Multiple roles of α-smooth muscle actin in mechanotransduction

Wang, Jiaxu; Zohar, Ron; McCulloch, Christopher A.

doi:10.1016/j.yexcr.2005.11.004

Cited by 159 publications

(128 citation statements)

References 108 publications

(126 reference statements)

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“…The role of SM α-actin in fibroblasts has received significant attention, as its expression is a hallmark for the modulation of fibroblast to myofibroblast phenotype (12,32,33). A powerful regulator of this modulation is TGF-β1, which induces SM α-actin protein and mRNA expression in both growing and quiescent fibroblasts (26).…”

Section: Discussionmentioning

confidence: 99%

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Liu

Chang

Grinnell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The most common genetic alterations for familial thoracic aortic aneurysms and dissections (TAAD) are missense mutations in vascular smooth muscle (SM) α-actin encoded by ACTA2. We focus here on ACTA2-R258C, a recurrent mutation associated with early onset of TAAD and occlusive moyamoya-like cerebrovascular disease. Recent biochemical results with SM α-actin-R258C predicted that this variant will compromise multiple actin-dependent functions in intact cells and tissues, but a model system to measure R258C-induced effects was lacking. We describe the development of an approach to interrogate functional consequences of actin mutations in affected patient-derived cells. Primary dermal fibroblasts from R258C patients exhibited increased proliferative capacity compared with controls, consistent with inhibition of growth suppression attributed to SM α-actin. Telomeraseimmortalized lines of control and R258C human dermal fibroblasts were established and SM α-actin expression induced with adenovirus encoding myocardin-related transcription factor A, a potent coactivator of ACTA2. Two-dimensional Western blotting confirmed induction of both wild-type and mutant SM α-actin in heterozygous ACTA2-R258C cells. Expression of mutant SM α-actin in heterozygous ACTA2-R258C fibroblasts abrogated the significant effects of SM α-actin induction on formation of stress fibers and focal adhesions, filamentous to soluble actin ratio, matrix contraction, and cell migration. These results demonstrate that R258C dominantly disrupts cytoskeletal functions attributed to SM α-actin in fibroblasts and are consistent with deficiencies in multiple cytoskeletal functions. Thus, cellular defects due to this ACTA2 mutation in both aortic smooth muscle cells and adventitial fibroblasts may contribute to development of TAAD and proliferative occlusive vascular disease.thoracic aortic aneurysms | ACTA2 mutation | vascular disease | cell migration | human fibroblasts

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Section: Discussionmentioning

confidence: 99%

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Liu

Chang

Grinnell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The expression of α-SMA, which is apparent in HuF during long term cell culture, is considered to be a phenotypic marker for myofibroblasts (Wang et al 2006). The term 'myofibroblast' was proposed many years ago for fibroblastic cells located within granulation tissue and exhibiting an important cytoplasmic microfilamentous apparatus (Gabbiani 2003).…”

Section: Discussionmentioning

confidence: 99%

“…The term 'myofibroblast' was proposed many years ago for fibroblastic cells located within granulation tissue and exhibiting an important cytoplasmic microfilamentous apparatus (Gabbiani 2003). The myofibroblasts are present in healing wounds, scars, and fibrocontractive lesions where they contribute to fibrosis (Wang et al 2006). The presence of α-SMA was not detected in mesenchymal progenitor cells isolated from the placenta, where placental membranes were removed (Zhang et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Multipotent properties of myofibroblast cells derived from human placenta

et al. 2008

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Human uterine fibroblasts (HuF) isolated from the maternal part (decidua parietalis) of a term placenta provide a useful model of in vitro cell differentiation into decidual cells (decidualization), critical for successful pregnancy. After isolation, the cells adhere to plastic and have either a small round or spindle-shaped morphology which later changes into a flattened pattern in culture. HuF robustly proliferate in culture until passage 20 and form colonies when plated at low densities. The cells express the mesenchymal cell markers fibronectin, integrin-β1, ICAM-1 (CD54), and collagen I. Flow cytometry of HuF detected the presence of CD34, a marker of hematopoietic stem cell lineage, and an absence of CD10, CD11b/Mac, CD14, CD45, and HLA type II. Furthermore, they also express the pluripotency markers SSEA-1, SSEA-4, Oct-4, Stro-1, and TRA-1−81 as detected by confocal microscopy. Treatment for 14−21 days with differentiation-inducing media led to the differentiation of HuF into osteoblasts, adipocytes, and chondrocytes. The presence of α-smooth muscle actin, calponin, and myosin light chain kinase in cultured HuF implies their similarity to myofibroblasts. Treatment of the HuF with DMSO causes reversion back into the spindle-shaped morphology and a loss of myofibroblast characteristics, suggesting a switch into a less differentiated phenotype. The unique abilities of HuF to exhibit multipotency, even with myofibroblast characteristics, and their ready availability and low maintenance requirements make them an interesting cell model for further exploration as a possible tool for regenerative medicine.

