cyclic stretch
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Benjamin W. Scandling ◽  
Jia Gou ◽  
Jessica Thomas ◽  
Jacqueline Xuan ◽  
Chuan Xue ◽  

Many cells in the body experience cyclic mechanical loading, which can impact cellular processes and morphology. In vitro studies often report that cells reorient in response to cyclic stretch of their substrate. To explore cellular mechanisms involved in this reorientation, a computational model was developed by utilizing the previous computational models of the actin-myosin-integrin motor-clutch system developed by others. The computational model predicts that under most conditions, actin bundles align perpendicular to the direction of applied cyclic stretch, but under specific conditions, such as low substrate stiffness, actin bundles align parallel to the direction of stretch. The model also predicts that stretch frequency impacts the rate of reorientation, and that proper myosin function is critical in the reorientation response. These computational predictions are consistent with reports from the literature and new experimental results presented here. The model suggests that the impact of different stretching conditions (stretch type, amplitude, frequency, substrate stiffness, etc.) on the direction of cell alignment can largely be understood by considering their impact on cell-substrate detachment events, specifically whether detachment occurs during stretching or relaxing of the substrate.

2021 ◽  
Zengyi Wang ◽  
Xida Liang ◽  
Shen Wu ◽  
Jingxue Zhang ◽  
Qian Liu ◽  

Abstract Background: Strong evidence of the correlation between age-related macular degeneration (AMD) and vitreomacular interface abnormality (VMIA). Meanwhile, as a crucial mechanism of retinal pigment epithelial (RPE) cells’ homeostasis, autophagy induction by cyclic stretch appears to be particularly significant.Methods: Cultured ARPE-19 cells were subjected to cyclic stretch (20% elongation, 1HZ) for 1h, 2h, 6h, 12h,24h and 48h by FX-5000 Tension System. Then, we observed the expression levels of LC3I, LC3II, Beclin-1, SQSTM1/p62, LAMP-1, mTOR and phosphorylated mTOR(pmTOR), AMPK and pAMPK, NADPH oxidase 4 (NOX4), and vascular endothelial growth factor (VEGF) in RPE cells under stretch by western blot and immunofluorescence.Results: We found autophagic proteins mostly induced by cyclic stretch in a time-dependent fashion via mTOR suppression and AMPK activation, except for SQSTM1/p62. 3-Methyladenine(3-MA), an inhibitor for autophagy, could reduce the up-regulation of autophagy due to cyclic stretch, leading to higher level of VEGF release after 24h cyclic stretch. Rapamycin could narrow the increase degree of VEGF and NOX4 by cyclic stretch by raise autophagic level in RPE cells.Conclusion: Stretch might induce autophagy in RPE cells by mTOR or AMPK pathway. Autophagy might play the protective function for RPE cells away from mechanical stress derived from VMIA-related AMD.

2021 ◽  
pp. 2101470
Inés López-Alonso ◽  
Cecilia López-Martínez ◽  
Paula Martín-Vicente ◽  
Laura Amado-Rodríguez ◽  
Adrián González-López ◽  

Mechanical stretch of cancer cells can alter their invasiveness. During mechanical ventilation, lungs may be exposed to an increased amount of stretch, but the consequences on lung tumors have not been explored. To characterize the influence of mechanical ventilation on the behavior of lung tumors, invasiveness assays and transcriptomic analyses were performed in cancer cell lines cultured in static conditions or under cyclic stretch. Mice harbouring lung melanoma implants were submitted to mechanical ventilation and metastatic spread was assessed. Additional in vivo experiments were performed to determine the mechano-dependent specificity of the response. Incidence of metastases was studied in a cohort of lung cancer patients that received mechanical ventilation compared with a matched group of non-ventilated patients. Stretch increases invasiveness in melanoma B16F10luc2 and lung adenocarcinoma A549 cells. We identified a mechanosensitive upregulation of pathways involved in cholesterol processing in vitro, leading to an increase in PCSK9 and LDLR expression, a decrease in intracellular cholesterol and preservation of cell stiffness. A course of mechanical ventilation in mice harboring melanoma implants increased brain and kidney metastases two weeks later. Blockade of PCSK9 using a monoclonal antibody increased cell cholesterol and stiffness and decreased cell invasiveness in vitro and metastasis in vivo. In patients, mechanical ventilation increased PCSK9 abundance in lung tumors and the incidence of metastasis, thus decreasing survival. Our results suggest that mechanical stretch promote invasiveness of cancer cells, which may have clinically relevant consequences. Pharmacological manipulation of cholesterol endocytosis could be a novel therapeutic target in this setting.

