Specific fibroblast subpopulations and neuronal structures provide local sources of Vegfc-processing components during zebrafish lymphangiogenesis

Guangxia Wang, Lars Muhl, Yvonne Padberg, Laura Dupont, Josi Peterson-Maduro, Martin Stehling, Ferdinand Noble, Alain Colige, Christer Betsholtz, Stefan Schulte-Merker () and Andreas Impel ()
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Guangxia Wang: Institute for Cardiovascular Organogenesis and Regeneration, WWU Münster
Lars Muhl: Karolinska Institutet
Yvonne Padberg: Institute for Cardiovascular Organogenesis and Regeneration, WWU Münster
Laura Dupont: GIGA, University of Liège
Josi Peterson-Maduro: Hubrecht Institute–KNAW & UMC Utrecht
Martin Stehling: Flow Cytometry Unit, Max Planck Institute for Molecular Biomedicine
Ferdinand Noble: Zoological Institute and Institute of Biological and Chemical Systems, Karlsruhe Institute of Technology (KIT)
Alain Colige: GIGA, University of Liège
Christer Betsholtz: Karolinska Institutet
Stefan Schulte-Merker: Institute for Cardiovascular Organogenesis and Regeneration, WWU Münster
Andreas Impel: Institute for Cardiovascular Organogenesis and Regeneration, WWU Münster

Nature Communications, 2020, vol. 11, issue 1, 1-21

Abstract: Abstract Proteolytical processing of the growth factor VEGFC through the concerted activity of CCBE1 and ADAMTS3 is required for lymphatic development to occur. How these factors act together in time and space, and which cell types produce these factors is not understood. Here we assess the function of Adamts3 and the related protease Adamts14 during zebrafish lymphangiogenesis and show both proteins to be able to process Vegfc. Only the simultaneous loss of both protein functions results in lymphatic defects identical to vegfc loss-of-function situations. Cell transplantation experiments demonstrate neuronal structures and/or fibroblasts to constitute cellular sources not only for both proteases but also for Ccbe1 and Vegfc. We further show that this locally restricted Vegfc maturation is needed to trigger normal lymphatic sprouting and directional migration. Our data provide a single-cell resolution model for establishing secretion and processing hubs for Vegfc during developmental lymphangiogenesis.

Date: 2020
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DOI: 10.1038/s41467-020-16552-7

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