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Review
. 2023 Jul 31;8(1):282.
doi: 10.1038/s41392-023-01501-9.

Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets

Xingpeng Di #  1 , Xiaoshuai Gao #  1 , Liao Peng #  1 , Jianzhong Ai  1 , Xi Jin  1 , Shiqian Qi  1   2 , Hong Li  1 , Kunjie Wang  3 , Deyi Luo  4
Affiliations
Review

Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets

Xingpeng Di et al. Signal Transduct Target Ther. .

Abstract

Cellular mechanotransduction, a critical regulator of numerous biological processes, is the conversion from mechanical signals to biochemical signals regarding cell activities and metabolism. Typical mechanical cues in organisms include hydrostatic pressure, fluid shear stress, tensile force, extracellular matrix stiffness or tissue elasticity, and extracellular fluid viscosity. Mechanotransduction has been expected to trigger multiple biological processes, such as embryonic development, tissue repair and regeneration. However, prolonged excessive mechanical stimulation can result in pathological processes, such as multi-organ fibrosis, tumorigenesis, and cancer immunotherapy resistance. Although the associations between mechanical cues and normal tissue homeostasis or diseases have been identified, the regulatory mechanisms among different mechanical cues are not yet comprehensively illustrated, and no effective therapies are currently available targeting mechanical cue-related signaling. This review systematically summarizes the characteristics and regulatory mechanisms of typical mechanical cues in normal conditions and diseases with the updated evidence. The key effectors responding to mechanical stimulations are listed, such as Piezo channels, integrins, Yes-associated protein (YAP) /transcriptional coactivator with PDZ-binding motif (TAZ), and transient receptor potential vanilloid 4 (TRPV4). We also reviewed the key signaling pathways, therapeutic targets and cutting-edge clinical applications of diseases related to mechanical cues.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Global overview of the mechanical cue-associated pathophysiological processes. The main components of biomechanical cues engage in several biological processes and diseases, such as pulmonary fibrosis, cardiac fibrosis, renal fibrosis, liver fibrosis, cancer cell behaviors, embryonic development, skin and wound repair, angiogenesis and vascular remodeling, and nervous system regeneration. ECM extracellular matrix. This figure was created using Biorender.com
Fig. 2
Fig. 2
Cellular mechanotransduction in tissues and organs. Typically, fluid shear force and hydrostatic pressure exist in blood vessels. Tensile force, hydrostatic pressure, and fluid shear force function in the urinary bladder. The fluid shear force and tensile force function in the intestine. The ECM stiffness functions in fibrotic liver. ECM extracellular matrix, EMT epithelial–to-mesenchymal transition. This figure was partly created using Biorender.com
Fig. 3
Fig. 3
Regulatory mechanisms of tensile force, hydrostatic pressure, and shear stress on different cell types. Red arrows refer to stretching force, green arrows refer to shear stress, and black arrows refer to hydrostatic pressure. ADRB β adrenoceptors, ECM extracellular matrix, ERK extracellular signal-related kinase, MCP1 monocyte chemotactic protein 1, MCPIP1 MCP1-induced protein, MMP matrix metalloprotease, mTOR mammalian target of rapamycin, NF-κB nuclear factor-κB, TGFβ transforming growth factor β, TNFα tumor necrosis factor α, VCAM-1 vascular cell adhesion molecule 1
Fig. 4
Fig. 4
Cellular mechanotransduction of ECM stiffness. The integrins convey mechanical and biochemical signals from ECM into cells and facilitate cell proliferation, differentiation, migration, and invasion. The RhoA/ROCK pathway is activated, enhancing collagen and fibronectin accumulation. Talin/FAK facilitates the assembly of F-actin to promote signal transduction. The actin connects with myosin II and conveys the mechanical cues to the nucleus. YAP/TAZ is translocated into the nucleus to promote the transcription of downstream genes, collagen synthesis, and cell differentiation. ECM extracellular matrix, ER endoplasmic reticulum, ERK extracellular signal-related kinase, FAK focal adhesion kinase, ILK integrin-linked kinase, P phosphate, TGFβ transforming growth factor β
