PT  - JOURNAL ARTICLE
AU  - Jana Koth
AU  - Xiaonan Wang
AU  - Abigail C. Killen
AU  - William T. Stockdale
AU  - Helen G. Potts
AU  - Andrew Jefferson
AU  - Florian Bonkhofer
AU  - Paul R. Riley
AU  - Roger Patient
AU  - Berthold Göttgens
AU  - Mathilda T.M. Mommersteeg
TI  - Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration
AID  - 10.1101/799163
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 799163
4099  - http://biorxiv.org/content/early/2019/10/14/799163.short
4100  - http://biorxiv.org/content/early/2019/10/14/799163.full
AB  - Runx1 is a transcription factor that plays a key role in determining the proliferative and differential state of multiple cell-types, during both development and adulthood. Here, we report how runx1 is specifically upregulated at the injury site during zebrafish heart regeneration, but unexpectedly, absence of runx1 results in enhanced regeneration. Using single cell sequencing, we found that the wild-type injury site consists of Runx1-positive endocardial cells and thrombocytes that induce expression of smooth muscle and collagen genes without differentiating into myofibroblasts. Both these populations are absent in runx1 mutants, resulting in a less collagenous and fibrinous scar. The reduction in fibrin in the mutant is further explained by reduced myofibroblast formation and by upregulation of components of the fibrin degradation pathway, including plasminogen receptor Annexin 2A as well as downregulation of plasminogen activator inhibitor serpine1 in myocardium and endocardium, resulting in increased levels of Plasminogen. In addition, we find enhanced myocardial proliferation as well as increased myocardial survival in the mutant. Our findings suggest that Runx1 controls the regenerative response of multiple cardiac cell-types and that targeting Runx1 is a novel therapeutic strategy to induce endogenous heart repair.