The details of how macrophages control different healing trajectories (regeneration vs. scar formation) remain poorly defined. Spiny mice (Acomys spp.) can regenerate external ear pinnae tissue, whereas lab mice (Mus musculus) form scar tissue in response to an identical injury. Here, we used this dual species system to dissect macrophage phenotypes between healing modes. We identified secreted factors from activated Acomys macrophages that induce a pro-regenerative phenotype in fibroblasts from both species. Transcriptional profiling of Acomys macrophages and subsequent in vitro tests identified VEGFC, PDGFA, and Lactotransferrin (LTF) as potential pro-regenerative modulators. Examining macrophages in vivo, we found that Acomys-resident macrophages secreted VEGFC and LTF, whereas Mus macrophages do not. Lastly, we demonstrate the requirement for VEGFC during regeneration and find that interrupting lymphangiogenesis delays blastema and new tissue formation. Together, our results demonstrate that cell-autonomous mechanisms govern how macrophages react to the same stimuli to differentially produce factors that facilitate regeneration.

巨噬细胞如何控制不同的愈合轨迹（再生与疤痕形成）的细节仍然不清楚。多刺小鼠（Acomys spp.）可以再生外耳耳廓组织，而实验室小鼠（Mus musculus）在受到相同损伤时会形成疤痕组织。在这里，我们使用这种双物种系统来剖析愈合模式之间的巨噬细胞表型。我们鉴定了激活的Acomys巨噬细胞的分泌因子，这些因子可诱导这两个物种的成纤维细胞出现促再生表型。Acomys巨噬细胞的转录谱和随后的体外测试确定 VEGFC、PDGFA 和乳转铁蛋白 (LTF) 是潜在的促再生调节剂。检查体内巨噬细胞，我们发现Acomys巨噬细胞分泌 VEGFC 和 LTF，而Mus巨噬细胞则不分泌 VEGFC 和 LTF。最后，我们证明了再生过程中对 VEGFC 的需求，并发现中断淋巴管生成会延迟胚基和新组织的形成。总之，我们的结果表明，细胞自主机制控制巨噬细胞如何对相同的刺激做出反应，以差异化地产生促进再生的因子。