Project description:A myofibroblast specific tamoxifen inducible Cre was used to assess the contribution of Yap in the mouse heart after myocardial infarction
Project description:A myofibroblast specific tamoxifen inducible Cre was used to assess the role of Yap and Wwtr1 in the mouse heart after myocardial infarction
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.
Project description:Characterization of myocardial B cells in naïve hearts, acutely injured hearts and acutely injured hearts of mice treated with Pirfenidone
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.
Project description:Myocardial CD19+CD11b+ and CD19+CD11b- cells were FACS sorted from transgenic mice expressing the Diphtheria Toxin (DT) receptor under the myocardial specific MLC2v promoter. Cells were sorted from hearts of mice not exposed to DT (naïve hearts), from the hearts of animals treated with DT 4 days prior to the experiment (DTR) and from the hearts of mice exposed to DT and fed chow enriched with the anti-inflammatory/anti-fibrotic drug Pirfenidone (0.5% in powdered chow, PFD)