RNA-seq of injured mouse hearts depleted for myofibroblast Yap and Wwtr1
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE163612 | GEO | 2022/10/29
REPOSITORIES: GEO
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Project description:A myofibroblast specific tamoxifen inducible Cre was used to assess the contribution of Yap in the mouse heart after myocardial infarction
2022-10-29 | GSE163269 | GEO
Project description:To assess the pathophysiological of genetic depletion of Yap and Wwtr1 in myofibroblasts following myocardial infarction, we utilized a Cre-lox system whereby the inducible Periostin promoter is leveraged to deplete both Yap and Wwtr1 from myofibroblasts in mice. Following myocardial infarction, myofibroblast depletion of both Yap and Wwtr1 significantly improves cardiac function after injury as compared to injured controls. Here, we have performed single cell RNA sequencing of interstitial cardiac cells 7 days post myocardial infarction to assess differentially express genes within cardiac fibroblasts and immune cell populations.
2023-02-27 | GSE204712 | GEO
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2022-10-29 | GSE163617 | GEO
Project description:Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell-type in terms of their origins and functional effects in vivo. Methods: Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen inducible Cre for cellular lineage tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Results: Lineage tracing with 4 additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin+ myofibroblasts reduces collagen production and scar formation after myocardial infarction. Periostin-traced myofibroblasts also revert back to a less activated state upon injury resolution. Conclusions: Our results define the myofibroblast as a periostin-expressing cell-type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21+ tissue-resident fibroblasts. Fluidigm C1 whole genome transcriptome analysis of lineage mapped cardiac myofibroblasts
2016-06-14 | E-GEOD-83337 | biostudies-arrayexpress
Project description:Primary neonatal rat cardiac fibroblasts were isolated and subjected to siRNA mediated Yap and/or Wwtr1 knockdown
2022-10-29 | GSE185368 | GEO
Project description:Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell-type in terms of their origins and functional effects in vivo. Methods: Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen inducible Cre for cellular lineage tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Results: Lineage tracing with 4 additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin+ myofibroblasts reduces collagen production and scar formation after myocardial infarction. Periostin-traced myofibroblasts also revert back to a less activated state upon injury resolution. Conclusions: Our results define the myofibroblast as a periostin-expressing cell-type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21+ tissue-resident fibroblasts.
2016-06-14 | GSE83337 | GEO
Project description:Cardiac trabeculation is a highly regulated process that starts with the delamination of cardiomyocytes from the compact wall to form stereotypical muscular ridges in the developing ventricle. The Hippo signaling pathway has been implicated in cardiac development but many questions remain. We investigated the role of Wwtr1, a nuclear effector of the Hippo pathway, in zebrafish and find that its loss results in hearts with reduced trabeculation. However, in mosaic animals, wwtr1-/- cardiomyocytes contribute more frequently than wwtr1+/- cardiomyocytes to the trabecular layer of wild-type hearts. To investigate this paradox, we examined the myocardial wall at early stages and find that loss of Wwtr1 leads to disruption of the compact wall architecture, as evidenced by the disorganized cortical actin structure and abnormal cell-cell junctions. The mutant compact wall is not able to support trabeculation as, in mosaic animals, wild-type cardiomyocytes are more frequently in the compact layer of mutant than heterozygous hearts. Therefore, we propose that Wwtr1 establishes the compact wall architecture necessary for trabeculation and that it also modulates a cardiomyocyte’s decision to enter the trabecular layer.
