Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration
- Children's Hospital Los Angeles, United States
- University of California, Los Angeles, United States
- University of Münster, Germany
Abstract
The cardiac lymphatic vascular system and its potentially critical functions in heart patients have been largely underappreciated, in part due to a lack of experimentally accessible systems. We here demonstrate that cardiac lymphatic vessels develop in young adult zebrafish, using coronary arteries to guide their expansion down the ventricle. Mechanistically, we show that in cxcr4a mutants with defective coronary artery development, cardiac lymphatic vessels fail to expand onto the ventricle. In regenerating adult zebrafish hearts the lymphatic vasculature undergoes extensive lymphangiogenesis in response to a cryoinjury. A significant defect in reducing the scar size after cryoinjury is observed in zebrafish with impaired Vegfc/Vegfr3 signaling that fail to develop intact cardiac lymphatic vessels. These results suggest that the cardiac lymphatic system can influence the regenerative potential of the myocardium.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 3, 4, 5 and 6
Article and author information
Author details
Michael RM Harrison
Stefan Schulte-Merker
Funding
National Heart, Lung, and Blood Institute (1R01HL130172)
- Ching-Ling Lien
Children's Hospital Los Angeles (2nd R01 and Team Awards)
- Ching-Ling Lien
American Heart Association (I81PA34180044)
- Ching-Ling Lien
California Institute for Regenerative Medicine (EDUC2-08418)
- Jessi Villafuerte
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experimentation: All zebrafish husbandry was performed under standard conditions, and all animal experiments were performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and following the ARRIVE guidelines provided by the National Centre for the Replacement, Refinement and Reduction of Animals in Research. All procedures were carried out as approved by the Children's Hospital Los Angeles (CHLA)institutional animal care and use committee (IACUC) protocols (#201-18 and 212-16).
Copyright
© 2019, Harrison et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,561
- views
-
- 743
- downloads
-
- 63
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration
eLife 8:e42762.
https://doi.org/10.7554/eLife.42762
Further reading
-
- Developmental Biology
- Stem Cells and Regenerative Medicine
Experiments on zebrafish show that the regeneration of the heart after an injury is supported by lymphatic vessels.
-
- Developmental Biology
- Genetics and Genomics
Smads and their transcription factor partners mediate the transcriptional responses of target cells to secreted ligands of the transforming growth factor-β (TGF-β) family, including those of the conserved bone morphogenetic protein (BMP) family, yet only a small number of direct target genes have been well characterized. In C. elegans, the BMP2/4 ortholog DBL-1 regulates multiple biological functions, including body size, via a canonical receptor-Smad signaling cascade. Here, we identify functional binding sites for SMA-3/Smad and its transcriptional partner SMA-9/Schnurri based on ChIP-seq peaks (identified by modEncode) and expression differences of nearby genes identified from RNA-seq analysis of corresponding mutants. We found that SMA-3 and SMA-9 have both overlapping and unique target genes. At a genome-wide scale, SMA-3/Smad acts as a transcriptional activator, whereas SMA-9/Schnurri direct targets include both activated and repressed genes. Mutations in sma-9 partially suppress the small body size phenotype of sma-3, suggesting some level of antagonism between these factors and challenging the prevailing model for Schnurri function. Functional analysis of target genes revealed a novel role in body size for genes involved in one-carbon metabolism and in the endoplasmic reticulum (ER) secretory pathway, including the disulfide reductase dpy-11. Our findings indicate that Smads and SMA-9/Schnurri have previously unappreciated complex genetic and genomic regulatory interactions that in turn regulate the secretion of extracellular components like collagen into the cuticle to mediate body size regulation.
