Conformational coupling of integrin and Thy-1 regulates Fyn priming and fibroblast mechanotransduction

Fiore, Vincent F.; Strane, Patrick W.; Bryksin, Anton V.; White, Eric S.; Hagood, James S.; Barker, Thomas H.

doi:10.1085/jgp.1465oia57

Cited by 9 publications

(16 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, several studies found these subdomains to be relevant for mechanosensing and force-dependent structural rearrangements. While talin is involved in integrin activation, it was demonstrated that also an integrin inhibitor, Thy-1, modulates mechanosensing (see Figure 3E) (136). Therefore, mechanosensing by integrins appears to rely on the proper balance between ligand binding and unbinding.…”

Section: Yap/tazmentioning

confidence: 95%

Cell Adhesion by Integrins

Bachmann

Kukkurainen

Hytönen

et al. 2019

Physiological Reviews

283

223

View full text Add to dashboard Cite

Integrins are heterodimeric cell surface receptors ensuring the mechanical connection between cells and the extracellular matrix. In addition to the anchorage of cells to the extracellular matrix, these receptors have critical functions in intracellular signaling, but are also taking center stage in many physiological and pathological conditions. In this review, we provide some historical, structural, and physiological notes so that the diverse functions of these receptors can be appreciated and put into the context of the emerging field of mechanobiology. We propose that the exciting journey of the exploration of these receptors will continue for at least another new generation of researchers.

show abstract

Section: Yap/tazmentioning

confidence: 95%

Cell Adhesion by Integrins

Bachmann

Kukkurainen

Hytönen

et al. 2019

Physiological Reviews

283

223

View full text Add to dashboard Cite

show abstract

“…Our work examines integrin expression and activation for the first time in the murine Myh11 lineage model of pericytes. Integrins are known to be important in mediating fibroblast differentiation into myofibroblast phenotypes [24,37,51,60], so we posited that they might play a role in the pericyte-to-myofibroblast transition. Our findings show a pronounced increase in pericyte αv and α6 protein expression.…”

Section: Discussionmentioning

confidence: 99%

“…These data further suggest additional regulatory mechanisms are at play that contribute to αvβ3 activation in the pericyte population, including known inside-out mechanisms of integrin activation due to exogenous agonists that are known to be present in the provisional wound repair environment, such as thrombin and others [53,63]. We might also speculate, based on our previous work, that contractile (αSMA+) pericytes engage a known integrin switch driven through a mechanically sensitive conformational change within fibronectin’s integrin binding domain that drives a strong preference for fibronectin-αvβ3 engagement [24,25,51]. In total, these data strongly suggest that there is a mechanically responsive/active, provisional matrix-engaged pericyte population during lung injury repair.…”

Section: Discussionmentioning

confidence: 99%

“…Specific integrin and ligand combinations can potentiate a range of cellular behaviors ranging from differentiation to apoptosis to extravasation. Fibroblast signaling through the αvb3 integrin is thought to be at equilibrium with signaling through α5β1, and when this balance is disrupted in disease (known as an 'integrin switch'), greater αvb3 integrin signaling drives disease phenotypes [24][25][26]. It is thought that this shift towards pro-myofibroblastic αvb3 signaling is derived from the increase in Arginine, Glycine, and Aspartate (RGD) ligand found in the fibronectin-rich provisional matrix in early stages of tissue remodeling [25,[27][28][29][30][31] Integrins are no less important in mediating the responses of pericytes to their biochemical and biomechanical environments.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Extracellular Matrix Remodeling Associated with Bleomycin-Induced Lung Injury Supports Pericyte-To-Myofibroblast Transition

Hannan

Miller

Hung

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Of the many origins of pulmonary myofibroblasts, microvascular pericytes are a known source. Prior literature has established the ability of pericytes to transition into myofibroblasts, but provide limited insight into molecular cues that drive this process during lung injury repair and fibrosis. Fibronectin and RGD-binding integrins have long been considered pro-fibrotic factors in myofibroblast biology, and here we test the hypothesis that these known myofibroblast cues coordinate pericyte-to-myofibroblast transitions. Specifically, we hypothesized that αvβ3 integrin engagement on fibronectin induces pericyte transition into myofibroblastic phenotypes in the murine bleomycin lung injury model. Myosin Heavy Chain 11 (Myh11)-CreERT2 lineage tracing in transgenic mice allows identification of cells of pericyte origin and provides a robust tool for isolating pericytes from tissues for further evaluation. We used this murine model to track and characterize pericyte behaviors during tissue repair. The majority of Myh11 lineage-positive cells are positive for the pericyte surface markers, PDGFRβ (55%) and CD146 (69%), and display typical pericyte morphology with spatial apposition to microvascular networks. After intratracheal bleomycin treatment of mice, Myh11 lineage-positive cells showed significantly increased contractile and secretory markers, as well as αv integrin expression. According to RNASeq measurements, many disease and tissue-remodeling genesets were upregulated in Myh11 lineage-positive cells in response to bleomycin-induced lung injury. In vitro, blocking αvβ3 binding through cyclo-RGDfK prevented expression of the myofibroblastic marker αSMA relative to controls. In response to RGD-containing provisional matrix proteins present in lung injury, pericytes may alter their integrin profile. This altered matrix-integrin axis contributes to pericyte-to-myofibroblastic transition and represents a possible therapeutic target for limiting the myofibroblastic burden in lung fibrosis.HighlightsPericyte lineage model enables study of transdifferentiating pericytesHigh dimensional flow cytometry used to characterize pulmonary stromal cellsPulmonary pericytes express matrix-remodeling genes and proteins in lung injuryMyofibroblasts derived from pericytes have active αvβ3 integrinIn vitro assay reveals necessity of RGD for pericyte transdifferentiation

show abstract

“…The migratory and proliferative fibroblasts organizing in distinct clusters is called fibroblastic foci and this depicts the typical phenotype of lung fibrosis featured by accumulation of exaggerated amounts of ECM that forms a stiff milieu (Liu et al 2010;Pardo and Selman 2016;Zhou et al 2013) where fibroblasts itself can sense the change of mechanical properties (Chen HP 2016;Coyer et al 2012;Hinz 2012). Indeed, accumulating evidence suggests that fibrotic extracellular matrix provide a feedforward mechanism that amplifies lung fibrosis (Hinz 2012;Rahaman et al 2014;Wipff et al 2007;Fiore et al 2015;Tschumperlin 2013). The transcriptional cofactors YAP and TAZ are robust mechanosensors which translocate from the cytoplasm to the nucleus depending on matrix stiffness and number of studies show that YAP/ TAZ are crucial for fibroblasts activation in responses to mechanical stress (matrix stiffness) which contributes to fibrotic features (Liu et al 2015;Noguchi S 2017;Piersma and Bank 2017;Noguchi et al 2018).…”

Section: Fibroblastmentioning

confidence: 99%

Alveolar cells under mechanical stressed niche: critical contributors to pulmonary fibrosis

Yang

Pan

Wang

et al. 2020

Mol Med

View full text Add to dashboard Cite

Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.

show abstract

Conformational coupling of integrin and Thy-1 regulates Fyn priming and fibroblast mechanotransduction

Cited by 9 publications

References 15 publications

Cell Adhesion by Integrins

Cell Adhesion by Integrins

Extracellular Matrix Remodeling Associated with Bleomycin-Induced Lung Injury Supports Pericyte-To-Myofibroblast Transition

Alveolar cells under mechanical stressed niche: critical contributors to pulmonary fibrosis

Contact Info

Product

Resources

About