Proper migration of lymphatic endothelial cells requires survival and guidance cues from arterial mural cells
- Uppsala University, Sweden
- Nippon Medical School, Japan
- WWU Münster, Germany
- National Cerebral and Cardiovascular Center, Japan
- University of Massachusetts Medical School, United States
Abstract
The migration of lymphatic endothelial cells (LECs) is key for the development of the complex and vast lymphatic vascular network that pervades most tissues in an organism. In zebrafish, arterial intersegmental vessels together with chemokines have been shown to promote lymphatic cell migration from the horizontal myoseptum (HM). We observed that emergence of mural cells around the intersegmental arteries coincides with lymphatic departure from HM which raised the possibility that arterial mural cells promote LEC migration. Our live imaging and cell ablation experiments revealed that LECs migrate slower and fail to establish the lymphatic vascular network in the absence of arterial mural cells. We determined that mural cells are a source for the C-X-C motif chemokine 12 (Cxcl12a and Cxcl12b), Vascular endothelial growth factor C (Vegfc) and Collagen and calcium-binding EGF domain-containing protein 1 (Ccbe1). We showed that chemokine and growth factor signalling function cooperatively to induce robust LEC migration. Specifically, Vegfc-Vegfr3 signalling, but not chemokines, induces extracellular signal-regulated kinase (ERK) activation in LECs, and has an additional pro-survival role in LECs during the migration. Together, the identification of mural cells as a source for signals that guide LEC migration and survival will be important in the future design for rebuilding lymphatic vessels in disease contexts.
Data availability
All data generated or analysed during this study are included in the manuscript and all the source are uploaded
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Integrated molecular analysis identifies new developmental pericyte markers in zebrafishNCBI Gene Expression Omnibus, GSE176129.
Article and author information
Author details
Katarzyna Koltowska
Funding
Knut och Alice Wallenbergs Stiftelse (2017.0144)
- Katarzyna Koltowska
Ragnar Söderbergs stiftelse (M13/17)
- Katarzyna Koltowska
Vetenskapsrådet (VR-MH-2016-01437)
- Katarzyna Koltowska
Ragnar Söderbergs stiftelse (M13/17)
- Di Peng
Jeanssons Stiftelser (n/a)
- Katarzyna Koltowska
Deutsche Forschungsgemeinschaft (CRC1348B08)
- Melina Hußmann
Deutsche Forschungsgemeinschaft (CRC1348B08)
- Stefan Schulte-Merker
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Gou Young Koh, Institute of Basic Science and Korea Advanced Institute of Science and Technology (KAIST), Korea (South), Republic of
Ethics
Animal experimentation: Animal experiments were carried out under ethical approval from the Swedish Board of Agriculture (5.2.18-7558/14).
Version history
- Preprint posted: June 30, 2021 (view preprint)
- Received: September 22, 2021
- Accepted: March 21, 2022
- Accepted Manuscript published: March 22, 2022 (version 1)
- Version of Record published: April 25, 2022 (version 2)
- Version of Record updated: June 12, 2023 (version 3)
Copyright
© 2022, Peng 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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Proper migration of lymphatic endothelial cells requires survival and guidance cues from arterial mural cells
eLife 11:e74094.
https://doi.org/10.7554/eLife.74094
Further reading
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- Developmental Biology
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During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.
