Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration.

Jana Koth,Roger K Patient,William T Stockdale,Andrew Jefferson,Mathilda T M Mommersteeg,Abigail C Killen,Florian Bonkhofer,Paul R Riley,Berthold Göttgens,Xiaonan Wang,Helen G Potts

doi:10.1242/dev.186569

Abstract

ABSTRACTRunx1 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, and that absence of runx1 results in increased myocardial survival and proliferation, and overall heart regeneration, accompanied by decreased fibrosis. 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. Both these populations cannot be identified in runx1 mutant wounds that contain less collagen and fibrin. The reduction in fibrin in the mutant is further explained by reduced myofibroblast formation and 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. Our findings suggest that Runx1 controls the regenerative response of multiple cardiac cell types and that targeting Runx1 is a novel therapeutic strategy for inducing endogenous heart repair.

Highlights

Heart regeneration potential varies considerably between species as well as with age
Runx1 becomes widely expressed in zebrafish hearts after injury To evaluate runx1 expression in the adult heart, we induced cryoinjury using a liquid nitrogen-cooled probe in the Tg(BAC-runx1P2: Citrine) zebrafish line, in which cytoplasmic Citrine fluorescence is placed under the control of the runx1 P2 promoter (Bonkhofer et al, 2019)
The expression of high levels of smooth muscle and collagen genes is a hallmark of myofibroblasts, but we identified both endocardial cells and thrombocytes as expressing myofibroblastlike genes after injury

Summary

Introduction

Heart regeneration potential varies considerably between species as well as with age. In models of successful regeneration, remaining cardiomyocytes have been shown to proliferate and to replace the fibrotic tissue with new heart muscle (Jopling et al, 2010; Kikuchi et al, 2010; Chablais et al, 2011; González-Rosa et al, 2011). This is dependent on a fine balance of interaction with other cell types, including the epicardium and endocardium (González-Rosa et al, 2017; Cao and Poss, 2018). We report a role for Runx in regulating the delicate balance between collagen and fibrin degradation, and myocardial regeneration

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Results

Conclusion