Role of the actin cytoskeleton in tuning cellular responses to external mechanical stress
Mechanical forces are essential for tissue homeostasis. In adherent cells, cell-matrix adhesions connect the extracellular matrix (ECM) with the cytoskeleton and transmit forces in both directions. Integrin receptors and signaling molecules in cell-matrix adhesions transduce mechanical into chemical signals, thereby regulating many cellular processes. This review focuses on how cellular mechanotransduction is tuned by actin-generated cytoskeletal tension that balances external with internal mechanical forces. We point out that the cytoskeleton rapidly responds to external forces by RhoA-dependent actin assembly and contraction. This in turn induces remodeling of cell-matrix adhesions and changes in cell shape and orientation. As a consequence, a cell constantly modulates its response to new bouts of external mechanical stimulation. Changes in actin dynamics are monitored by MAL/MKL-1/MRTF-A, a co-activator of serum response factor. Recent evidence suggests that MAL is also involved in coupling mechanically induced changes in the actin cytoskeleton to gene expression. Compared with other, more rapid and transient signals evoked at the cell surface, this parallel mechanotransduction pathway is more sustained and provides spatial and temporal specificity to the response. We describe examples of genes that are regulated by mechanical stress in a manner depending on actin dynamics, among them the ECM protein, tenascin-C.
Available from: Gerd Bobe
- "Decreased IL-6 in oaTSB may have reflected better mechanical homeostasis (Asparuhova, Gelman & Chiquet, 2009; Chan et al., 2011; Gardner et al., 2012) in the cells in oaTSB: the majority of cells in oaTSB were uniformly positive for ASM, while 10–50% of nTSB cells were ASM positive. Synoviocytes increase expression of intracellular ASM in response to TGFβ-1 (Xu et al., 2012). "
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ABSTRACT: Meniscal tears are a common cause of stifle lameness in dogs. Use of autologous synoviocytes from the affected stifle is an attractive cell source for tissue engineering replacement fibrocartilage. However, the diseased state of these cells may impede in vitro fibrocartilage formation. Synoviocytes from 12 osteoarthritic ("oaTSB") and 6 normal joints ("nTSB") were cultured as tensioned bioscaffolds and compared for their ability to synthesize fibrocartilage sheets. Gene expression of collagens type I and II were higher and expression of interleukin-6 was lower in oaTSB versus nTSB. Compared with nTSB, oaTSB had more glycosaminoglycan and alpha smooth muscle staining and less collagen I and II staining on histologic analysis, whereas collagen and glycosaminoglycan quantities were similar. In conclusion, osteoarthritic joint-origin synoviocytes can produce extracellular matrix components of meniscal fibrocartilage at similar levels to normal joint-origin synoviocytes, which makes them a potential cell source for canine meniscal tissue engineering.
Available from: Kyoko Imanaka-Yoshida
- "Mechanical inputs can be also detected by mechanosensing apparatus of the focal adhesion complex and transduced to the cytoskeleton (Wang et al., 2009). Chiquet and coworkers have shown a mechanism by which a mechano-signal is transduced at the linkage between the ECM and cytoskeleton, which controls TNC transcription mediated by megakaryoblastic leukemia 1 (MAL or MKL1)/myocardin-related transcription factor A (MRTFA) (Chiquet et al., 2007, 2009; Asparuhova et al., 2009, 2011; Brosig et al., 2010). The cycle stretch of fibroblasts up-regulates TNC transcription, independent of de novo protein synthesis, paracrine factors such as TGFβ, and mitogen-activated protein kinases (MAPKs), but depends on actomyosin contractility controlled by the RhoA/ROCK pathway (Sarasa-Renedo et al., 2006) (Figure 1). "
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ABSTRACT: Living tissue is composed of cells and extracellular matrix (ECM). In the heart and blood vessels, which are constantly subjected to mechanical stress, ECM molecules form well-developed fibrous frameworks to maintain tissue structure. ECM is also important for biological signaling, which influences various cellular functions in embryonic development, and physiological/pathological responses to extrinsic stimuli. Among ECM molecules, increased attention has been focused on matricellular proteins. Matricellular proteins are a growing group of non-structural ECM proteins highly up-regulated at active tissue remodeling, serving as biological mediators. Tenascin-C (TNC) is a typical matricellular protein, which is highly expressed during embryonic development, wound healing, inflammation, and cancer invasion. The expression is tightly regulated, dependent on the microenvironment, including various growth factors, cytokines, and mechanical stress. In the heart, TNC appears in a spatiotemporal-restricted manner during early stages of development, sparsely detected in normal adults, but transiently re-expressed at restricted sites associated with tissue injury and inflammation. Similarly, in the vascular system, TNC is strongly up-regulated during embryonic development and under pathological conditions with an increase in hemodynamic stress. Despite its intriguing expression pattern, cardiovascular system develops normally in TNC knockout mice. However, deletion of TNC causes acute aortic dissection (AAD) under strong mechanical and humoral stress. Accumulating reports suggest that TNC may modulate the inflammatory response and contribute to elasticity of the tissue, so that it may protect cardiovascular tissue from destructive stress responses. TNC may be a key molecule to control cellular activity during development, adaptation, or pathological tissue remodeling.
Available from: Richard L Goodwin
- "This opposing trend is the same in the in vivo cases (i.e. if CTGF transcripts are upregulated, then KLF2, TGFβ123, and RhoA transcripts are downregulated). While RhoA/actin dynamics are necessary for CTGF and tenascin C induction (Asparuhova et al., 2009), they are also necessary for other cell processes such as cytoskeletal actin organization. Possibly, at this early stage in development, fibrous ECM proteins, while they are characteristically more organized, are not the primary cellular output in response to external mechanical stimuli. "
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ABSTRACT: One percent of infants are born with congenital heart disease (CHD), which commonly involves outflow tract (OFT) defects. These infants often require complex surgeries, which are associated with long term adverse remodeling effects, and receive replacement valves with limited strength, biocompatibility, and growth capability. To address these problematic issues, researchers have carried out investigations in valve development and valve mechanics. A longstanding hypothesis is that flow-induced forces regulate fibrous valve development, however, the specific mechanisms behind this mechanotransduction remain unclear. The purpose of this study was to implement an in vitro system of outflow tract development to test the response of embryonic OFT tissues to fluid flow. A dynamic, three-dimensional bioreactor system was used to culture embryonic OFT tissue under different levels of flow as well as the absence of flow. In the absence of flow, OFT tissues took on a more primitive phenotype that is characteristic of early OFT cushion development where widely dispersed mesenchymal cells are surrounded by a sparse, disorganized extracellular matrix (ECM). Whereas OFT tissues subjected to physiologically matched flow formed compact mounds of cells, initated, fibrous ECM development, while prolonged supraphysiological flow resulted in abnormal tissue remodeling. This study indicates that both the timing and magnitude of flow alter cellular processes that determine if OFT precursor tissue undergoes normal or pathological development. Specifically, these experiments showed that flow-generated forces regulate the deposition and localization of fibrous ECM proteins, indicating that mechanosensitive signaling pathways are capable of driving pathological OFT development if flows are not ideal.
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