Department of Pathology, School of Medicine, University of Washington, USA.
J Mol Cell Cardiol. 2013 Oct;63:122-34. doi: 10.1016/j.yjmcc.2013.07.014. Epub 2013 Aug 1.
In Duchenne muscular dystrophy (DMD), progressive accumulation of cardiac fibrosis promotes heart failure. While the cellular origins of fibrosis in DMD hearts remain enigmatic, fibrotic tissue conspicuously forms near the coronary adventitia. Therefore, we sought to characterize the role of coronary adventitial cells in the formation of perivascular fibrosis. Utilizing the mdx model of DMD, we have identified a population of Sca1+, PDGFRα+, CD31-, and CD45- coronary adventitial cells responsible for perivascular fibrosis. Histopathology of dystrophic hearts revealed that Sca1+ cells extend from the adventitia and occupy regions of perivascular fibrosis. The number of Sca1+ adventitial cells increased two-fold in fibrotic mdx hearts vs. age matched wild-type hearts. Moreover, relative to Sca1-, PDGFRα+, CD31-, and CD45- cells and endothelial cells, Sca1+ adventitial cells FACS-sorted from mdx hearts expressed the highest level of Collagen1α1 and 3α1, Connective tissue growth factor, and Tgfβr1 transcripts. Surprisingly, mdx endothelial cells expressed the greatest level of the Tgfβ1 ligand. Utilizing Collagen1α1-GFP reporter mice, we confirmed that the majority of Sca1+ adventitial cells expressed type I collagen, an abundant component of cardiac fibrosis, in both wt (71%±4.1) and mdx (77%±3.5) hearts. In contrast, GFP+ interstitial fibroblasts were PDGFRα+ but negative for Sca1. Treatment of cultured Collagen1α1-GFP+ adventitial cells with TGFβ1 resulted in increased collagen synthesis, whereas pharmacological inhibition of TGFβR1 signaling reduced the fibrotic response. Therefore, perivascular cardiac fibrosis by coronary adventitial cells may be mediated by TGFβ1 signaling. Our results implicate coronary endothelial cells in mediating cardiac fibrosis via transmural TGFβ signaling, and suggest that the coronary adventitia is a promising target for developing novel anti-fibrotic therapies.
在杜氏肌营养不良症（DMD）中，心脏纤维化的进行性积累会导致心力衰竭。虽然 DMD 心脏纤维化的细胞来源仍然难以捉摸，但纤维组织明显形成于冠状动脉外膜附近。因此，我们试图描述冠状动脉外膜细胞在血管周围纤维化形成中的作用。利用 DMD 的 mdx 模型，我们鉴定出一群 Sca1+、PDGFRα+、CD31-和 CD45-的冠状动脉外膜细胞，它们负责血管周围纤维化。营养不良心脏的组织病理学显示，Sca1+细胞从外膜延伸并占据血管周围纤维化区域。与年龄匹配的野生型心脏相比，纤维化的 mdx 心脏中的 Sca1+外膜细胞数量增加了两倍。此外，与 Sca1-、PDGFRα+、CD31-和 CD45-细胞和内皮细胞相比，从 mdx 心脏分选的 Sca1+外膜细胞表达最高水平的 Collagen1α1 和 3α1、结缔组织生长因子和 Tgfβr1 转录本。令人惊讶的是，mdx 内皮细胞表达了最高水平的 TGFβ1 配体。利用 Collagen1α1-GFP 报告小鼠，我们证实大多数 Sca1+外膜细胞在 wt（71%±4.1）和 mdx（77%±3.5）心脏中都表达大量的心脏纤维化成分 I 型胶原。相比之下，GFP+间质成纤维细胞是 PDGFRα+但 Sca1-。用 TGFβ1 处理培养的 Collagen1α1-GFP+外膜细胞会导致胶原合成增加，而 TGFβR1 信号通路的药理学抑制会减少纤维化反应。因此，冠状动脉外膜细胞的血管周围心脏纤维化可能是由 TGFβ1 信号介导的。我们的结果表明，冠状动脉内皮细胞通过跨壁 TGFβ 信号介导心脏纤维化，并提示冠状动脉外膜是开发新型抗纤维化疗法的有前途的靶点。
