Abstract Body: The adult mammalian heart lacks regenerative capacity after injury, leading to heart failure. Unlike most adult mammals, Acomys preserves myocardial structure following ischemic injury. We tested the hypothesis that Acomys cardiac resident macrophages promote cardioprotection through a pro-angiogenic response. We depleted cardiac resident macrophages in Acomys using anti-CD115 antibody prior to myocardial infarction. Cardiac function was assessed by echocardiography (mixed-effects analysis; n=4-5/group; p<0.001 vs. control), and capillary density and fibrosis were quantified histologically (unpaired t-test; n=4-5/group; p<0.01 vs. control).
Macrophage depletion impaired cardiac function (EF 31±7%, FS 29±3%), worsened remodeling, and reduced angiogenesis in ischemic (85.7%) and peri-infarct (33.3%) regions. Bulk RNA-seq demonstrated increased pro-inflammatory and pro-fibrotic gene expression with reduced pro-angiogenic signaling following depletion. Comparative snRNA-seq in Acomys and Mus revealed enhanced macrophage-endothelial crosstalk and higher expression of angiogenic secretomes in Acomys after injury. CellChat analysis identified augmented MIF signaling with macrophages as dominant signal senders.
MIF overexpression in Mus improved cardiac function (EF 54±9%, FS 24±6%) and increased peri-infarct capillary density (76.2%), whereas MIF antagonism in Acomys had no significant functional effect, suggesting pathway redundancy in regenerative species.
These findings identify resident macrophages as central mediators of post-injury vascular preservation in Acomys. Gain-of-function insights highlight MIF potential as a target to modulate innate immunity post-injury. Targeting single pathways may be insufficient in Acomys species with inherent regenerative abilities. Current studies in our laboratory are exploring the underlying pathways that enhance angiogenesis in Acomys.