Control of cellular responses to mechanical cues through YAP/TAZ regulation

Abstract

To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression stress. These forces can be generated both internally and externally in response to physical properties, like substrate stiffness, cell contractility, and forces generated by adjacent cells. Mechanical cues have important roles in cell fate decisions regarding proliferation, survival, and differentiation as well as the processes of tissue regeneration and wound repair. Aberrant remodeling of the extracellular space and/or defects in properly responding to mechanical cues likely contributes to various disease states, such as fibrosis, muscle diseases, and cancer. Mechanotransduction involves the sensing and translation of mechanical forces into biochemical signals, like activation of specific genes and signaling cascades that enable cells to adapt to their physical environment. The signaling pathways involved in mechanical signaling are highly complex, but numerous studies have highlighted a central role for the Hippo pathway and other signaling networks in regulating the YAP and TAZ (YAP/TAZ) proteins to mediate the effects of mechanical stimuli on cellular behavior. How mechanical cues control YAP/TAZ has been poorly understood. However, rapid progress in the last few years is beginning to reveal a surprisingly diverse set of pathways for controlling YAP/TAZ. In this review, we will focus on how mechanical perturbations are sensed through changes in the actin cytoskeleton and mechanosensors at focal adhesions, adherens junctions, and the nuclear envelope to regulate YAP/TAZ.

Xanthan gum and locust bean gum substrate improves bovine embryo development

“…We did, however, examine the mechano‐sensing mechanism induced in response to growth on the XG‐LBG substrate. In general, stiffness is detected by focal adhesion or contraction of the cells, and the cytoskeleton plays a major role in signal transduction (Dasgupta & McCollum, 2019). In addition, increased expression of the genes associated with the focal adhesion pathway is one of the most important distinguishing features between in vivo‐developed blastocysts and in vitro ‐ developed blastocysts in cows (Noguchi, et al., 2020).…”

“…In the present study, XG‐LBG gel increased F‐actin expression levels and improved localization of E‐cadherin. These cytoskeletal elements regulate nuclear YAP localization through complex feedback loops including mechanical connections between the cytoskeleton and nucleus, nuclear flattening, and actin‐associated inactivation of LATS induces the nuclear import of YAP (Dasgupta & McCollum, 2019; Elosegui‐Artola et al., 2017). This study showed that culturing embryos on XG‐LBG increased nuclear‐expression levels of YAP and increased downstream CTGF protein levels.…”

“…The ATP content in embryos (1 day after incubation) was also examined. Mechanosense stimulation based on the stiffness of the culture substrate is transduced through the cytoskeleton, where Hippo‐YAP signalling plays a crucial role (Seo & Kim, 2018; Smith et al, 2018), and is followed by increased CTGF expression and cellular proliferation (Dasgupta & McCollum, 2019). To determine the underlying molecular mechanism of the effects of XG‐LBG gel, embryos were cultured for 1 day on a gel or plastic substrate, and the expression levels of F‐actin, E‐cadherin and CTGF were evaluated, and the nuclear localization of YAP was confirmed.…”

“…These signals are transduced to several upstream Hippo pathway kinases that phosphorylate large tumour suppressor (LATS)1/2. The phosphorylated LATS1/2 in turn phosphorylates Yes‐associated protein (YAP), inducing its translocation to the nuclear (Dasgupta & McCollum, 2019), which is reported to be a major event in follicle development (Chang et al, 2015). In this study, we examined the effects of using a soft substrate made of XG‐LBG on bovine embryo development and proceeded to determine the expression levels of cytoskeleton proteins, YAP and connective tissue growth factor (CTGF) in an effort to uncover the underlying molecular mechanism responsible for the soft matrix‐derived effects on embryonic development.…”

Interaktion zwischen Muskel und Knochen – ein Wechselspiel zwischen Physik und Biologie

“…Der Verlust der PTH1R-Expression in osteogenen Zellen hemmt die Mechanosensitivität, und eine neuere klinische Studie kommt zu dem Ergebnis, dass die Kombination aus mechanischer Stimulation und Teriparatid mit Blick auf den Gewinn an Knochenmasse wesentlich effektiver ist als Teriparatid alleine [47,48]. Aber auch für die "neueren" starken Modulatoren der osteogenen Differenzierung in Entwicklung und Regeneration wurde in jüngster Zeit von unserer Arbeitsgruppe und anderen nachgewiesen, dass sie durch mechanische Reize moduliert werden können [49][50][51][52][53]. Insofern ist alleine die Übertragung physikalischer Kräfte durch Muskelaktivität ein plausibler und gut belegter Mechanismus der Interaktion zwischen Muskel und Knochen.…”