TGF-β/Smad3 signalling regulates the transition of bone marrow-derived macrophages into myofibroblasts during tissue fibrosis.
TGF-β/Smad3 signalling regulates the transition of bone marrow-derived macrophages into myofibroblasts during tissue fibrosis.
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DOI：
10.18632/oncotarget.6604
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发表时间：
2016-02-23
期刊：
影响因子：
--
通讯作者：
Lan HY
中科院分区：
文献类型：
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作者：
Wang S;Meng XM;Ng YY;Ma FY;Zhou S;Zhang Y;Yang C;Huang XR;Xiao J;Wang YY;Ka SM;Tang YJ;Chung AC;To KF;Nikolic-Paterson DJ;Lan HY
肌成纤维细胞是组织纤维化过程中产生胶原蛋白的主要细胞类型，但其起源仍存在争议。虽然肾纤维化中骨髓来源的肌成纤维细胞已有报道，但调节其转变为肌成纤维细胞的细胞起源和机制仍不清楚。在本研究中，通过过继转移 GFP+ 或染料标记的巨噬细胞进行的细胞谱系追踪研究发现，在单侧输尿管梗阻的小鼠模型中，来自骨髓的单核细胞/巨噬细胞可以通过巨噬细胞-肌成纤维细胞转变 (MMT) 过程产生肌成纤维细胞。 MMT细胞是纤维化肾脏中产生胶原蛋白的成纤维细胞的主要来源，占α-SMA+肌成纤维细胞的60%以上。 MMT 过程主要发生在 M2 型巨噬细胞内，并受到 TGF-β/Smad3 信号传导的调节，因为 GFP+ 嵌合小鼠骨髓区室中 Smad3 的缺失可阻止 M2 巨噬细胞转变为 MMT 细胞和进行性肾纤维化。 Smad3 缺失骨髓巨噬细胞的体外研究也表明，Smad3 是 TGF-β1 诱导的 MMT 和胶原蛋白生成所必需的。总之，我们已经证明骨髓源性成纤维细胞通过 MMT 过程起源于单核细胞/巨噬细胞群。这一过程导致进行性肾组织纤维化，并受到 TGF-β/Smad3 信号传导的调节。
Myofibroblasts are a main cell-type of collagen-producing cells during tissue fibrosis, but their origins remains controversial. While bone marrow-derived myofibroblasts in renal fibrosis has been reported, the cell origin and mechanisms regulating their transition into myofibroblasts remain undefined. In the present study, cell lineage tracing studies by adoptive transfer of GFP+ or dye-labelled macrophages identified that monocyte/macrophages from bone marrow can give rise to myofibroblasts via the process of macrophage-myofibroblast transition (MMT) in a mouse model of unilateral ureteric obstruction. The MMT cells were a major source of collagen-producing fibroblasts in the fibrosing kidney, accounting for more than 60% of α-SMA+ myofibroblasts. The MMT process occurred predominantly within M2-type macrophages and was regulated by TGF-β/Smad3 signalling as deletion of Smad3 in the bone marrow compartment of GFP+ chimeric mice prevented the M2 macrophage transition into the MMT cells and progressive renal fibrosis. In vitro studies in Smad3 null bone marrow macrophages also showed that Smad3 was required for TGF-β1-induced MMT and collagen production. In conclusion, we have demonstrated that bone marrow-derived fibroblasts originate from the monocyte/macrophage population via a process of MMT. This process contributes to progressive renal tissue fibrosis and is regulated by TGF-β/Smad3 signalling.