One of the major obstacles in heart regeneration is the formation of a fibrotic scar, thought to result from the deposition of collagen and fibrin by epicardial myofibroblasts. Preventing scarring therefore has significant therapeutic potential. Here, Mathilda Mommersteeg and colleagues investigate the role of transcription factor Runx1 during zebrafish heart regeneration. Using fluorescent transgenic reporters and single-cell sequencing, they show that runx1 becomes widely expressed in the heart after injury, specifically in populations of endocardial cells and thrombocytes. These populations express genes associated with scarring, such fibrin and collagen, and smooth muscle genes that suggest an identity similar to myofibroblasts. In runx1 mutant zebrafish, however, these subsets of endocardial cells and thrombocytes are absent, and the wounds contain less collagen and fibrin, which indicates that these cells might contribute to collagen deposition instead of epicardium-derived myofibroblasts. The authors show that runx1 mutant animals also have increased myocardial cell survival and proliferation following heart injury, and increased expression of fibrin degradation (fibrinolysis) genes through upregulation of the plasminogen receptor annexin 2A. Conversely, wild-type fish strongly upregulate serpine1 upon injury, which inhibits fibrinolysis. This research demonstrates that Runx1 negatively regulates regenerative responses in the heart, providing a new therapeutic target for heart regeneration.
Heart scarring run by Runx1
Heart scarring run by Runx1. Development 15 April 2020; 147 (8): e0808. doi:
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