title: Macrophages are essential for the early wound healing response and the formation of a fibrovascular scar.
abstract: 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-1β 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.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, and Department of Dermatology, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Lizhi
authors.initials: L
authors.lastname: He
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Marneros
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D002829:Choroid / Q000293:injuries; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004847:Epithelial Cells / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D007378:Interleukins / Q000502:physiology; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000502:physiology; D055213:Retinal Pigment Epithelium / Q000293:injuries; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D014945:Wound Healing / Q000502:physiology*
chemical_list: D000199:Actins; D007378:Interleukins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse