents a prestressed myosin II‐actin bundle. MT, microtubule. IF, intermediate filament. FA, cytoplasmic focal adhesion proteins. Filamentous actin (F‐actin) interacts with a nesprin. Nesprins (Nesprin‐1 and ‐2 (green), ‐3 (purple) and ‐4 (blue); KASH proteins) and SUNs (Sun 1 and 2) belong to the LINC (linker of nucleoskeleton and cytoskeleton) complex (all not drawn to scale)