Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, Florida, USA.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
J Clin Invest. 2024 Aug 27;134(20):e173858. doi: 10.1172/JCI173858.
Tissue regeneration is orchestrated by macrophages that clear damaged cells and promote regenerative inflammation. How macrophages spatially adapt and diversify their functions to support the architectural requirements of actively regenerating tissue remains unknown. In this study, we reconstructed the dynamic trajectories of myeloid cells isolated from acutely injured and early stage dystrophic muscles. We identified divergent subsets of monocytes/macrophages and DCs and validated markers (e.g., glycoprotein NMB [GPNMB]) and transcriptional regulators associated with defined functional states. In dystrophic muscle, specialized repair-associated subsets exhibited distinct macrophage diversity and reduced DC heterogeneity. Integrating spatial transcriptomics analyses with immunofluorescence uncovered the ordered distribution of subpopulations and multilayered regenerative inflammation zones (RIZs) where distinct macrophage subsets are organized in functional zones around damaged myofibers supporting all phases of regeneration. Importantly, intermittent glucocorticoid treatment disrupted the RIZs. Our findings suggest that macrophage subtypes mediated the development of the highly ordered architecture of regenerative tissues, unveiling the principles of the structured yet dynamic nature of regenerative inflammation supporting effective tissue repair.
组织再生是由巨噬细胞协调的，巨噬细胞清除受损细胞并促进再生性炎症。巨噬细胞如何在空间上适应并多样化其功能以支持活跃再生组织的结构要求尚不清楚。在这项研究中，我们重建了从急性损伤和早期营养不良肌肉中分离的髓样细胞的动态轨迹。我们确定了单核细胞/巨噬细胞和 DC 的不同亚群，并验证了与特定功能状态相关的标志物（例如，糖蛋白 NMB [GPNMB]）和转录调节因子。在营养不良的肌肉中，专门的修复相关亚群表现出不同的巨噬细胞多样性和减少的 DC 异质性。将空间转录组学分析与免疫荧光相结合，揭示了亚群的有序分布和多层再生炎症区 (RIZ)，其中不同的巨噬细胞亚群在围绕受损肌纤维的功能区组织，支持再生的所有阶段。重要的是，间歇性糖皮质激素治疗破坏了 RIZ。我们的研究结果表明，巨噬细胞亚型介导了再生组织高度有序结构的发育，揭示了支持有效组织修复的再生炎症的结构化但动态性质的原则。
