Macrophages directly contribute collagen to scar formation as part of heart regeneration in zebrafish and heart repair in mice. This finding by Paul Riley and colleagues develops the current paradigm of scar formation, in which collagen is generated exclusively via macrophage-mediated activation of cardiac fibroblasts into myofibroblasts.
In zebrafish, resection of the ventricle results in complete heart regeneration, without scar formation. By contrast, heart cryoinjury results in transient scar formation and delayed regeneration. In neonatal mice, the heart can regenerate during the first 7 days after birth, after which regenerative capacity is replaced by fibrotic scar formation.
In both zebrafish and mice, unbiased transcriptomics revealed an upregulation of the expression of collagens in cardiac macrophages after heart injury. In zebrafish, adoptive transfer of macrophages expressing fluorescently tagged collagen into the cryo-injured heart indicated a direct contribution of macrophage-produced collagen to scar formation. Moreover, the transfer of macrophages from resection-injured (scar-free) hearts into cryo-injured (scar-inducing) hearts resulted in excessive scarring, indicating that donor macrophages from adult zebrafish retained plasticity and could be reprogrammed by the change from a regenerative to a scar-forming environment.
Adoptive transfer of splenic macrophages expressing GFPtpz-labelled collagen from adult mice into the hearts of adult wild-type mice undergoing myocardial infarction surgery resulted in the presence of extensive GFPtpz+ collagen in the infarct scar. Of note, transfer of GFPtpz-collagen-labelled macrophages from adult mice into the hearts of neonatal mice undergoing cardiac injury blocked regeneration and resulted in scarring containing GFPtpz+ collagen. This lack of plasticity of macrophages from adult mice (in contrast to those from adult zebrafish) might partly underlie the loss of cardiac regenerative capacity in adult mice and the absence of cardiac regenerative capacity in humans.
Riley and colleagues now plan further characterization and quantification of the relative contributions of macrophages and myofibroblasts to collagen deposition in the injured hearts of zebrafish and mice. They also hope to extrapolate their research to patients with acute myocardial infarction to determine what role the direct production of collagen by macrophages might have in humans.
“This lack of plasticity of macrophages from adult mice … might partly underlie the loss of cardiac regenerative capacity”
“Recent studies have revealed somewhat surprising roles for macrophages in the heart, such as in electrical conductance,” comments Rebecca Richardson (University of Bristol, UK), who was not involved in the study. “This study demonstrates additional surprising roles for cardiac macrophages, namely that they can directly make scar collagen themselves. Future research will determine the full functional relevance of this macrophage-derived collagen (as opposed to typical myofibroblast-derived collagen).”
Simões, F. C. et al. Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair. Nat. Commun. 11, 600 (2020)
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Cao, J. & Poss, K. D. The epicardium as a hub for heart regeneration. Nat. Rev. Cardiol. 15, 631–647 (2018)
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Lim, G.B. Macrophages produce collagen for myocardial scar formation. Nat Rev Cardiol 17, 267 (2020). https://doi.org/10.1038/s41569-020-0353-4