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.
Reviewing Editor
- Marianne E Bronner, California Institute of Technology, United States
Publication history
- Received: December 10, 2018
- Accepted: November 5, 2019
- Accepted Manuscript published: November 8, 2019 (version 1)
- Version of Record published: November 27, 2019 (version 2)
- Version of Record updated: December 4, 2019 (version 3)
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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- Cell Biology
- Developmental Biology
Successful regeneration requires the coordinated execution of multiple cellular responses to injury. In amputated zebrafish fins, mature osteoblasts dedifferentiate, migrate towards the injury and form proliferative osteogenic blastema cells. We show that osteoblast migration is preceded by cell elongation and alignment along the proximodistal axis, which require actomyosin, but not microtubule turnover. Surprisingly, osteoblast dedifferentiation and migration can be uncoupled. Using pharmacological and genetic interventions, we found that NF-ĸB and retinoic acid signalling regulate dedifferentiation without affecting migration, while the complement system and actomyosin dynamics affect migration but not dedifferentiation. Furthermore, by removing bone at two locations within a fin ray, we established an injury model containing two injury sites. We found that osteoblasts dedifferentiate at and migrate towards both sites, while accumulation of osteogenic progenitor cells and regenerative bone formation only occur at the distal-facing injury. Together, these data indicate that osteoblast dedifferentiation and migration represent generic injury responses that are differentially regulated and can occur independently of each other and of regenerative growth. We conclude that successful fin bone regeneration appears to involve the coordinated execution of generic and regeneration-specific responses of osteoblasts to injury.
