ptx3a+ fibroblast/epicardial cells provide a transient macrophage niche to promote heart regeneration

• Published in: Cell reports (Cambridge) 2024-04, Vol.43 (4), p.114092-114092, Article 114092
• Main Authors: Sun, Jisheng, Peterson, Elizabeth A., Chen, Xin, Wang, Jinhu
• Format: Article
• Language: English
• Subjects: Animals; C-Reactive Protein - genetics; C-Reactive Protein - metabolism; CP: Immunology; CP: Stem cell research; csf1a; epicardium; Fibroblasts - metabolism; heart; Heart - physiology; Heart Injuries - metabolism; Heart Injuries - pathology; macrophage; Macrophages - metabolism; Pericardium - cytology; Pericardium - metabolism; ptx3a; regeneration; Regeneration - physiology; Serum Amyloid P-Component - genetics; Serum Amyloid P-Component - metabolism; zebrafish; Zebrafish - metabolism; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114092

Macrophages conduct critical roles in heart repair, but the niche required to nurture and anchor them is poorly studied. Here, we investigated the macrophage niche in the regenerating heart. We analyzed cell-cell interactions through published single-cell RNA sequencing datasets and identified a strong interaction between fibroblast/epicardial (Fb/Epi) cells and macrophages. We further visualized the association of macrophages with Fb/Epi cells and the blockage of macrophage response without Fb/Epi cells in the regenerating zebrafish heart. Moreover, we found that ptx3a+ epicardial cells associate with reparative macrophages, and their depletion resulted in fewer reparative macrophages. Further, we identified csf1a expression in ptx3a+ cells and determined that pharmacological inhibition of the csf1a pathway or csf1a knockout blocked the reparative macrophage response. Moreover, we found that genetic overexpression of csf1a enhanced the reparative macrophage response with or without heart injury. Altogether, our studies illuminate a cardiac Fb/Epi niche, which mediates a beneficial macrophage response after heart injury. [Display omitted] •ptx3a+ cells associate with reparative macrophages in regenerating hearts•ptx3a+ cells stimulate reparative macrophage response during heart regeneration•Csf1 activation in epicardial cells is conserved in regenerating models•Csf1 upregulation is required for endogenous heart regeneration Sun et al. report that ptx3a+ epicardial cells are essential for immune regulation during heart regeneration by expressing csf1a to modulate reparative macrophage response upon heart injury.