Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
Nat Commun. 2020 Jan 30;11(1):600. doi: 10.1038/s41467-019-14263-2.
Canonical roles for macrophages in mediating the fibrotic response after a heart attack include extracellular matrix turnover and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal that macrophages directly contribute collagen to the forming post-injury scar. Unbiased transcriptomics shows an upregulation of collagens in both zebrafish and mouse macrophages following heart injury. Adoptive transfer of macrophages, from either collagen-tagged zebrafish or adult mouse GFPtpz-collagen donors, enhances scar formation via cell autonomous production of collagen. In zebrafish, the majority of tagged collagen localises proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-deposited collagen and that predominantly laid-down by myofibroblasts. Macrophage-specific targeting of col4a3bpa and cognate col4a1 in zebrafish significantly reduces scarring in cryoinjured hosts. Our findings contrast with the current model of scarring, whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair.
巨噬细胞在介导心肌梗死后纤维化反应中的典型作用包括细胞外基质的转化和激活心肌成纤维细胞以启动胶原蛋白沉积。在这里，我们揭示了巨噬细胞直接为形成损伤后的疤痕提供胶原蛋白。无偏倚转录组学显示，在心肌损伤后，斑马鱼和小鼠巨噬细胞中的胶原蛋白都上调。从胶原标记的斑马鱼或成年小鼠 GFPtpz-胶原供体中过继转移的巨噬细胞通过胶原蛋白的自主产生增强了疤痕形成。在斑马鱼中，标记的胶原主要位于损伤附近的上覆心外膜区域内，这表明巨噬细胞沉积的胶原蛋白与主要由肌成纤维细胞沉积的胶原蛋白之间可能存在区别。在斑马鱼中，巨噬细胞特异性靶向 col4a3bpa 和同源 col4a1 可显著减少冷冻损伤宿主的疤痕形成。我们的研究结果与目前的疤痕形成模型形成对比，在该模型中，胶原蛋白沉积完全归因于肌成纤维细胞，并且表明巨噬细胞在心脏修复过程中直接参与纤维化。
