Canonical roles for macrophages in mediating the fibrotic response after a heart attack include extracellular matrix turnover and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal that macrophages directly contribute collagen to the forming post-injury scar. Unbiased transcriptomics shows an upregulation of collagens in both zebrafish and mouse macrophages following heart injury. Adoptive transfer of macrophages, from either collagen-tagged zebrafish or adult mouse GFPtpz-collagen donors, enhances scar formation via cell autonomous production of collagen. In zebrafish, the majority of tagged collagen localises proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-deposited collagen and that predominantly laiddown by myofibroblasts. Macrophage-specific targeting of col4a3bpa and cognate col4a1 in zebrafish significantly reduces scarring in cryoinjured hosts. Our 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.

Neural crest (NC) is a vertebrate-specific population of multipotent embryonic cells predisposed to particular derivatives along the anteroposterior (A-P) axis. While only cranial NC progenitors give rise to ectomesenchymal cell types, trunk NC is biased for neuronal cell fates. By integrating multimodal single-cell analysis we uncovered heterogenous NC cells across the entire A-P axis expressing NC regulator foxd3. We pinpointed to its specific cranial and trunk auto-regulated enhancers. The trunk foxd3 enhancer, however, did not mark the bona fide NC, but bipotent tailbud neuromesodermal progenitors (NMps). A subset of these NMp-derived pro-neural cells appeared to give rise to neuronal trunk NC in amniotes in vivo, suggesting that at least a portion of trunk NC progenitors with a bias for neuronal fates originated from NMps in vivo.

No abstract