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Effect of mechanically responsive miRNAs on biomechanical properties of airway smooth muscle cells and their related drug development studies [miRNA-Seq]

ABSTRACT: In the short two decades since microRNAs (miRNAs) were discovered, scientists have focused more attention on the biological field of miRNAs. A deeper understanding of the role of miRNAs in development and disease has made miRNAs a powerful tool and target for new therapeutic approaches. However, whether miRNAs are involved in the response of ASMCs to high stretch and high matrix stiffness and their underlying mechanisms remain unclear, especially the relationship between the expression of miRNAs and the biomechanical behavior of ASMCs remains unclear. In this study, we combined bioinformatics and cell mechanics approaches to screen stretch-sensitive and matrix stiffness-sensitive miRNAs and investigate their effects on the biomechanical behaviors of ASMCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206433 | GEO | 2023/03/01

REPOSITORIES: GEO

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Project description:Despite their emerging relevance to fully understand disease pathogenesis, we have as yet a poor understanding as to how biomechanical signals are integrated with specific biochemical pathways to determine cell behaviour. Mesothelial-to-mesenchymal transition (MMT) markers colocalized with TGF-beta1-dependent signalling and yes-associated protein (YAP) activation across biopsies from different pathologies exhibiting peritoneal fibrosis, supporting mechanotransduction as a central driving component of these class of fibrotic lesions and its crosstalk with specific signaling pathways. Transcriptome and proteome profiling of the response of mesothelial cells (MCs) to linear cyclic stretch revealed molecular changes compatible with bona fide MMT, which (i) overlapped with established YAP target gene subsets, and (ii) were largely dependent on endogenous TGF-beta1 signaling. Importantly, TGF-beta1 blockade blunts the transcriptional upregulation of the se gene signatures, but not the mechanical activation and nuclear translocation of YAP per se. We studied the role therein of caveolin-1 (Cav1), a plasma membrane mechanotransducer. Exposure of Cav1-deficient MCs to cyclic stretch led to a robust upregulation of MMT-related gene programs, which was blunted upon TGF-beta1 inhibition. Conversely, Cav1 depletion enhanced both TGF-beta1 and TGFBRI expression. Cav1 genetic deficiency exacerbated MMT and PA fibrosis in an experimental model of peritoneal ischaemic buttons. Taken together, these results support that Cav1-YAP/TAZ fine-tune the fibrotic response through the modulation of MMT, onto which TGF-beta1-dependent signaling coordinately converges. Our findings reveal a cooperation between biomechanical and biochemical signals in the triggering of MMT, representing a novel potential opportunity to intervene mechanically-induced disorders coursing with peritoneal fibrosis, such as post-surgical adhesions. This SuperSeries is composed of the SubSeries listed below.

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Effect of mechanically responsive miRNAs on biomechanical properties of airway smooth muscle cells and their related drug development studies [miRNA-Seq]

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