Vegfc/d-dependent regulation of the lymphatic vasculature during cardiac regeneration is influenced by injury context

The lymphatic vasculature mediates essential physiological functions including fluid homeostasis, lipid and hormone transport, and immune cell trafficking. Recent studies have suggested that promoting lymphangiogenesis enhances cardiac repair following injury, but it is unknown whether lymphangiogen...

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Bibliographic Details
Published in:npj Regenerative medicine 2019-08, Vol.4 (1), p.18-14, Article 18
Main Authors: Vivien, Céline J., Pichol-Thievend, Cathy, Sim, Choon Boon, Smith, Jacob B., Bower, Neil I., Hogan, Benjamin M., Hudson, James E., Francois, Mathias, Porrello, Enzo R.
Format: Article
Language:English
Subjects:
631/443/592/16
631/443/592/2725
Biomaterials
Biomedical and Life Sciences
Biomedicine
Cell Biology
Homeostasis
Immunology
Regenerative Medicine/Tissue Engineering
Stem Cells
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Summary:The lymphatic vasculature mediates essential physiological functions including fluid homeostasis, lipid and hormone transport, and immune cell trafficking. Recent studies have suggested that promoting lymphangiogenesis enhances cardiac repair following injury, but it is unknown whether lymphangiogenesis is required for cardiac regeneration. Here, we describe the anatomical distribution, regulation, and function of the cardiac lymphatic network in a highly regenerative zebrafish model system using transgenic reporter lines and loss-of-function approaches. We show that zebrafish lacking functional vegfc and vegfd signaling are devoid of a cardiac lymphatic network and display cardiac hypertrophy in the absence of injury, suggesting a role for these vessels in cardiac tissue homeostasis. Using two different cardiac injury models, we report a robust lymphangiogenic response following cryoinjury, but not following apical resection injury. Although the majority of mutants lacking functional vegfc and vegfd signaling were able to mount a full regenerative response even in the complete absence of a cardiac lymphatic vasculature, cardiac regeneration was severely impaired in a subset of mutants, which was associated with heightened pro-inflammatory cytokine signaling. These findings reveal a context-dependent requirement for the lymphatic vasculature during cardiac growth and regeneration.
ISSN:2057-3995
2057-3995
DOI:10.1038/s41536-019-0079-2