The cardiopharyngeal mesoderm contributes to lymphatic vessel development in mouse

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Abstract

Lymphatic vessels are crucial for tissue homeostasis and immune responses in vertebrates. Recent studies have demonstrated that lymphatic endothelial cells (LECs) arise from both venous sprouting (lymphangiogenesis) and de novo production from non-venous origins (lymphvasculogenesis), which is similar to blood vessel formation through angiogenesis and vasculogenesis. However, the contribution of LECs from non-venous origins to lymphatic networks is considered to be relatively small. Here, we identify the Islet1 (Isl1)-expressing cardiopharyngeal mesoderm (CPM) as a non-venous origin of craniofacial and cardiac LECs. Genetic lineage tracing with Isl1^Cre/+ and Isl1^CreERT2/+ mice suggested that a subset of CPM cells gives rise to LECs. These CPM-derived LECs are distinct from venous-derived LECs in terms of their developmental processes and anatomical locations. Later, they form the craniofacial and cardiac lymphatic vascular networks in collaboration with venous-derived LECs. Collectively, our results demonstrate that there are two major sources of LECs, the cardinal vein and the CPM. As the CPM is evolutionarily conserved, these findings may improve our understanding of the evolution of lymphatic vessel development across species. Most importantly, our findings may provide clues to the pathogenesis of lymphatic malformations, which most often develop in the craniofacial and mediastinal regions.

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All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figure 1H-source data 1, Figure 2 - Figure supplement 1I-source data 1, Figure 2H-source data 1, Figure 2P-source data 1, Figure 4O-source data 1, Figure 5 - Figure supplement 1A-F-source data 1, Figure 5 - Figure supplement 1O and P-source data 1, Figure 5K-R-source data 1, and Figure 6-Figure supplement 2-source data1.

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Kazuaki Maruyama

Department of Physiological Chemistry and Metabolism, University of Tokyo, Bunkyo-ku, Japan

For correspondence
k.maruyama0608@gmail.com

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3935-328X
Sachiko Miyagawa-Tomita

Department of Animal Nursing Science, Yamazaki University of Animal Health Technology, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Yuka Haneda

Department of Physiological Chemistry and Metabolism, University of Tokyo, Bunkyo-ku, Japan

Competing interests
The authors declare that no competing interests exist.
Mayuko Kida

Department of Physiological Chemistry and Metabolism, University of Tokyo, Bunkyo-ku, Japan

Competing interests
The authors declare that no competing interests exist.
Fumio Matsuzaki

Laboratory for Cell Asymmetry, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7902-4520
Kyoko Imanaka-Yoshida

Department of Pathology and Matrix Biology, Mie University, Mie, Japan

Competing interests
The authors declare that no competing interests exist.
Hiroki Kurihara

Department of Physiological Chemistry and Metabolism, University of Tokyo, Bunkyo-ku, Japan

For correspondence
kuri-tky@umin.net

Competing interests
The authors declare that no competing interests exist.

Funding

Core Research for Evolutional Science and Technology (JPMJCR13W2)

Hiroki Kurihara

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were approved by the University of Tokyo (ethical approval number: H17-250) and Mie University (ethical approval number: 728) animal care and use committee, and were performed in accordance with institutional guidelines.

Copyright

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.