Maintenance of primary hepatocyte functions in vitro by inhibiting mechanical tension-induced YAP activation
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PROVIDER: PRJNA574958 | ENA |
REPOSITORIES: ENA
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Project description:It has been a long-standing challenge to maintain the functions of hepatocytes in vitro. In the present study, we found that mechanical tension-induced yes-associated protein (Yap) activation triggered hepatocyte dedifferentiation. Alleviation of mechanical tension by confinement of cell spreading was sufficient to inhibit hepatocyte dedifferentiation. Based on this finding, we identified a small molecular cocktail LBDXL through reiterative chemical screening that could maintain hepatocyte functions over the long term and in vivo repopulation capacity by targeting actin polymerization and actomyosin contraction.
2019-10-30 | GSE138158 | GEO
Project description:Constitutive androstane receptor (CAR) agonists, such as TCPOBOP, are known to cause robust hepatocyte proliferation and hepatomegaly in mice along with induction of drug metabolism genes, without any associated liver injury. Yes-associated protein (YAP) is a key transcription regulator that tightly controls organ size including that of liver. Ours and other previous studies suggested increased nuclear localization and activation of YAP after TCPOBOP treatment in mice and potential role of YAP in CAR-driven proliferative response. Here, we investigated a direct role of YAP in CAR-driven hepatomegaly and hepatocyte proliferation using hepatocyte-specific YAP-KO mice. AAV8-TBG-CRE vector was injected to YAP-floxed mice for achieving hepatocyte-specific YAP deletion followed by TCPOBOP treatment. YAP deletion did not alter protein expression of CAR or CAR-driven induction of drug metabolism genes (including Cyp2b10, Cyp2c55 and UGT1a1). However, YAP deletion substantially reduced TCPOBOP-induced hepatocyte proliferation. TCPOBOP-driven cell cycle activation was disrupted in YAP-KO mice due to delayed (and decreased) induction of cyclin D1 and higher expression of p21, resulting in decreased phosphorylation of retinoblastoma (Rb) protein. Further, induction of other cyclins, which are sequentially involved in progression through cell cycle (including cyclin E1, A2 and B1) and important mitotic regulators (such as aurora B kinase and polo-like kinase 1) was remarkably reduced in YAP-KO mice. Microarray analysis revealed that 26% of TCPOBOP‐responsive genes mainly related to proliferation, but not to drug metabolism, were altered by YAP deletion. YAP regulated these proliferation genes via alerting expression of cMyc and FOXM1, two critical transcriptional regulators of CAR-mediated hepatocyte proliferation. Conclusion: Our study revealed an important role of YAP signaling in CAR-driven hepatocyte proliferation; however, CAR-driven induction of drug metabolism genes was independent of YAP. We used microarrays to detail the global programme of gene expression in livers of hepatocyte-specific YAP KO mice following TCPOBOP treatment
2021-09-09 | GSE148607 | GEO
Project description:Cells integrate mechanical cues to direct fate specification to maintain tissue function and homeostasis. While disruption of these cues is known to lead to aberrant cell behavior and chronic diseases (e.g. tendinopathies), the underlying mechanisms by which mechanical signals maintain cell function is not well understood. Here, we show using a novel model of tendon de-tensioning that loss of tensile cues in vivo acutely changes nuclear morphology, positioning, and expression of catabolic gene programs. Using paired ATAC/RNAseq, we further identify that a loss of cellular tension rapidly reduces chromatin accessibility in the vicinity of Yap/Taz genomic targets while also increasing expression of genes involved in matrix catabolism. Overexpression of Yap resulted in a reduction of chromatin accessibility at these matrix catabolic genes, and their transcript levels. Concordantly, depletion of Yap/Taz elevated their expression. Finally, we demonstrate that overexpression of Yap not only prevents the induction of a broad catabolic program following a loss of cellular tension, but also preserves the underlying chromatin state from force induced alterations. Taken together, these results provide novel mechanistic details by which mechanical signals regulate tendon cell function to preserve matrix homeostasis through a Yap/Taz axis.
