Godwin J W, Debuque R, Salimova E, Rosenthal N A
The Jackson laboratory, Bar Harbor, ME 04609, USA.
Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
NPJ Regen Med. 2017;2. doi: 10.1038/s41536-017-0027-y. Epub 2017 Jul 27.
In dramatic contrast to the poor repair outcomes for humans and rodent models such as mice, salamanders and some fish species are able to completely regenerate heart tissue following tissue injury, at any life stage. This capacity for complete cardiac repair provides a template for understanding the process of regeneration and for developing strategies to improve human cardiac repair outcomes. Using a cardiac cryo-injury model we show that heart regeneration is dependent on the innate immune system, as macrophage depletion during early time points post-injury results in regeneration failure. In contrast to the transient extracellular matrix (ECM) that normally accompanies regeneration, this intervention resulted in a permanent, highly cross-linked extracellular matrix scar derived from alternative fibroblast activation and lysyl-oxidase enzyme synthesis. The activation of cardiomyocyte proliferation was not affected by macrophage depletion, indicating that cardiomyocyte replacement is an independent feature of the regenerative process, and is not sufficient to prevent fibrotic progression. These findings highlight the interplay between macrophages and fibroblasts as an important component of cardiac regeneration, and the prevention of fibrosis as a key therapeutic target in the promotion of cardiac repair in mammals.
与人类以及小鼠等啮齿动物模型糟糕的修复结果形成鲜明对比的是，蝾螈和一些鱼类能够在任何生命阶段的组织损伤后完全再生心脏组织。这种完全心脏修复的能力为理解再生过程以及制定改善人类心脏修复结果的策略提供了一个模板。我们使用心脏冷冻损伤模型表明，心脏再生依赖于先天免疫系统，因为在损伤后早期时间点清除巨噬细胞会导致再生失败。与正常伴随再生的短暂细胞外基质（ECM）不同，这种干预导致了一种源自替代性成纤维细胞激活和赖氨酰氧化酶合成的永久性、高度交联的细胞外基质瘢痕。巨噬细胞清除并不影响心肌细胞增殖的激活，这表明心肌细胞替代是再生过程的一个独立特征，并且不足以阻止纤维化进展。这些发现突出了巨噬细胞和成纤维细胞之间的相互作用是心脏再生的一个重要组成部分，以及预防纤维化是促进哺乳动物心脏修复的关键治疗靶点。