Sergio Aguilera Suarez ◽  
Nadia Chandra Sekar ◽  
Ngan Nguyen ◽  
Austin Lai ◽  
Peter Thurgood ◽  

Here, we describe a motorized cam-driven system for the cyclic stretch of aortic endothelial cells. Our modular design allows for generating customized spatiotemporal stretch profiles by varying the profile and size of 3D printed cam and follower elements. The system is controllable, compact, inexpensive, and amenable for parallelization and long-term experiments. Experiments using human aortic endothelial cells show significant changes in the cytoskeletal structure and morphology of cells following exposure to 5 and 10% cyclic stretch over 9 and 16 h. The system provides upportunities for exploring the complex molecular and cellular processes governing the response of mechanosensitive cells under cyclic stretch.

Rashika Joshi ◽  
Matthew R. Batie ◽  
Qiang Fan ◽  
Brian Michael Varisco

Most lung development occurs in the context of cyclic stretch. Alteration of the mechanical microenvironment is a common feature of many pulmonary diseases with congenital diaphragmatic hernia (CDH) and fetal tracheal occlusion (FETO, a therapy for CDH) being extreme examples with changes in lung structure, cell differentiation and function. To address limitations in cell culture and in vivo mechanotransductive models we developed two mouse lung organoid (mLO) mechanotransductive models using postnatal day 5 (PND5) mouse lung CD326-positive cells and fibroblasts subjected to increased, decreased, and cyclic strain. In the first model, mLOs were exposed to forskolin (FSK) and/or disrupted (DIS) and evaluated at 20 hours. mLO cross-sectional area changed by +59%, +24% and -68% in FSK, control, and DIS mLOs respectively. FSK-treated organoids had twice as many proliferating cells as other organoids. In the second model, 20 hours of 10.25% biaxial cyclic strain increased the mRNAs of lung mesenchymal cell lineages compared to static stretch and no stretch. Cyclic stretch increased TGF-β and integrin-mediated signaling with upstream analysis indicating roles for histone deacetylases, microRNAs, and long non-coding RNAs. Cyclic stretch mLOs increased αSMA- and αSMA-PDGFRα-double positive cells compared to no stretch and static stretch mLOs. In this PND5 mLO mechanotransductive model, cell proliferation is increased by static stretch, and cyclic stretch induces mesenchymal gene expression changes important in postnatal lung development.

2021 ◽  
Vol 22 (23) ◽  
pp. 12928
Constança Júnior ◽  
Maria Narciso ◽  
Esther Marhuenda ◽  
Isaac Almendros ◽  
Ramon Farré ◽  

