Macrophages directly contribute collagen to scar formation during heart repair and regeneration

Canonical roles for macrophages in mediating the fibrotic response after a heart attack (myocardial infarction) include turnover of the extracellular matrix and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal that macrophages can directly contribute collagen to the forming scar through studying the functional kinetics of fibrosis during zebrafish heart regeneration. Unbiased transcriptomics revealed an upregulation of collagen isoforms in zebrafish macrophages following injury. Adoptive transfer of macrophages from collagen-tagged transgenic zebrafish donors enhanced scar formation and induced fibrosis in the heart, via cell autonomous production of collagen. The majority of tagged collagen was deposited proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-collagen deposition and that predominantly laid-down by activated myofibroblasts. Macrophage-specific targeting of collagen 4a binding protein and cognate collagen 4a1 followed by adoptive transfer led to significantly reduced pericardiac scarring in cryoinjured hosts. These findings contrast with the current model of scarring whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair.