Islet vascularization is regulated by primary endothelial cilia via VEGF-A dependent signaling
- Karolinska Institute, Sweden
- Helmholtz Zentrum München, Germany
- Karolinska Institutet, Sweden
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
Jantje Mareike Gerdes
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).
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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Islet vascularization is regulated by primary endothelial cilia via VEGF-A dependent signaling
eLife 9:e56914.
https://doi.org/10.7554/eLife.56914
Further reading
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- Cancer Biology
- Cell Biology
The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here, we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses revealed elevated plectin levels in liver tumors, which correlated with poor prognosis for HCC patients. Using autochthonous and orthotopic mouse models we demonstrated that genetic and pharmacological inactivation of plectin potently suppressed the initiation and growth of HCC. Moreover, plectin targeting potently inhibited the invasion potential of human HCC cells and reduced their metastatic outgrowth in the lung. Proteomic and phosphoproteomic profiling linked plectin-dependent disruption of cytoskeletal networks to attenuation of oncogenic FAK, MAPK/Erk, and PI3K/Akt signatures. Importantly, by combining cell line-based and murine HCC models, we show that plectin inhibitor plecstatin-1 (PST) is well-tolerated and potently inhibits HCC progression. In conclusion, our study demonstrates that plectin-controlled cytoarchitecture is a key determinant of HCC development and suggests that pharmacologically induced disruption of mechanical homeostasis may represent a new therapeutic strategy for HCC treatment.
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- Cell Biology
- Medicine
Background:
It has been reported that loss of PCBP2 led to increased reactive oxygen species (ROS) production and accelerated cell aging. Knockdown of PCBP2 in HCT116 cells leads to significant downregulation of fibroblast growth factor 2 (FGF2). Here, we tried to elucidate the intrinsic factors and potential mechanisms of bone marrow mesenchymal stromal cells (BMSCs) aging from the interactions among PCBP2, ROS, and FGF2.
Methods:
Unlabeled quantitative proteomics were performed to show differentially expressed proteins in the replicative senescent human bone marrow mesenchymal stromal cells (RS-hBMSCs). ROS and FGF2 were detected in the loss-and-gain cell function experiments of PCBP2. The functional recovery experiments were performed to verify whether PCBP2 regulates cell function through ROS/FGF2-dependent ways.
Results:
PCBP2 expression was significantly lower in P10-hBMSCs. Knocking down the expression of PCBP2 inhibited the proliferation while accentuated the apoptosis and cell arrest of RS-hBMSCs. PCBP2 silence could increase the production of ROS. On the contrary, overexpression of PCBP2 increased the viability of both P3-hBMSCs and P10-hBMSCs significantly. Meanwhile, overexpression of PCBP2 led to significantly reduced expression of FGF2. Overexpression of FGF2 significantly offset the effect of PCBP2 overexpression in P10-hBMSCs, leading to decreased cell proliferation, increased apoptosis, and reduced G0/G1 phase ratio of the cells.
Conclusions:
This study initially elucidates that PCBP2 as an intrinsic aging factor regulates the replicative senescence of hBMSCs through the ROS-FGF2 signaling axis.
Funding:
This study was supported by the National Natural Science Foundation of China (82172474).
