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Islet Studies
Placental growth factor in beta cells plays an essential role in gestational beta-cell growth
  1. Weixia Yang1,2,
  2. Yinan Jiang2,
  3. Yan Wang2,
  4. Ting Zhang2,
  5. Qun Liu2,3,
  6. Chaoban Wang2,4,
  7. Grant Swisher2,
  8. Nannan Wu2,5,
  9. Chelsea Chao2,
  10. Krishna Prasadan2,
  11. George K Gittes2,
  12. Xiangwei Xiao2
  1. 1Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, China
  2. 2Department of Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  3. 3Department of Endocrinology, the First Affiliated Hospital of NanChang University, Nanchang, China
  4. 4Department of Pediatric Endocrinology, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
  5. 5Department of Endocrinology, Lu He Hospital, Capital Medical University, Beijing, China
  1. Correspondence to Dr Xiangwei Xiao; xiangwei.xiao{at}chp.edu

Abstract

Objective Pancreatic beta cells proliferate in response to metabolic requirements during pregnancy, while failure of this response may cause gestational diabetes. A member of the vascular endothelial growth factor family, placental growth factor (PlGF), typically plays a role in metabolic disorder and pathological circumstance. The expression and function of PlGF in the endocrine pancreas have not been reported and are addressed in the current study.

Research design and methods PlGF levels in beta cells were determined by immunostaining or ELISA in purified beta cells in non-pregnant and pregnant adult mice. An adeno-associated virus (AAV) serotype 8 carrying a shRNA for PlGF under the control of a rat insulin promoter (AAV–rat insulin promoter (RIP)–short hairpin small interfering RNA for PlGF (shPlGF)) was prepared and infused into mouse pancreas through the pancreatic duct to specifically knock down PlGF in beta cells, and its effects on beta-cell growth were determined by beta-cell proliferation, beta-cell mass and insulin release. A macrophage-depleting reagent, clodronate, was coapplied into AAV-treated mice to study crosstalk between beta cells and macrophages.

Results PlGF is exclusively produced by beta cells in the adult mouse pancreas. Moreover, PlGF expression in beta cells was significantly increased during pregnancy. Intraductal infusion of AAV–RIP–shPlGF specifically knocked down PlGF in beta cells, resulting in compromised beta-cell proliferation, reduced growth in beta-cell mass and impaired glucose tolerance during pregnancy. Mechanistically, PlGF depletion in beta cells reduced islet infiltration of trophic macrophages, which appeared to be essential for gestational beta-cell growth.

Conclusions Our study suggests that increased expression of PlGF in beta cells may trigger gestational beta-cell growth through recruited macrophages.

  • gestational diabetes mellitus
  • placenta
  • macrophage
  • beta-cell growth
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjdrc-2019-000921

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    Footnotes

    • Contributors WY, YJ, YW, TZ, QL, CW, GS, CC, NW, KP and GKG: acquisition and analysis of data; XX: study conception and design, funding, acquisition, analysis and interpretation of data, manuscript writing and guarantee of the study.

    • Funding This work was supported by tenure-track Assistant Professor Startup from Division of Pediatric Surgery of Children’s Hospital of Pittsburgh (to XX) and funding of Children’s Hospital of Pittsburgh of the UPMC health system (RAC, to XX), National Nature Science Foundation of China (grant number 81600599, to WY), Foundation for Young Scholars of Affiliated Hospital of Nantong University (grant number TDFY0303, to WY) and the project funded by the Priority Academic Program Development of Nantong Talent Center (grant number 2016-III-458, to WY).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval All animal experiments were approved by the Institutional Animal Care and Use Committee at University of Pittsburgh.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. This does not include identifiable patient data.