Fibroblast Primary Cilia Are Required for Cardiac Fibrosis
Fibroblast Primary Cilia Are Required for Cardiac Fibrosis
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DOI：
10.1161/circulationaha.117.028752
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发表时间：
2019-05-14
期刊：
影响因子：
37.8
通讯作者：
Hill, Joseph A.
中科院分区：
文献类型：
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作者：
Villalobos, Elisa;Criollo, Alfredo;Hill, Joseph A.
背景：初级纤毛是一种单一的细胞结构，从许多细胞类型的表面延伸出来，在脊椎动物的发育中发挥着至关重要的作用，包括心脏的发育。虽然纤毛细胞在发育中的心脏中已有描述，但初级纤毛在成人心脏中的作用尚未报道。再加上编码多种纤毛蛋白的基因突变是多囊肾病（一种具有多种心血管表现的疾病）的基础，促使我们鉴定成年心脏中含有初级纤毛的细胞，并确定初级纤毛是否在疾病相关的重塑中发挥作用。 方法：对来自 C57BL/6 小鼠胚胎、新生小鼠和成年小鼠的心脏组织进行组织学分析，以评估初级纤毛。使用纤毛特异性抗体（乙酰化微管蛋白、γ-微管蛋白、多囊蛋白 [PC] 1、PC2 和 KIF3A）、成纤维细胞（波形蛋白、α-平滑肌肌动蛋白和成纤维细胞特异性蛋白-1）和心肌细胞（α-辅肌动蛋白）特异性抗体，使用三种损伤模型（心尖切除、缺血/再灌注和心肌梗死）来识别纤毛细胞的位置和细胞类型和肌钙蛋白 I)。使用类似的方法来评估梗塞的人心肌组织中的初级纤毛。我们研究了仅在肌成纤维细胞中沉默 PC1 的小鼠，并评估了 PC1 在成年大鼠成纤维细胞和肌成纤维细胞的纤维形成中的作用。 结果：我们在小鼠、大鼠和人类心脏中鉴定出了初级纤毛，特别是在心脏成纤维细胞中。纤毛成纤维细胞在心肌损伤区域富集。在初级纤毛耗尽的成纤维细胞中，转化生长因子 ss-1 信号传导和 SMAD3 激活受到损害。细胞外基质蛋白水平和收缩功能也受损。在体内，心肌梗塞后激活的成纤维细胞中PC1的消耗损害了重塑反应。结论：新生儿和成人心脏中的成纤维细胞含有初级纤毛。这种细胞器及其必需的信号蛋白 PC1 是纤维形成的关键要素所必需的，包括转化生长因子 ss-1-SMAD3 激活、细胞外基质蛋白的产生和细胞收缩性。总之，这些发现表明该细胞器和 PC1 在疾病相关的病理性心脏重塑中发挥着关键作用，并表明常染色体显性多囊肾病的一些心血管表现直接源自心肌自主异常。
BACKGROUND: The primary cilium is a singular cellular structure that extends from the surface of many cell types and plays crucial roles in vertebrate development, including that of the heart. Whereas ciliated cells have been described in developing heart, a role for primary cilia in adult heart has not been reported. This, coupled with the fact that mutations in genes coding for multiple ciliary proteins underlie polycystic kidney disease, a disorder with numerous cardiovascular manifestations, prompted us to identify cells in adult heart harboring a primary cilium and to determine whether primary cilia play a role in disease-related remodeling.METHODS: Histological analysis of cardiac tissues from C57BL/6 mouse embryos, neonatal mice, and adult mice was performed to evaluate for primary cilia. Three injury models (apical resection, ischemia/reperfusion, and myocardial infarction) were used to identify the location and cell type of ciliated cells with the use of antibodies specific for cilia (acetylated tubulin, gamma-tubulin, polycystin [PC] 1, PC2, and KIF3A), fibroblasts (vimentin, a-smooth muscle actin, and fibroblast-specific protein-1), and cardiomyocytes (a-actinin and troponin I). A similar approach was used to assess for primary cilia in infarcted human myocardial tissue. We studied mice silenced exclusively in myofibroblasts for PC1 and evaluated the role of PC1 in fibrogenesis in adult rat fibroblasts and myofibroblasts.RESULTS: We identified primary cilia in mouse, rat, and human heart, specifically and exclusively in cardiac fibroblasts. Ciliated fibroblasts are enriched in areas of myocardial injury. Transforming growth factor ss-1 signaling and SMAD3 activation were impaired in fibroblasts depleted of the primary cilium. Extracellular matrix protein levels and contractile function were also impaired. In vivo, depletion of PC1 in activated fibroblasts after myocardial infarction impaired the remodeling response.CONCLUSIONS: Fibroblasts in the neonatal and adult heart harbor a primary cilium. This organelle and its requisite signaling protein, PC1, are required for critical elements of fibrogenesis, including transforming growth factor ss-1-SMAD3 activation, production of extracellular matrix proteins, and cell contractility. Together, these findings point to a pivotal role of this organelle, and PC1, in disease-related pathological cardiac remodeling and suggest that some of the cardiovascular manifestations of autosomal dominant polycystic kidney disease derive directly from myocardium-autonomous abnormalities.