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Cardiac fibrosis versus regeneration: lessons learned from the zebrafish

Final Report Summary - CAREFISH (Cardiac fibrosis versus regeneration: lessons learned from the zebrafish)

The global goal of this project was to gain further insight into the molecular mechanism through which zebrafish is able to regenerate its ventricle after a cryoinjury [1-3]. We studied in detail how the zebrafish heart recovers its function upon cardiac cryoinjury. Using echocardiography, we found that in zebrafish cryoinjury has a long-lasting effect in the contractility of newly formed cardiomyocytes, which partially mimics what is observed in humans after myocardial infarction. Functional assessment of heart regeneration by echocardiography allows for a better understanding of the mechanisms involved in cardiac regeneration and has the advantage of being easily transferable to other cardiovascular disease models. The host lab has previously shown that cardiac regeneration in the zebrafish is preceded by massive collagen deposition and that the epicardium is an important source of fibroblasts [4]. This layer is composed of a heterogeneous cell population. In order to better understand the different populations of epicardial derived cells we compared the epicardial expression pattern during cardiac regeneration of several transgenic reporter lines [5]. Next, we studied the changes in gene expression during fibrotic tissue degradation and myocardial regeneration, specifically focusing on extracellular matrix production and degradation. We found a group of genes previously described to play a key role in the cross-linking of collagen and elastin fibbers. Previous studies have demonstrated the important role played by collagen cross-linking in maintaining scar structure as well as the difficulty the organisms have to degrade this mature scar tissue, which in the case of myocardial infarction leads to heart failure[6].
Our current findings indicate that a fibrotic response precedes cardiac regeneration in a model of ventricular cryoinjury. Moreover, the fibrotic response might be important to allow correct regeneration to proceed, since blocking of collagen maturation impairs cardiac regeneration. These results suggest that a fine balance between a fibrotic response and myocardial regeneration are at play in the injured adult zebrafish heart.
1. Chablais, F., Veit, J., Rainer, G., and Jazwinska, A. (2011). The zebrafish heart regenerates after cryoinjury-induced myocardial infarction. BMC Developmental Biology 11, 21.
2. González-Rosa, J.M. Martín, V., Peralta, M., Torres, M., and Mercader, N. (2011). Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish. Development 138, 1663-1674.
3. Schnabel K1, W.C. Kurth T, Weidinger G. (2011). Regeneration of cryoinjury induced necrotic heart lesions in zebrafish is associated with epicardial activation and cardiomyocyte proliferation. Plos One 6.
4. González-Rosa, J.M. Peralta, M., and Mercader, N. (2012). Pan-epicardial lineage tracing reveals that epicardium derived cells give rise to myofibroblasts and perivascular cells during zebrafish heart regeneration. Developmental biology 370, 173-186.
5. Peralta, M., González-Rosa, J.M. Marques, I.J. and Mercader, N. (2014). The Epicardium in the Embryonic and Adult Zebrafish. Journal of developmental biology 2, 101-116.
6. Sivakumar P., G.S. Sarkar S. , Sen S. (2008). Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy. Molecular Cell Biochemistry 307, 159-167.