The zebrafish heart regenerates after ventricular damage through a process involving inflammation, fibrotic tissue deposition/removal and myocardial regeneration. Using 3D whole-mount imaging, we reveal a highly dynamic endocardium during cardiac regeneration, including changes in cell morphology, behaviour and gene expression. These events lay the foundation for an initial expansion of the endocardium that matures to form a coherent endocardial structure within the injury site. We studied two important endocardial molecules, Serpine1 and Notch, which are implicated in different aspects of endocardial regeneration. Notch signalling regulates developmental gene expression and features of endocardial maturation. Also, Notch manipulation interferes with attenuation of the inflammatory response and cardiomyocyte proliferation and dedifferentiation. serpine1 is strongly expressed very early in the wound endocardium, with decreasing expression at later time points. serpine1 expression persists in Notch-abrogated hearts, via what appears to be a conserved mechanism. Functional inhibition studies show that Serpine1 controls endocardial maturation and proliferation and cardiomyocyte proliferation. Thus, we describe a highly dynamic endocardium in the regenerating zebrafish heart, with two key endocardial players, Serpine1 and Notch signalling, regulating crucial regenerative processes.
The authors declare no competing or financial interests.
J.M., D.G., A.G.-R., R.T.-C. performed experiments. J.M. and J.L.d.l.P. designed experiments, reviewed the data and wrote the manuscript. All authors reviewed the manuscript during its preparation.
This work was supported by grants SAF2013-45543-R, RD12/0042/0005 (RIC), RD12/0019/0003 (TERCEL) and CB16/11/00399 (CIBER CV) from the Spanish Ministry of Economy, Industry and Competitiveness [Ministerio de Economía, Industria y Competitividad (MINECO)]; FP7-ITN 215761 (NotchIT) and PITN-GA-2011-289600 (CardioNeT) from the European Commission to J.L.d.l.P. J.M. held a PhD fellowship linked to grant FP7-ITN 215761 (NotchIT). The cost of this publication has been paid in part with Fonds Européen de Développement Régional (FEDER) funds. The CNIC is supported by MINECO and the Pro-CNIC Foundation, and is a ‘Severo Ochoa' Center of Excellence (MINECO award SEV-2015-0505).
RNA-seq data are deposited at NCBI Gene Expression Omnibus under accession number GSE68650.
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.143362.supplemental
- Received August 12, 2016.
- Accepted February 20, 2017.