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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-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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE146955 | GEO | 2020/08/21

REPOSITORIES: GEO

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Project description:Chronic exposure to biological incompatibility of peritoneal dialysis solution is one of the principal causes of ultrafiltration failure (UF). However, the changes of peritoneal cell composition and molecular mechanism of peritoneal microenvironment after long-term PD are unclear. Single-cell RNA sequencing was performed to profile cell composition and transcriptome characteristics in effluent obtained from patients undergoing PD with short vintage (SV), long vintage without ultrafiltration failure (LV_NOT_UF), and long vintage with ultrafiltration failure (LV_UF). A total of 6 SV patients, 6 LV_NOT_UF patients, and 4 LV_UF patients were enrolled. The median PD duration of the three groups were 5 months (range:1.0–6.0 months), 137 months (range: 92–189 months) and 132 months (range: 120–161 months), with no significant differences in age (38.3 ± 21.5 years, 45.7 ± 10.6 years and 41.0 ± 16.7 years, P>0.05) and gender (male%: 33.3%, 50.0% and 25.0%, P>0.05). scRNA-seq data annotated 8 main cell types including epithelial-like mesothelial cells (E-MCs), mesenchymal-like mesothelial cells (M-MCs), fibroblast, plasma B cells, conventional dendritic cells, plasmacytoid dendritic cells, natural killer T cells, and myeloid cells. LV_UF patients showed higher proportion of E-MCs, which exhibited activated autophagy and had properties of both anti-inflammatory and pro-inflammatory, and neutrophil- and autophagy-related DEGs of E-MCs were upregulated in the LV_UF group. In contrast, the M-MCs and the AQP1 expression in the peritoneal mesenchyme were reduced in the LV_UF group compared to the other groups. The neutrophils in PD effluent were elevated in the LV_UF group, while the M2-like MRC1-macrophages gradually decreased from the SV, LV_NOT_UF to LV_UF group. Compared with the LV_NOT_UF group, the upregulated DEGs of monocytes/macrophages in the LV_UF group not only involved in pro-inflammatory response, but also promoted EMT progress. Additionally, neutrophils and monocytes/macrophages both interacted with MCs. Our study uncovers peritoneal different individual cell populations and cellular functions in different stages of PD which indicates the dynamic changes of microenvironments of peritoneal membrane. These findings provide new insights into the novel roles of mesothelial cells and inflammatory cells in UF.

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

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