Intracellular uptake of macromolecules by brain lymphatic endothelial cells during zebrafish embryonic development

  1. Max van Lessen
  2. Shannon Shibata-Germanos
  3. Andreas van Impel
  4. Thomas A Hawkins
  5. Jason Rihel
  6. Stefan Schulte-Merker  Is a corresponding author
  1. Westfälische Wilhelms-Universität Münster, Germany
  2. University College London, United Kingdom

Abstract

The lymphatic system controls fluid homeostasis and the clearance of macromolecules from interstitial compartments. In mammals brain lymphatics were only recently discovered, with significant implications for physiology and disease. We examined zebrafish for the presence of brain lymphatics and found loosely connected endothelial cells with lymphatic molecular signature covering parts of the brain without forming endothelial tubular structures. These brain lymphatic endothelial cells (BLECs) derive from venous endothelium, are distinct from macrophages, and are sensitive to loss of Vegfc. BLECs endocytose macromolecules in a selective manner, which can be blocked by injection of mannose receptor ligands. This first report on brain lymphatic endothelial cells in a vertebrate embryo identifies cells with unique features, including the uptake of macromolecules at a single cell level. Future studies will address whether this represents an uptake mechanism that is conserved in mammals and how these cells affect functions of the embryonic and adult brain.

Article and author information

Author details

  1. Max van Lessen

    Institute of Cardiovascular Organogenesis and Regeneration, Westfälische Wilhelms-Universität Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Shannon Shibata-Germanos

    Department of Cell and Developmental Biology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Andreas van Impel

    Institute of Cardiovascular Organogenesis and Regeneration, Westfälische Wilhelms-Universität Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Thomas A Hawkins

    Department of Cell and Developmental Biology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Jason Rihel

    Department of Cell and Developmental Biology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Stefan Schulte-Merker

    Institute for Cardiovascular Organogenesis and Regeneration, Westfälische Wilhelms-Universität Münster, Muenster, Germany
    For correspondence
    schultes@ukmuenster.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3617-8807

Funding

Deutsche Forschungsgemeinschaft (FOR2325)

  • Stefan Schulte-Merker

Deutsche Forschungsgemeinschaft (CiM 1003)

  • Max van Lessen

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

Ethics

Animal experimentation: Experimental procedures were conducted under project licence awarded to J.R. from the UK Home Office (Permit Number: 70/7612), according to the UK Animals (Scientific Procedures) Act 1986.

Copyright

© 2017, van Lessen 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.

Metrics

  • 5,503
    views
  • 884
    downloads
  • 80
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Max van Lessen
  2. Shannon Shibata-Germanos
  3. Andreas van Impel
  4. Thomas A Hawkins
  5. Jason Rihel
  6. Stefan Schulte-Merker
(2017)
Intracellular uptake of macromolecules by brain lymphatic endothelial cells during zebrafish embryonic development
eLife 6:e25932.
https://doi.org/10.7554/eLife.25932

Share this article

https://doi.org/10.7554/eLife.25932

Further reading

    1. Developmental Biology
    Michele Bertacchi, Gwendoline Maharaux ... Michèle Studer
    Research Article

    The morphogen FGF8 establishes graded positional cues imparting regional cellular responses via modulation of early target genes. The roles of FGF signaling and its effector genes remain poorly characterized in human experimental models mimicking early fetal telencephalic development. We used hiPSC-derived cerebral organoids as an in vitro platform to investigate the effect of FGF8 signaling on neural identity and differentiation. We found that FGF8 treatment increases cellular heterogeneity, leading to distinct telencephalic and mesencephalic-like domains that co-develop in multi-regional organoids. Within telencephalic domains, FGF8 affects the anteroposterior and dorsoventral identity of neural progenitors and the balance between GABAergic and glutamatergic neurons, thus impacting spontaneous neuronal network activity. Moreover, FGF8 efficiently modulates key regulators responsible for several human neurodevelopmental disorders. Overall, our results show that FGF8 signaling is directly involved in both regional patterning and cellular diversity in human cerebral organoids and in modulating genes associated with normal and pathological neural development.

    1. Cell Biology
    2. Developmental Biology
    Sarah Rubin, Ankit Agrawal ... Elazar Zelzer
    Research Article Updated

    Chondrocyte columns, which are a hallmark of growth plate architecture, play a central role in bone elongation. Columns are formed by clonal expansion following rotation of the division plane, resulting in a stack of cells oriented parallel to the growth direction. In this work, we analyzed hundreds of Confetti multicolor clones in growth plates of mouse embryos using a pipeline comprising 3D imaging and algorithms for morphometric analysis. Surprisingly, analysis of the elevation angles between neighboring pairs of cells revealed that most cells did not display the typical stacking pattern associated with column formation, implying incomplete rotation of the division plane. Morphological analysis revealed that although embryonic clones were elongated, they formed clusters oriented perpendicular to the growth direction. Analysis of growth plates of postnatal mice revealed both complex columns, composed of ordered and disordered cell stacks, and small, disorganized clusters located in the outer edges. Finally, correlation between the temporal dynamics of the ratios between clusters and columns and between bone elongation and expansion suggests that clusters may promote expansion, whereas columns support elongation. Overall, our findings support the idea that modulations of division plane rotation of proliferating chondrocytes determines the formation of either clusters or columns, a multifunctional design that regulates morphogenesis throughout pre- and postnatal bone growth. Broadly, this work provides a new understanding of the cellular mechanisms underlying growth plate activity and bone elongation during development.