2018-04-10 | GSE103169 | GEO
Project description:Pericryptal myofibroblasts in the colon and rectum play an important role in regulating the normal colorectal stem cell niche and facilitating tumour progression. Myofibroblasts have previously mostly been distinguished from normal fibroblasts only by the expression of α smooth muscle actin (αSMA). We now identify AOC3, a surface monoamine oxidase, as a new marker of myofibroblasts by showing that it is the target protein of the myofibroblast reacting monoclonal antibody (mAb), PR2D3. The normal and tumour tissue distribution and the cell line reactivity of AOC3 match that expected for myofibroblasts. We have shown that the surface expression of AOC3 is sensitive to digestion by trypsin and collagenase and that anti-AOC3 antibodies can be used for FACS sorting of myofibroblasts obtained by non-enzymatic procedures. Whole genome microarray mRNA expression profiles of myofibroblasts and skin fibroblasts revealed four additional genes that are significantly expressed differentially between these two cell types; NKX2-3 and LRRC17 are expressed in myofibroblasts and SHOX2 and TBX5 in skin fibroblasts. Transforming Growth Factor β (TGFβ) substantially down-regulated AOC3 expression in myofibroblasts but not in skin fibroblasts, in which it dramatically increased the expression of αSMA. A knockdown of NKX2-3 in myofibroblasts caused a decrease of myofibroblast-related gene expression and an increased expression of the fibroblast associated gene, SHOX2, suggesting that NKX2-3 is a key mediator for maintaining myofibroblast characteristics. Our results show that colorectal myofibroblasts, as defined by the expression of AOC3, NKX2-3 and other markers, are a distinctly different cell type from TGFβ activated fibroblasts. colorectal myofibroblast specific markers and expression profiles were sought by comparing four primary myofibroblast cultures to a panel of four dermal and foreskin fibroblast cell lines Four primary myofibroblast cultures established from adult human colon compared to four skin fibroblast cell lines to identify intestinal myofibroblast specific markers
2016-04-06 | E-GEOD-77474 | biostudies-arrayexpress
Project description:Fibrotic diseases account for nearly half of all deaths in the developed world. Despite its importance, the pathogenesis of fibrosis remains poorly understood. Recently, the two mechanosensitive transcription cofactors YAP and TAZ have emerged as important profibrotic regulators in multiple murine tissues. Despite this growing recognition, a number of important questions remain unanswered, including which cell types require YAP/TAZ activation for fibrosis to occur and the time course of this activation. Here, we present a detailed analysis of the role that myofibroblast YAP and TAZ play in organ fibrosis and the kinetics of their activation. Using analyses of cells, as well as multiple murine and human tissues, we demonstrated that myofibroblast YAP and TAZ were activated early after organ injury and that this activation was sustained. We further demonstrated the critical importance of myofibroblast YAP/TAZ in driving progressive scarring in the kidney, lung, and liver, using multiple transgenic models in which YAP and TAZ were either deleted or hyperactivated. Taken together, these data establish the importance of early injury-induced myofibroblast YAP and TAZ activation as a key event driving fibrosis in multiple organs. This information should help guide the development of new antifibrotic YAP/TAZ inhibition strategies.
2022-02-22 | GSE135327 | GEO
Project description:The differentiation of fibroblasts into myofibroblasts mediates tissue wound healing and fibrotic remodeling. To better understand this process we performed a genome-wide screen in fibroblasts, which identified the RNA-binding protein muscleblind-like 1 (MBNL1) as a potent regulator of myofibroblast differentiation. MBNL1 promoted transformation of fibroblasts into myofibroblasts, while loss of Mbnl1 abrogated myofibroblast differentiation and impaired the fibrotic phase of wound healing in mouse models of myocardial infarction and dermal injury. Conditional fibroblast-specific MBNL1 transgenic mice showed a fibrotic phenotype in the absence of injury. Mechanistically, MBNL1 directly bound to and regulated the alternative splicing and stability of a network of myofibroblast differentiation specific genes, such as the nodal transcriptional regulator serum response factor (SRF). CRISPR-Cas9 mediated gene editing of the MBNL1 binding site in Srf impaired myofibroblast differentiation. These data establish a new RNA-dependent paradigm through MBNL1 that underlies global myofibroblast differentiation, the fibrotic response, and tissue wound healing.
2015-10-20 | GSE74185 | GEO