CAREFISH · Cardiac fibrosis versus regeneration: lessons learned from the zebrafish
FP7 — People (Marie Curie Actions)
- Duration
- 2013-05-01 → 2015-04-30
- EU contribution
- €173,371
- Participants
- 1
- Scheme
- MC-IEF
Lines connect the coordinator with its partners.
Results in brief
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.
Data: CORDIS, © European Union
Project objective
Myocardial infarction (MI) leading to ischemic heart disease is the most common cause of death worldwide. In mammals, MI results in the in the replacement of the damaged myocardium with a scar. However, other animals, such as teleost fish have a remarkable capacity to regenerate damaged tissue replacing it with newly formed tissue. Recently, a zebrafish model of MI has been established. Cryoinjury (CI) of 25% of the ventricle leads to massive cell death and the deposition of fibrotic tissue. While in mammals cardiac fibrosis is irreversible, in the zebrafish the scar regresses and the injured area is replaced by new cardiomyocytes. Although the regenerative capacity of the zebrafish heart was described a decade ago, little is known about its molecular mechanisms.The aim of this project is to analyse the fate of myofibroblast during cardiac regeneration in the zebrafish. Only few apoptotic myofibroblasts are detected after CI leaving several questions unanswered as to what happens to these cells.Another important aspect is to understand the molecular mechanisms behind cardiac regeneration in a MI-model in zebrafish. We will test if cardiac regeneration is accomplished by the re-expression of developmentally active genes. We will study the role of the transcription factor tbx1 (involved in cardiac development in zebrafish as well as in humans), which has been identified in a recent screen performed in the host group. We will also analyse the function of molecules secreted from the epicardium. This mesothelial layer has been recently shown to play a pivotal role during cardiac repair and, given its accessibility, poses an attractive target for therapeutic intervention.In sum, this project will characterize how in zebrafish mechanisms driving cardiomyocyte proliferation and scar formation are outbalanced to allow cardiac regeneration and propose that the findings may ultimately contribute to future therapies for the improvement of human cardiovascular health.
Original text from CORDIS.
Participants
- CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (F.S.P.) · MadridCoordinatorSpain
Links
Data: CORDIS, © European Union