Pulmonary fibrosis (PF) is a progressive disease that disrupts the mechanical homeostasis of the lung extracellular matrix (ECM). These effects are particularly relevant in the lung context, given the dynamic nature of cyclic stretch that the ECM is continuously subjected to during breathing. This work uses an in vivo model of pulmonary fibrosis to characterize the macro- and micromechanical properties of lung ECM subjected to stretch. To that aim, we have compared the micromechanical properties of fibrotic ECM in baseline and under stretch conditions, using a novel combination of Atomic Force Microscopy (AFM) and a stretchable membrane-based chip. At the macroscale, fibrotic ECM displayed strain-hardening, with a stiffness one order of magnitude higher than its healthy counterpart. Conversely, at the microscale, we found a switch in the stretch-induced mechanical behaviour of the lung ECM from strain-hardening at physiological ECM stiffnesses to strain-softening at fibrotic ECM stiffnesses. Similarly, we observed solidification of healthy ECM versus fluidization of fibrotic ECM in response to stretch. Our results suggest that the mechanical behaviour of fibrotic ECM under stretch involves a potential built-in mechanotransduction mechanism that may slow down the progression of PF by steering resident fibroblasts away from a pro-fibrotic profile.

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3123
Brandan Walters ◽  
Paul A. Turner ◽  
Bernd Rolauffs ◽  
Melanie L. Hart ◽  
Jan P. Stegemann

Adipose-derived stem cells (ASCs) are an abundant and easily accessible multipotent stem cell source with potential application in smooth muscle regeneration strategies. In 3D collagen hydrogels, we investigated whether sustained release of growth factors (GF) PDGF-AB and TGF-β1 from GF-loaded microspheres could induce a smooth muscle cell (SMC) phenotype in ASCs, and if the addition of uniaxial cyclic stretch could enhance the differentiation level. This study demonstrated that the combination of cyclic stretch and GF release over time from loaded microspheres potentiated the differentiation of ASCs, as quantified by protein expression of early to late SMC differentiation markers (SMA, TGLN and smooth muscle MHC). The delivery of GFs via microspheres produced large ASCs with a spindle-shaped, elongated SMC-like morphology. Cyclic strain produced the largest, longest, and most spindle-shaped cells regardless of the presence or absence of growth factors or the growth factor delivery method. Protein expression and cell morphology data confirmed that the sustained release of GFs from GF-loaded microspheres can be used to promote the differentiation of ASCs into SMCs and that the addition of uniaxial cyclic stretch significantly enhances the differentiation level, as quantified by intermediate and late SMC markers and a SMC-like elongated cell morphology.

Ziyi Wang ◽  
Jiyuan Chen ◽  
Aleksandra Babicheva ◽  
Pritesh P. Jain ◽  
Marisela Rodriguez ◽  

Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca2+ and Na+ influx in multiple types of cells. Little is known about the functional role of Piezo1 in the lung vasculature and its potential pathogenic role in pulmonary arterial hypertension (PAH). Pulmonary arterial endothelial cells (PAECs) are constantly under mechanic stretch and shear stress that are sufficient to activate Piezo channels. Here we report that Piezo1 is significantly upregulated in PAECs from patients with idiopathic PAH and animals with experimental pulmonary hypertension (PH) compared to normal controls. Membrane stretch by decreasing extracellular osmotic pressure or by cyclic stretch (18% CS) increases Ca2+-dependent phosphorylation (p) of AKT and ERK, and subsequently upregulates expression of Notch ligands, Jagged1/2 (Jag1 and Jag-2), and Delta like-4 (DLL4) in PAECs. siRNA-mediated downregulation of Piezo1 significantly inhibited the stretch-mediated pAKT increase and Jag-1 upregulation, while downregulation of AKT by siRNA markedly attenuated the stretch-mediated Jag1 upregulation in human PAECs. Furthermore, the mRNA and protein expression level of Piezo1 in the isolated pulmonary artery, which mainly contains pulmonary arterial smooth muscle cells (PASMCs), from animals with severe PH was also significantly higher than that from control animals. Taken together, our study suggests that membrane stretch-mediated Ca2+ influx through Piezo1 is an important trigger for pAKT-mediated upregulation of Jag-1 in PAECs. Upregulation of the mechanosensitive channel Piezo1 and the resultant increase in the Notch ligands (Jag-1/2 and DLL4) in PAECs may play a critical pathogenic role in the development of pulmonary vascular remodeling in PAH and PH.

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