Collagen XII Contributes to Epicardial and Connective Tissues in the Zebrafish Heart during Ontogenesis and Regeneration

Abstract

Zebrafish heart regeneration depends on cardiac cell proliferation, epicardium activation and transient reparative tissue deposition. The contribution and the regulation of specific collagen types during the regenerative process, however, remain poorly characterized. Here, we identified that the non-fibrillar type XII collagen, which serves as a matrix-bridging component, is expressed in the epicardium of the zebrafish heart, and is boosted after cryoinjury-induced ventricular damage. During heart regeneration, an intense deposition of Collagen XII covers the outer epicardial cap and the interstitial reparative tissue. Analysis of the activated epicardium and fibroblast markers revealed a heterogeneous cellular origin of Collagen XII. Interestingly, this matrix-bridging collagen co-localized with fibrillar type I collagen and several glycoproteins in the post-injury zone, suggesting its role in tissue cohesion. Using SB431542, a selective inhibitor of the TGF-β receptor, we showed that while the inhibitor treatment did not affect the expression of collagen 12 and collagen 1a2 in the epicardium, it completely suppressed the induction of both genes in the fibrotic tissue. This suggests that distinct mechanisms might regulate collagen expression in the outer heart layer and the inner injury zone. On the basis of this study, we postulate that the TGF-β signaling pathway induces and coordinates formation of a transient collagenous network that comprises fibril-forming Collagen I and fiber-associated Collagen XII, both of which contribute to the reparative matrix of the regenerating zebrafish heart.

Zebrafish heart regeneration: 15 years of discoveries

“…Both the epicardium and the endocardium create a “regenerative scaffold” that provides support and guidance during myocardial regeneration. Specifically, the epicardium and EPDCs strongly express extracellular matrix proteins such as fibronectin, periostin, collagen I and collagen XII (González‐Rosa et al., ; Marro, Pfefferli, de Preux Charles, Bise, & Jaźwińska, ; Wang et al., ). Epicardial production of Cxcl12 is also involved in guiding cardiomyocytes into the wound area and chemical inhibition of Cxcr4 receptors or prevention of fibronectin production significantly affects the correct integration of cardiomyocytes into the regenerated area (Itou et al., ; Wang et al., ).…”

Parental stressor exposure simultaneously conveys both adaptive and maladaptive larval phenotypes through epigenetic inheritance in the zebrafish (Danio rerio)

“…In addition, to better understand the full implications of parental exposure on F 1 survival, we also assessed variables directly related to reproductive success such as fecundity, fertilization, and egg and sperm quality. We also histologically assessed tissue disruption of the gonads and cardiac collagen deposition, which have been associated with oil exposure (Chablais et al, 2011;Gemberling et al, 2013;Grivas et al, 2014;Horn and Trafford, 2016;Kikuchi, 2014;Marro et al, 2016). Having assessed parental effects of oil exposure, we then determined whether the parental exposures transferred epigenetic signals enhancing survival of the offspring.…”

Altered haemodynamics causes aberrations in the epicardium

“…Epicardial fibroblasts are in part responsible for the production of collagen XII, a fibril‐associated collagen with interrupted triple helices (FACIT), which forms complexes with collagen I (Marro et al. ). Collagen XII was found in the epicardium and subepicardium of early zebrafish embryos, outlining the ventricles; as development progresses, its expression increased until it fully encases the heart and penetrates into the compact myocardium (Marro et al.…”

“…Collagen XII was found in the epicardium and subepicardium of early zebrafish embryos, outlining the ventricles; as development progresses, its expression increased until it fully encases the heart and penetrates into the compact myocardium (Marro et al. ). Further, its expression in bone and skeletal muscle has been associated with modifying the stiffness of the tissue in response to shear stress (Chiquet et al.…”