Macrophages Are Essential for the Early Wound Healing Response and the Formation of a Fibrovascular Scar
Macrophages Are Essential for the Early Wound Healing Response and the Formation of a Fibrovascular Scar
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DOI：
10.1016/j.ajpath.2013.02.032
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发表时间：
2013-06-01
影响因子：
6
通讯作者：
Marneros, Alexander G.
中科院分区：
文献类型：
--
作者：
He, Lizhi;Marneros, Alexander G.
创伤后，多种细胞类型相互作用形成纤维血管瘢痕;这些瘢痕的形成和细胞起源尚不完全清楚。我们用激光损伤的脉络膜新生血管模型来确定导致纤维血管瘢痕形成的时空细胞事件。激光损伤后，F4/80（+）骨髓细胞浸润伤口部位，并诱导邻近视网膜色素上皮细胞中平滑肌肌动蛋白（SMA）表达，随后形成SMA（+）NG 2（+）肌纤维母细胞支架，然后内皮细胞浸润其中形成纤维血管病变。纤维血管支架的细胞强烈表达促血管生成因子IL-1 β，而视网膜色素上皮细胞是VEGF-A的主要来源。随后的脉络膜新生血管仅限于由该成肌纤维细胞支架划分的区域，并且独立于上皮或骨髓来源的VEGF-A发生。SMA（+）NG 2（+）成肌纤维细胞、F4/80（+）巨噬细胞和相邻上皮细胞在伤口愈合反应的早期阶段活跃增殖。细胞谱系示踪实验表明SMA（+）NG 2（+）成肌纤维细胞支架来源于脉络膜周细胞样细胞。巨噬细胞的靶向消融抑制了这种纤维血管支架的形成，并且表达分析显示这些巨噬细胞是Arg 1（+）YM 1（+）F4/80（+）交替激活的M2样巨噬细胞，其不需要IL-4/STAT 6或IL-10信号传导来激活。因此，巨噬细胞对于早期伤口愈合反应和纤维血管瘢痕的形成是必需的。
After wounding, multiple cell types interact to form a fibrovascular scar; the formation and cellular origins of these scars are incompletely understood. We used a laser-injury wound model of choroidal neovascularization in the eye to determine the spatiotemporal cellular events that Lead to formation of a fibrovascular scar. After Laser injury, F4/80(+) myeloid cells infiltrate the wound site and induce smooth muscle actin (SMA) expression in adjacent retinal pigment epithelial cells, with subsequent formation of a SMA(+)NG2(+) myofibroblastic scaffold, into which endothelial cells then infiltrate to form a fibrovascular Lesion. Cells of the fibrovascular scaffold express the proangiogenic factor IL-1 beta strongly, whereas retinal pigment epithelial cells are the main source of VEGF-A. Subsequent choroidal neovascularization is limited to the area demarcated by this myofibroblastic scaffold and occurs independently of epithelial- or myeloid-derived VEGF-A. The SMA(+)NG2(+) myofibroblastic cells, F4/80(+) macrophages, and adjacent epithelial cells actively proliferate in the early phase of the wound healing response. Cell-lineage tracing experiments suggest that the SMA(+)NG2(+) myofibroblastic scaffold originates from choroidal pericyte-like cells. Targeted ablation of macrophages inhibits the formation of this fibrovascular scaffold, and expression analysis reveals that these macrophages are Arg1(+)YM1(+)F4/80(+) alternatively activated M2-Like macrophages, which do not require IL-4/STAT6 or IL-10 signaling for their activation. Thus, macrophages are essential for the early wound healing response and the formation of a fibrovascular scar.