Caveolin1 and YAP drive mechanically induced mesothelial to mesenchymal transition and fibrosis

Abstract

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-β1-dependent signaling and yesassociated 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 were largely dependent on endogenous TGF-β1 signaling. Importantly, TGF-β1 blockade blunts the transcriptional upregulation of these 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-β1 inhibition. Conversely, CAV1 depletion enhanced both TGF-β1 and TGFBRI expression, whereas its reexpression blunted mechanical stretching-induced MMT. CAV1 genetic deficiency exacerbated MMT and adhesion formation in an experimental murine 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-β1-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.

Mechanisms of Peritoneal Fibrosis: Focus on Immune Cells–Peritoneal Stroma Interactions

“…Moreover, the coexpression of bona fide MMT markers such as aSMA and fsp1 absent in epithelial-like MCs with mesothelial/ epithelial markers has been demonstrated in vivo both in peritoneum after PD and in peritoneal adhesion (75,77,78,82).…”

“…It has been recently demonstrated that exposure of MCs to linear cyclic stretch in vitro leads to several cellular modifications corresponding to bona fide MMT induction. The experimental data are summarized in a model where a cross-talk between biomechanical and biochemical signals result in the induction of MMT ( 77 ).…”

TGFβ signaling networks in ovarian cancer progression and plasticity

“…A variation on the classic cancer EMT of tumor cells is mesothelial-mesenchymal transition (MMT) of the PMCs, wherein PMCs transition into mesenchymal cells (MCs), acquiring migratory and fibroblast like phenotypes [ 183 ], much like cancer associated fibroblast (CAFs). MMT has been extensively investigated in other tissues during fibrosis of the peritoneal membrane and in cancers such as mesothelioma [ 184 ]. The “activation”/MMT process could thus play an active role in facilitating metastasis as TGFβ is also produced by the peritoneum itself [ 185 ].…”

Decellularized Disc Hydrogels for hBMSCs tissue-specific differentiation and tissue regeneration

“…TGF-β1, identified in DAF-G, was reported to mediate YAP1 activation via PI3K/Akt pathway, resulting in myofibroblasts phenotype [ 74 , 75 ]. YAP1 target gene subsets were also largely dependent on endogenous TGF-β1 signaling [ 76 ]. Therefore, high expression of TGF-β1 in DAF-G may also contribute to observed YAP1 activation in DAF-G 2D.…”