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.

Towards an integrative understanding of cancer mechanobiology: calcium, YAP, and microRNA under biophysical forces

“…[40][41][42][43] At the same time, cells actively generate and apply endogenous forces to their surroundings. 31,41,44 The biophysical cues are sensed and transduced into intracellular biochemical and genetic signaling and further regulate specific cellular functions. This process is known as mechanochemical This journal is © The Royal Society of Chemistry 2022 transduction or mechanotransduction (Fig.…”

“…19,[45][46][47][48][49] For example, cytoskeleton, such as filamentous (F)-actin, microtubules (MTs), and intermediate filaments (IFs), and their associated motor proteins, such as myosin II, act as molecular connectors to transmit forces directly from the extracellular environment, through the membrane mechanosensors, into the nucleus. 31 Unlike diffusion-based chemical signal propagation, this force/deformation-based mechanical signal transmission can modulate the nucleus and affect gene activation within milliseconds. [50][51][52][53] Dysregulated mechanotransduction often results in diseases.…”

“…[14][15][16][19][20][21][22][23][24][25][26][27][28][29] Advances in the understanding of mechanotransduction have led to the design and development of new classes of pharmaceuticals, drug testing and delivery systems, wearable therapeutic devices, and engineered tissues that leverage biomechanics or target mechanobiology pathways to enable innovative combinatorial therapeutics. [30][31][32][33][34][35][36][37][38][39] In this review, we focus on reporting the interplay between biomechanical signals and three important biochemical effectors during tumor progression: (1) calcium ions (Ca 2+ ), (2) yesassociated protein (YAP), and (3) microRNAs (miRNAs). Two other recent reviews discuss other types of biochemical effectors involved in cancer mechanobiology.…”

“…Two other recent reviews discuss other types of biochemical effectors involved in cancer mechanobiology. 7,31 During cancer progression, Ca 2+ and YAP serve as critical signaling messengers to regulate gene-expression and cell functions, which are simultaneously modulated by miRNAs. However, how Ca 2+ , YAP, and miRNA interact with each other to influence the activities of cancer cells remains incompletely understood.…”

Nuclear activation in dual-durotaxing cells on a matrix with cell-scale stiffness-heterogeneity

“…The cell shape has been revealed to modulate cell functions such as proliferation and differentiation by altering the intracellular prestress 15,16 generated by mechanotransductive linkages between the ECM, focal adhesions, cytoskeletons, and the cell nucleus 17 . Such a mechanical network influences chromatin behavior and finally regulates gene expression [18][19][20][21] .…”