Biology subjects

Marin-Juez, R.

Publications and source records attributed to Marin-Juez, R..

4 recordsLinked to original sources

bioRxiv2025

Scube2 Modulates Coronary Vessel Formation during Cardiac Growth and Regeneration in Zebrafish

Coronary vessel formation is essential for cardiac growth and regeneration, yet the mechanisms regulating these processes remain incompletely defined. In this study, we identified and characterized Scube2 as a novel regulator in coronary vessel formation and heart regeneration. Scube2 is expressed in the epicardium covering the coronary vasculature under homeostatic conditions in adult hearts and is strongly upregulated after cardiac injury. Zebrafish scube2 mutant exhibits reduced coronary vessel coverage during cardiac growth and pronounced myocardial defects, including abnormal vessel morphology, disorganized contractile fibers, and mitochondrial damage. Following injury, scube2 mutant hearts show impaired revascularization and persistent fibrosis, indicating defective regeneration. Mechanistically, transcriptomic profiling of scube2 mutant hearts reveals attenuated expression of angiogenic-related genes, including those mediated by vascular endothelial and platelet-derived growth factors, consistent with reduced proliferation of endothelial cells and cardiomyocytes during repair. In a gain-of-function setting, SCUBE2 enhances platelet-derived growth factor signaling by promoting receptor activation in HEK293 cells. These findings support a novel role for Scube2 in cardiac growth and regeneration by modulating coronary vessel formation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/695032v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@7c5b5org.highwire.dtl.DTLVardef@451c40org.highwire.dtl.DTLVardef@141c88forg.highwire.dtl.DTLVardef@1d63765_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2024

flt1 inactivation promotes zebrafish cardiac regeneration by enhancing endothelial activity and limiting the fibrotic response

Summary statementflt1 inactivation promotes zebrafish cardiac regeneration by enhancing coronary revascularization and endocardial expansion, while limiting myofibroblast differentiation. VEGFA administration has been explored as a pro-angiogenic therapy for cardiovascular diseases including heart failure for several years, but with little success. Here we investigate a different approach to augment VEGFA bioavailability: by deleting the VEGFA decoy receptor VEGFR1/FLT1, one can achieve more physiological VEGFA concentrations. We find that following cryoinjury, zebrafish flt1 mutant hearts display enhanced coronary revascularization and endocardial expansion, increased cardiomyocyte dedifferentiation and proliferation, and decreased scarring. Suppressing Vegfa signaling in flt1 mutants abrogates these beneficial effects of flt1 deletion. Transcriptomic analyses of cryoinjured flt1 mutant hearts reveal enhanced endothelial MAPK/ERK signaling and downregulation of the transcription factor gene egr3. Using newly generated genetic tools, we observe egr3 upregulation in the regenerating endocardium, and find that Egr3 promotes myofibroblast differentiation. These data indicate that with enhanced Vegfa bioavailability, the endocardium limits myofibroblast differentiation via egr3 downregulation, thereby providing a more permissive microenvironment for cardiomyocyte replenishment after injury.

molecular biology↗

bioRxiv2024

The transmembrane glycoprotein Gpnmb is required for the immune and fibrotic responses during zebrafish heart regeneration

Myocardial infarction occurs when coronary supply of oxygen and nutrients to part of the heart is interrupted. In contrast to adult mammals, adult zebrafish have a unique ability to regenerate their heart after cardiac injury. Several processes are involved in this regenerative response including inflammation, coronary endothelial cell proliferation and revascularization, endocardial expansion, cardiomyocyte repopulation, and transient scar formation. To identify potential regulators of zebrafish cardiac regeneration, we profiled the transcriptome of regenerating coronary endothelial cells at 7 days post cryoinjury (dpci) and observed the significant upregulation of dozens of genes including gpnmb. Gpnmb (glycoprotein non-metastatic melanoma protein B) is a transmembrane glycoprotein implicated in inflammation resolution and tissue regeneration. Transcriptomic profiling data of cryoinjured zebrafish hearts reveal that gpnmb is mostly expressed by macrophages. To investigate gpnmb function during zebrafish cardiac regeneration, we generated a full locus deletion (FLD) allele. We find that after cardiac cryoinjury, animals lacking gpnmb exhibit neutrophil retention and decreased macrophage recruitment as well as reduced myofibroblast numbers. Moreover, loss of gpnmb impairs coronary endothelial cell regeneration and cardiomyocyte dedifferentiation. Transcriptomic analyses of cryoinjured gpnmb mutant hearts identified enhanced collagen gene expression and the activation of extracellular matrix (ECM) related pathways. Furthermore, gpnmb mutant hearts exhibit larger fibrotic scars revealing additional defects in cardiac regeneration. Altogether, these data indicate that gpnmb expressing macrophages modulate inflammation and ECM deposition after cardiac cryoinjury in zebrafish and further highlight the importance of this subset of immune cells to support a regenerative response.

molecular biology↗

bioRxiv2019

RNA-seq analysis of a zebrafish tlr2 mutant shows a broad function of this Toll-like receptor in transcriptional and metabolic control and defense to Mycobacterium marinum infection

BackgroundThe function of Toll-like receptor 2 (TLR2) in host defense against pathogens, especially Mycobacterium tuberculosis (Mtb) is poorly understood. To investigate the role of TLR2 during mycobacterial infection, we analyzed the response of tlr2 zebrafish mutant larvae to infection with Mycobacterium marinum (Mm), a close relative to Mtb, as a model for tuberculosis. We measured infection burdens and transcriptome responses using RNA deep sequencing in mutant and control larvae.\n\nResultstlr2 mutant embryos at 2 dpf do not show morphological alterations or differences in the number of macrophages and neutrophils when compared to control embryos. However, we found substantial changes in gene expression in these mutants, particularly in developmental and metabolic pathways, when compared with the heterozygote tlr2+/- control. After Mm infection, bacterial burden was six to ten fold higher in tlr2-/- larvae than in tlr2+/-, or tlr2+/+ larvae, indicating that Tlr2 acts as a protective factor in zebrafish host defense. RNAseq analysis of infected tlr2-/- versus tlr2+/- shows that the number of up-regulated and down-regulated genes in response to infection was greatly diminished in tlr2 mutants by at least 2 fold and 10 fold, respectively. Analysis of the transcriptome data and qPCR validation shows that Mm infection of tlr2 mutants leads to decreased mRNA levels of genes involved in inflammation and immune responses, including il1b, tnfb, cxcl11aa/ac, fosl1a, and cebpb. Furthermore, RNAseq analyses revealed that the expression of genes for Maf family transcription factors, vitamin D receptors, and Dicps proteins is significantly altered in tlr2 mutants with or without infection. In addition, the data indicate a function of Tlr2 in the control of induction of cytokines and chemokines, such as the CXCR3-CXCL11 signaling axis.\n\nConclusionThe transcriptome and infection burden analyses give support for a function of TLR2 in host defense against mycobacteria. Transcriptome analysis revealed tlr2-specific pathways involved in Mm infection, which are related to responses to Mtb infection in human macrophages. Considering its dominant function in control of transcriptional processes that govern defense responses and metabolism, the TLR2 protein can be expected to be also of importance for other infectious diseases and interactions with the microbiome.

immunology↗