Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9415-20. doi: 10.1073/pnas.1300290110. Epub 2013 May 20.
The failure to replace damaged body parts in adult mammals results from a muted growth response and fibrotic scarring. Although infiltrating immune cells play a major role in determining the variable outcome of mammalian wound repair, little is known about the modulation of immune cell signaling in efficiently regenerating species such as the salamander, which can regrow complete body structures as adults. Here we present a comprehensive analysis of immune signaling during limb regeneration in axolotl, an aquatic salamander, and reveal a temporally defined requirement for macrophage infiltration in the regenerative process. Although many features of mammalian cytokine/chemokine signaling are retained in the axolotl, they are more dynamically deployed, with simultaneous induction of inflammatory and anti-inflammatory markers within the first 24 h after limb amputation. Systemic macrophage depletion during this period resulted in wound closure but permanent failure of limb regeneration, associated with extensive fibrosis and disregulation of extracellular matrix component gene expression. Full limb regenerative capacity of failed stumps was restored by reamputation once endogenous macrophage populations had been replenished. Promotion of a regeneration-permissive environment by identification of macrophage-derived therapeutic molecules may therefore aid in the regeneration of damaged body parts in adult mammals.
成年哺乳动物未能替换受损的身体部位是由于生长反应减弱和纤维瘢痕形成。尽管浸润的免疫细胞在决定哺乳动物伤口修复的不同结果方面起着主要作用，但对于能够在成年时重新生长完整身体结构的再生能力强的物种（如蝾螈）中的免疫细胞信号的调节知之甚少。在这里，我们对蝾螈（一种水生蝾螈）肢体再生过程中的免疫信号进行了全面分析，并揭示了巨噬细胞浸润在再生过程中的时间限定性要求。尽管在蝾螈中保留了许多哺乳动物细胞因子/趋化因子信号的特征，但它们的动态部署更为复杂，在肢体截肢后最初的 24 小时内同时诱导炎症和抗炎标志物。在此期间进行系统性巨噬细胞耗竭会导致伤口闭合，但肢体再生永久失败，伴有广泛的纤维化和细胞外基质成分基因表达失调。一旦内源性巨噬细胞群体得到补充，通过重新截肢就可以恢复失败残肢的完全肢体再生能力。通过鉴定巨噬细胞衍生的治疗分子来促进再生许可环境，因此可能有助于成年哺乳动物受损身体部位的再生。
