Cardiac fibroblasts (CFs) respond to injury by transitioning through multiple cell states, including resting CFs, activated CFs, and myofibroblasts. We report here that Hippo signaling cell-autonomously regulates CF fate transitions and proliferation, and non-cell-autonomously regulates both myeloid and CF activation in the heart. Conditional deletion of Hippo pathway kinases, Lats1 and Lats2, in uninjured CFs initiated a self-perpetuating fibrotic response in the adult heart that was exacerbated by myocardial infarction (MI). Single cell transcriptomics showed that uninjured Lats1/2 mutant CFs spontaneously transitioned to a myofibroblast cell state. Through gene regulatory network reconstruction, we found that Hippo-deficient myofibroblasts deployed a network of transcriptional regulators of endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) consistent with elevated secretory activity. We observed an expansion of myeloid cell heterogeneity in uninjured Lats1/2 CKO hearts with similarity to cells recovered from control hearts post-MI. Integrated genome-wide analysis of Yap chromatin occupancy revealed that Yap directly activates myofibroblast cell identity genes, the proto-oncogene Myc, and an array of genes encoding pro-inflammatory factors through enhancer-promoter looping. Our data indicate that Lats1/2 maintain the resting CF cell state through restricting the Yap-induced injury response.

中文翻译：

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成年静息心脏成纤维细胞中 Hippo 通路的缺失会引发细胞状态转变，并伴有自发和自我维持的纤维化。


心脏成纤维细胞 (CF) 通过转变多种细胞状态来响应损伤，包括静止 CF、激活 CF 和肌成纤维细胞。我们在此报告，Hippo 信号细胞自主调节 CF 命运转变和增殖，并且非细胞自主调节心脏中的骨髓和 CF 激活。在未受伤的 CF 中，有条件地删除 Hippo 通路激酶 Lats1 和 Lats2，会在成人心脏中引发自我持续的纤维化反应，而心肌梗塞 (MI) 会加剧这种反应。单细胞转录组学表明，未受伤的 Lats1/2 突变体 CF 自发转变为肌成纤维细胞状态。通过基因调控网络重建，我们发现 Hippo 缺陷的肌成纤维细胞部署了内质网（ER）应激的转录调节因子网络，以及与分泌活性升高一致的未折叠蛋白反应（UPR）。我们观察到未受伤的 Lats1/2 CKO 心脏中骨髓细胞异质性的扩大，与 MI 后从对照心脏中恢复的细胞相似。对 Yap 染色质占据的全基因组综合分析表明，Yap 直接激活肌成纤维细胞识别基因、原癌基因 Myc 以及通过增强子-启动子循环编码促炎因子的一系列基因。我们的数据表明，Lats1/2 通过限制 Yap 诱导的损伤反应来维持静息 CF 细胞状态。