Abstract
The wound healing process after human myocardial infarction (MI) involves complex events to replace damaged tissue with a collagen-rich fibrotic scar, in which the muscular contraction of the affected cardiac tissue may loss its function permanently. In contrast, zebrafish displays a powerful capacity of scar-free regeneration post-cardiac injury. This implies that heart regeneration of zebrafish must have a unique mechanism to resolve the scarring retention issue. We thus adapted the ventricular cryoinjury model in this study to investigate what factors regulate scar formation and reduction during zebrafish heart regeneration. Previous studies have revealed that syndecan-4 (SDC4) plays a crucial role in regulating cardiac fibroblasts and inflammation following injury in higher vertebrates. Interestingly, our zebrafish heart regeneration microarray data indicated Sdc4 may associate with these processes. Therefore, we hypothesized that Sdc4 may be differentially regulated in scar-free repair during zebrafish heart regeneration. To investigate this hypothesis, we first conduced an expression analysis to check whether sdc4 and scar associated genes were up-regulated after heart injury in adult zebrafish. Next, we induced heart specific sdc4-knockdown via siRNA and SilenceMag magnetofection technology which enclaved the zebrafish heart with a forced magnetic field. As expected, we found decreased sdc4 expression corresponded well to zebrafish heart scar retention by AFOG staining, in which collagen deposition was inhibited. Moreover, we found mmp9 and mmp2 were also up-regulated, which supports Sdc4’s role in ECM remodeling and regression. Finally, we found tgfb1a expression was linked with sdc4 regulation, which supports the involvement of a unique Sdc4-Tgf-β signaling axis in the scar-free healing of zebrafish heart. In conclusion, Sdc4 could be a critical regulator for scar formation and retention during zebrafish heart regeneration.