2022-07-14 | GSE207896 | GEO
Project description:Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP
2022-04-04 | PXD025910 | Pride
Project description:The renewing human epidermis constantly senses and adapts to a wide range of mechanical cues that are ubiquitous throughout life. The mechanisms of how mechanical forces are responded by interfollicular epidermal stem cells (IFESCs) and are transmitted directly into nucleus to modify gene expression was discovered to be mediated by transcriptional coactivators YAP. Interestingly, YAP, a critical modulator in controlling organ size by regulating both cell proliferation and apoptosis, was also found to induce self-renewal or amplification of epidermal progenitor/stem cells, and balance epidermal growth and differentiation. Because growth regulation imposed by different stimuli is achieved through distinct YAP target genes even in a single cell type. This study used chromatin immunoprecipitation (ChIP) coupled with human promoter tiling microarray analysis (ChIP-on-chip) to profile YAP at promoters genome-wide. The goal of the study was to identify the target genes occupied by YAP in IFESCs under the mechanical stretch condition.
2018-07-24 | GSE71314 | GEO
Project description:Endothelial cell (EC) attachment to the matrix and adjacent cells generates a mechanical environment that maintains a restrictive barrier against the uncontrolled influx of circulating protein and immune cells. Mechanisms that mediate the transition from restrictive to leaky endothelium, a hallmark of tissue injury exemplified by acute lung injury (ALI), remain elusive. Here, we show that FAK sensing and transmission of mechanical tension to the EC nucleus governs cell fate. In FAK-deleted EC, increased EC tension activated DNMT3a, which induced methylation of the KLF2 promoter leading to impaired synthesis of KLF2 and restrictive EC transcriptome, including S1PR1. FAK suppressed DNMT3a activity by restricting the tyrosine phosphorylation of nuclear envelope protein, emerin at Y74/Y95, and its localization in a nuclear cap. Inhibiting emerin phosphorylation or DNMT3a activity in damaged lungs enabled KLF2 transcription of S1PR1, rescuing the restrictive EC phenotype. Our works reveal a paradigm whereby FAK sensing of tension transmission to the nucleus maintains restrictive EC transcriptome and lung homeostasis.
2022-08-28 | GSE212037 | GEO
Project description:Mechanical Tension Mobilizes Lgr6+ Epidermal Stem Cells to Drive Skin Growth
| PRJNA775997 | ENA
Project description:TEAD1 emerged as an estrogen-sensitive gene that was upregulated in a HFD mouse model and in NAFLD patients. We investigated the roles of TEAD in NAFLD by treating primary human hepatocyte spheroids with two small molecule inhibitors blocking the TEAD/YAP interaction. One small molecule blocks the interaction by inhibiting TEAD autopalmitoylation (TEADap), the second small molecule blocks the interaction by binding to the surface of the TEAD protein (TEADsf).
2024-02-22 | E-MTAB-13207 | biostudies-arrayexpress
Project description:Tissue-scale architecture and mechanical properties instruct cell behavior in physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that ECM stiffness, spatial confinements, and applied forces including stretching of the mouse skin regulate mitochondrial dynamics. Actomyosin tension promotes phosphorylation of MIEF1, limiting the recruitment of DRP1 at mitochondria, peri-mitochondrial F-actin formation, and mitochondrial fission. Strikingly, mitochondrial fission is also a general mechanotransduction mechanism. Indeed we found that DRP1- and MIEF1-dependent fission is required and sufficient to regulate three transcription factors of broad relevance such as YAP-TAZ, SREBP1-2, and NRF2 to control cell proliferation, lipogenesis, antioxidant metabolism, chemotherapy resistance, and adipocyte differentiation in response to mechanical cues. This extends to the mouse liver, where DRP1 regulates hepatocyte proliferation and identity, hallmark YAP-dependent phenotypes. We propose that mitochondria fulfill a unifying signaling function by which the mechanical tissue microenvironment coordinates complementary cell functions.
2024-09-02 | PXD040502 | Pride
Project description:Impact of static mechanical tension on global gene expressison in dendritic cell culture
2021-11-14 | GSE162061 | GEO