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“…1A, middle and right blots, hypoxia increased ␣-SMA and vimentin expression, whereas it decreased E-Cadherin levels in MLE 12 and A549 cells after 8 days of exposure. ␣-SMA can form filament bundles, contributing to contractile activity and spreading of fibroblasts (47). We assessed the formation of ␣-SMA fibers using confocal immunofluorescence microscopy, and as shown in Fig.…”

Section: Hypoxia Induces Emt In Transformed and Primary Aecmentioning

confidence: 99%

Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1

Zhou

Dada²,

Wu³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

193

170

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-Patients with acute lung injury develop hypoxia, which may lead to lung dysfunction and aberrant tissue repair. Recent studies have suggested that epithelial-mesenchymal transition (EMT) contributes to pulmonary fibrosis. We sought to determine whether hypoxia induces EMT in alveolar epithelial cells (AEC). We found that hypoxia induced the expression of ␣-smooth muscle actin (␣-SMA) and vimentin and decreased the expression of E-cadherin in transformed and primary human, rat, and mouse AEC, suggesting that hypoxia induces EMT in AEC. Both severe hypoxia and moderate hypoxia induced EMT. The reactive oxygen species (ROS) scavenger Euk-134 prevented hypoxia-induced EMT. Moreover, hypoxia-induced expression of ␣-SMA and vimentin was prevented in mitochondria-deficient 0 cells, which are incapable of ROS production during hypoxia. CoCl2 and dimethyloxaloylglycine, two compounds that stabilize hypoxiainducible factor (HIF)-␣ under normoxia, failed to induce ␣-SMA expression in AEC. Furthermore, overexpression of constitutively active HIF-1␣ did not induce ␣-SMA. However, loss of HIF-1␣ or HIF-2␣ abolished induction of ␣-SMA mRNA during hypoxia. Hypoxia increased the levels of transforming growth factor (TGF)-␤1, and preincubation of AEC with SB431542, an inhibitor of the TGF-␤1 type I receptor kinase, prevented the hypoxia-induced EMT, suggesting that the process was TGF-␤1 dependent. Furthermore, both ROS and HIF-␣ were necessary for hypoxia-induced TGF-␤1 upregulation. Accordingly, we have provided evidence that hypoxia induces EMT of AEC through mitochondrial ROS, HIF, and endogenous TGF-␤1 signaling. alveolar epithelial cells; pulmonary fibrosis; transforming growth factor-␤1 EPITHELIAL-MESENCHYMAL TRANSITION (EMT) is a cellular process during which epithelial cells acquire mesenchymal properties while losing cell-cell interactions and apicobasal polarity (33,44). EMT is characterized by changes in cell morphology and acquisition of mesenchymal markers such as ␣-smooth muscle actin (␣-SMA) and vimentin as well as loss of epithelial makers, including E-cadherin (53). Transforming growth factor (TGF)-␤1 is considered to be the prototypical cytokine for the induction of EMT (53). Active TGF-␤1 binds to the transmembrane serine-threonine kinase receptor II and receptor I and activates Smad-mediated transcription of target genes, including ␣-SMA and vimentin, which leads to EMT (33,53,54). TGF-␤1 is reported to induce EMT in renal proximal tubular epithelial cells, lens epithelial cells, and, most recently, alveolar epithelial cells (AEC) (19,23,40,48,55).AEC perform many tasks necessary for normal alveolus functioning, including surfactant protein production and fluid and ion transport (17, 57). Recent evidence suggests that AEC may undergo EMT, contributing to the pathogenesis of pulmonary fibrosis (26,49).AEC are exposed to hypoxia in human lung diseases, including acute lung injury and pulmonary fibrosis (20, 41, 57). It has been described that during hypoxia, mitochondria increase the production of reactive oxy...

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Multiple roles of α-smooth muscle actin in mechanotransduction

Cited by 159 publications

References 108 publications

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Multipotent properties of myofibroblast cells derived from human placenta

Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1

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