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.
Ethics
Animal experimentation: Animal experiments were carried out under ethical approval from the Swedish Board of Agriculture (5.2.18-7558/14).
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
The evolutionarily conserved Hippo (Hpo) pathway has been shown to impact early development and tumorigenesis by governing cell proliferation and apoptosis. However, its post-developmental roles are relatively unexplored. Here, we demonstrate its roles in post-mitotic cells by showing that defective Hpo signaling accelerates age-associated structural and functional decline of neurons in Caenorhabditis elegans. Loss of wts-1/LATS, the core kinase of the Hpo pathway, resulted in premature deformation of touch neurons and impaired touch responses in a yap-1/YAP-dependent manner, the downstream transcriptional co-activator of LATS. Decreased movement as well as microtubule destabilization by treatment with colchicine or disruption of microtubule-stabilizing genes alleviated the neuronal deformation of wts-1 mutants. Colchicine exerted neuroprotective effects even during normal aging. In addition, the deficiency of a microtubule-severing enzyme spas-1 also led to precocious structural deformation. These results consistently suggest that hyper-stabilized microtubules in both wts-1-deficient neurons and normally aged neurons are detrimental to the maintenance of neuronal structural integrity. In summary, Hpo pathway governs the structural and functional maintenance of differentiated neurons by modulating microtubule stability, raising the possibility that the microtubule stability of fully developed neurons could be a promising target to delay neuronal aging. Our study provides potential therapeutic approaches to combat age- or disease-related neurodegeneration.
