Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration
- Weizmann Institute of Science, Israel
- Stanford University, United States
- Max Planck Institute for Heart and Lung Research, Germany
- Duke University, United States
Abstract
In recent years there has been increasing interest in the role of lymphatics in organ repair and regeneration, due to their importance in immune surveillance and fluid homeostasis. Experimental approaches aimed at boosting lymphangiogenesis following myocardial infarction in mice, were shown to promote healing of the heart. Yet, the mechanisms governing cardiac lymphatic growth remain unclear. Here we identify two distinct lymphatic populations in the hearts of zebrafish and mouse, one that forms through sprouting lymphangiogenesis, and the other by coalescence of isolated lymphatic cells. By tracing the development of each subset, we reveal diverse cellular origins and differential response to signaling cues. Finally, we show that lymphatic vessels are required for cardiac regeneration in zebrafish as mutants lacking lymphatics display severely impaired regeneration capabilities. Overall, our results provide novel insight into the mechanisms underlying lymphatic formation during development and regeneration, opening new avenues for interventions targeting specific lymphatic populations.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files
Article and author information
Author details
Funding
H2020 European Research Council (335605)
- Karina Yaniv
National Institutes of Health (R01 HL131319)
- Kenneth D Poss
National Institutes of Health (R01 136182)
- Kenneth D Poss
American Heart Association
- Kenneth D Poss
Fondation Leducq
- Kenneth D Poss
United States-Israel Binational Science Foundation (2015289)
- Karina Yaniv
Minerva Foundation (712610)
- Karina Yaniv
H&M Kimmel Inst. for Stem cell research, the Estate of Emile Mimran
- Karina Yaniv
National Institutes of Health (RO1-HL128503)
- Kristy Red-Horse
New York Stem Cell Foundation
- Kristy Red-Horse
Max-Planck-Gesellschaft
- Didier Y Stainier
Fondation Leducq
- Didier Y Stainier
National Institutes of Health (R01 HL081674)
- Kenneth D Poss
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#01470218-2) of the Weizmann Institute of Science. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Weizmann Institute of Science. All surgery in fish was performed under tricaine anesthesia, and every effort was made to minimize suffering.
Copyright
© 2019, Gancz 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.
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Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration
eLife 8:e44153.
https://doi.org/10.7554/eLife.44153
Further reading
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- 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.
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- Developmental Biology
The lateral line system enables fishes and aquatic-stage amphibians to detect local water movement via mechanosensory hair cells in neuromasts, and many species to detect weak electric fields via electroreceptors (modified hair cells) in ampullary organs. Both neuromasts and ampullary organs develop from lateral line placodes, but the molecular mechanisms underpinning ampullary organ formation are understudied relative to neuromasts. This is because the ancestral lineages of zebrafish (teleosts) and Xenopus (frogs) independently lost electroreception. We identified Bmp5 as a promising candidate via differential RNA-seq in an electroreceptive ray-finned fish, the Mississippi paddlefish (Polyodon spathula; Modrell et al., 2017, eLife 6: e24197). In an experimentally tractable relative, the sterlet sturgeon (Acipenser ruthenus), we found that Bmp5 and four other Bmp pathway genes are expressed in the developing lateral line, and that Bmp signalling is active. Furthermore, CRISPR/Cas9-mediated mutagenesis targeting Bmp5 in G0-injected sterlet embryos resulted in fewer ampullary organs. Conversely, when Bmp signalling was inhibited by DMH1 treatment shortly before the formation of ampullary organ primordia, supernumerary ampullary organs developed. These data suggest that Bmp5 promotes ampullary organ development, whereas Bmp signalling via another ligand(s) prevents their overproduction. Taken together, this demonstrates opposing roles for Bmp signalling during ampullary organ formation.
