1. Cell Biology
  2. Developmental Biology
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Islet vascularization is regulated by primary endothelial cilia via VEGF-A dependent signaling

  1. Yan Xiong
  2. M Julia Scerbo
  3. Anett Seelig
  4. Francesco Volta
  5. Nils O'Brien
  6. Andrea Dicker
  7. Daniela Padula
  8. Heiko Lickert
  9. Jantje Mareike Gerdes  Is a corresponding author
  10. Per-Olof Berggren
  1. Karolinska Institute, Sweden
  2. Helmholtz Zentrum München, Germany
  3. Karolinska Institutet, Sweden
Research Article
  • Cited 4
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Cite this article as: eLife 2020;9:e56914 doi: 10.7554/eLife.56914

Abstract

Islet vascularization is essential for intact islet function and glucose homeostasis. We have previously shown that primary cilia directly regulate insulin secretion. However, it remains unclear whether they are also implicated in islet vascularization. At eight weeks, murine Bbs4‑/- islets show significantly lower intra-islet capillary density with enlarged diameters. Transplanted Bbs4-/- islets exhibit delayed re-vascularization and reduced vascular fenestration after engraftment, partially impairing vascular permeability and glucose delivery to b-cells. We identified primary cilia on endothelial cells as the underlying cause of this regula tion, via the vascular endothelial growth factor A (VEGF-A)/VEGF receptor 2 (VEGFR2) pathway. In vitro silencing of ciliary genes in endothelial cells disrupts VEGF-A/VEGFR2 internalization and downstream signaling. Consequently, key features of angiogenesis including proliferation and migration are attenuated in human BBS4 silenced endothelial cells. We conclude that endothelial cell primary cilia regulate islet vascularization and vascular barrier function via the VEGF-A/VEGFR2 signaling pathway.

Data availability

All data generated or analyzed during this study are included in this mansucript and supporting files.

Article and author information

Author details

  1. Yan Xiong

    Rolf Luft Center for endocrinology and diabetes, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2339-130X
  2. M Julia Scerbo

    Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Anett Seelig

    Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Francesco Volta

    Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Nils O'Brien

    Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Andrea Dicker

    Rolf Luft Center for Endocrinology and Diabetes, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  7. Daniela Padula

    Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Heiko Lickert

    Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Jantje Mareike Gerdes

    Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München, Garching, Germany
    For correspondence
    jantje.gerdes@helmholtz-muenchen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6885-5441
  10. Per-Olof Berggren

    Rolf Luft Center for endocrinology and diabetes, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

Funding

Deutsches Zentrum fuer Diabetesforschung

  • Jantje Mareike Gerdes

Berth von Kantzows Stiftelse

  • Per-Olof Berggren

Skandia Insurance Company Ltd

  • Per-Olof Berggren

ERC (ERC-2018-AdG 834860 EYELETS)

  • Per-Olof Berggren

FP7 People: Marie-Curie Actions (International Reintegration Grant PIRG07-GA-2010-268397)

  • Jantje Mareike Gerdes

Swedish Research Council

  • Per-Olof Berggren

Novo Nordisk Fonden

  • Per-Olof Berggren

Karolinska Institutet

  • Yan Xiong

Swedish Strategic Research Program Diabetes

  • Per-Olof Berggren

Swedish Diabetes Association

  • Per-Olof Berggren

Family Knut och Alice Wallenberg Foundation

  • Per-Olof Berggren

Diabetes Research Wellness Foundation

  • Per-Olof Berggren

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

Ethics

Animal experimentation: This study was performed in strict accordance to the German and Swedish animal welfare legislation. Experimental procedures involving live animals were carried out in accordance with animal welfare regulations and with approval of the Regierung Oberbayern (Az 55.2-1-54-2532-187-15 and ROB-55.2-2532.Vet_02-14-157) or in accordance with the Karolinska Institutet's guidelines for the care and use of animals in research, and were approved by the institute's Animal Ethics Committee respectively (Ethical permit number 19462-2017).

Reviewing Editor

  1. Lotte B Pedersen, University of Copenhagen, Denmark

Publication history

  1. Received: March 13, 2020
  2. Accepted: November 16, 2020
  3. Accepted Manuscript published: November 17, 2020 (version 1)
  4. Version of Record published: November 27, 2020 (version 2)

Copyright

© 2020, Xiong 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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