Abstract
Zebrafish could be an interesting translational model to understand and improve the post-infarction trial and possible regeneration in humans. The adult zebrafish is able to regenerate efficiently after resecting nearly 20% of the ventricular apex. This process requires the concert activation of the epicardium and endocardium, as well as trans-differentiation of pre-existing cardiomyocytes that together replace the lost tissue. The molecular mechanisms involved in this activation process are not completely clarified. In this work, in order to investigate if the downregulation of these miRNAs (miRs) are linked with the activation of epicardium, the expressions of miR-133a, b and miR-1 during regeneration were analysed. qPCR analyses in whole-heart, or from distinct dissected epicardial cells comparing to regenerative clot (containing cardiomyocytes, fibroblasts and endocardial cells) by a laser-micro-dissector, have indicated that already at 24 h there is a downregulation of miRs: (1) miR-133a and miR-1 in the epicardium and (2) miR-133b and miR-1 in the regenerative clot. All the miRs remain downregulated until 7 days post-surgery. With the aim to visualize the activations of heart component in combination with miRs, we developed immunohistochemistry using antibodies directed against common markers in mammals as well as zebrafish: Wilms tumour 1 (WT1), a marker of epicardium; heat-shock protein 70 (HSP70), a chaperon activated during regeneration; and the Cardiac Troponin T (cTnT), a marker of differentiated cardiomyocytes. All these markers are directly or indirectly linked to the investigated miRs. WT1 and HSP70 strongly marked the regeneration site just at 2–3 days postventricular resection. In coherence, cTnT intensively marked the regenerative portion from 7 days onwards. miRs-1 and -133 (a,b) have been strongly involved in the activation of epicardium and regenerative clot during the regeneration process in zebrafish. This study can be a useful translational model to understand the early epicardial activation in which miRs-133a and miR-1 seem to play a central role as observed in the human heart.
Highlights
Zebrafish could be an interesting translational model to understand and improve the post-infarction trial and possible regeneration in humans
epicardium-derived cells (EDC) and epicardial cells (EPCs) respond to fibroblast growth factors (FGFs) in both embryogenesis and regeneration processes and undergo a number of cellular modifications[11] that is required to activate the transition from epithelial to mesenchymal cells, such as cytoskeletal rearrangement and expression of hyaluronan-mediated motility receptor, neccessaries to move in the damage site 12,13
The microRNAs play a regulatory role in the development and homoeostasis of different tissues[15,16,17], including the heart[15,17,18,19]. They are involved in the activation of fibroblasts in producing FGFs20,21 as well as the hypertrophic response of epithelial and muscular cells after injury to compensate for the loss of contractile tissue17. miR-1/miR-133 are mainly implicated in post lesion in mammals as well as in zebrafish[14,17,22,23]
Summary
Zebrafish could be an interesting translational model to understand and improve the post-infarction trial and possible regeneration in humans. With the aim to visualize the activations of heart component in combination with miRs, we developed immunohistochemistry using antibodies directed against common markers in mammals as well as zebrafish: Wilms tumour 1 (WT1), a marker of epicardium; heat-shock protein 70 (HSP70), a chaperon activated during regeneration; and the Cardiac Troponin T (cTnT), a marker of differentiated cardiomyocytes All these markers are directly or indirectly linked to the investigated miRs. WT1 and HSP70 strongly marked the regeneration site just at 2–3 days postventricular resection. The microRNAs (miRs) play a regulatory role in the development and homoeostasis of different tissues[15,16,17], including the heart[15,17,18,19] In the latter, they are involved in the activation of fibroblasts in producing FGFs20,21 as well as the hypertrophic response of epithelial and muscular cells after injury to compensate for the loss of contractile tissue. They are involved in the activation of fibroblasts in producing FGFs20,21 as well as the hypertrophic response of epithelial and muscular cells after injury to compensate for the loss of contractile tissue17. miR-1/miR-133 are mainly implicated in post lesion in mammals as well as in zebrafish[14,17,22,23]
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