Fig. 5
Fig. 5
Mechanisms of integrins responding to mechanical stimulation. The β integrin interacts with ILK and talin to trigger downstream cascades. ECM extracellular matrix, ILK integrin-linked kinase
Fig. 6
Fig. 6
A schematic view of the fibrotic response. The innate and adaptive immune systems are activated at the tissue repair stage. The pro-inflammatory chemokines and cytokines secreted by macrophage cells trigger the inflammatory recruitment process. TGFβ1, IL-17, and IL-18 from immune cells promote fibroblast proliferation and transformation. In addition, type I and type II immunity are cross-activated for defense and metabolic homeostasis maintenance. The adaptive immune CD4+ Th2 cell can directly activate fibroblasts by IL-4 and IL-21, independent of TGFβ1 induced fibrosis. Excessive ECM deposition leads to fibrosis ultimately. ECM extracellular matrix, EMT epithelial-to-mesenchymal transition, IL interleukin, ILC2 group 2 innate lymphoid cells, MMP matrix metalloprotease, Th2 T helper 2, TGFβ1 transforming growth factor β1, TNF tumor necrosis factor
Fig. 7
Fig. 7
Biochemical mechanisms of SARS-CoV-2-induced lung fibrosis. SARS-CoV-2 initially binds to ACE2 of the epithelial cells to activate integrins or CD98. Integrins, especially αVβ6, can assist the SARS-CoV-2 binding to ACE2, thus enhancing the ability of viral infectivity. After SARS-CoV-2 is inhaled, the virus replicates through the JNK and mTOR signaling, which facilitate the generation of NLRP3 inflammasome. Meanwhile, the type II alveolar epithelium cell injury induces pro-inflammatory recruitment of immune cells, such as macrophages. The cytokine storm will then be released and triggers the proliferation and migration of fibroblasts. Besides, the activation of TGFβ triggered by integrins, IL-1, and IL-6 promotes ECM deposition and FMT. ACE2 angiotensin-converting enzyme 2, CAMK calmodulin kinase, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, ECM extracellular matrix, FMT fibroblast-to-myofibroblast transformation, IL interleukin, TGFβ1 transforming growth factor β1
Fig. 8
Fig. 8
The mechanisms of mechanical cues-induced cancer cell behavior in tumor microenvironment. Mechanical cues induced cancer cell growth, invasion, migration and metastasis in multiple signaling pathways. Cancer-associated fibroblasts engage in ECM remodeling process, which trigger cancer cell migration and dissemination. ECF extracellular fluid, ECM extracellular matrix, EMT epithelial-to-mesenchymal transition, HDAC6 histone deacetylase 6, NHE1 Na+/H+ exchanger 1, TRPV4 transient receptor potential vanilloid 4. This figure was created using Biorender.com
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References

    1. Tschumperlin DJ. Mechanotransduction. Compr. Physiol. 2011;1:1057–1073. doi: 10.1002/cphy.c100016. - DOI - PubMed
    1. Fernandez-Sanchez M-E, Brunet T, Röper J-C, Farge E. Mechanotransduction’s impact on animal development, evolution, and tumorigenesis. Annu. Rev. Cell Dev. Biol. 2015;31:373–397. doi: 10.1146/annurev-cellbio-102314-112441. - DOI - PubMed
    1. Mascharak S, et al. Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing. Cell Stem Cell. 2022;29:315–327.e6. doi: 10.1016/j.stem.2021.12.011. - DOI - PMC - PubMed
    1. Marinval N, Chew SY. Mechanotransduction assays for neural regeneration strategies: a focus on glial cells. APL Bioeng. 2021;5:021505. doi: 10.1063/5.0037814. - DOI - PMC - PubMed
    1. Long Y, Niu Y, Liang K, Du Y. Mechanical communication in fibrosis progression. Trends Cell Biol. 2022;32:70–90. doi: 10.1016/j.tcb.2021.10.002. - DOI - PubMed

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