ESPE2024 Poster Category 1 Late Breaking 2 (10 abstracts)
ER stress relief drives ß-cell proliferation
Stephanie Bourgeois 1 , Willem Staels 1 , Annelore Van Mulders 1 , Lien Willems 1 , Sophie Coenen 1 , Laure Degroote 1 , Julie Pierreux 1 , Gunter Leuckx 1 , Yves Heremans 1 , Nico De Leu 1 , Harry Heimberg 1 , Miriam Cnop 2 , Xiaoyan Yi 2 , Kiavash Movahedi 1 , Daliya Kancheva 1 , Isabelle Scheyltjens 1 , Eelco de Koning 3 & Françoise Carlotti 3
1Vrije Universiteit Brussel, 1090 Brussels, Belgium. 2Université Libre de Bruxelles, 1070 Anderlecht, Belgium. 3Leiden University, 2333 Leiden, Netherlands
Introduction: Regenerating endogenous pancreatic β-cells is a potentially curative yet currently elusive strategy for diabetes therapy. Mimicking the microenvironment of the developing pancreas and leveraging vascular signals, critical to pancreatic endocrinogenesis, may promote β-cell regeneration. We aimed to investigate whether recovery from experimental hypovascularization of the endocrine pancreas could trigger mouse ß-cell proliferation.
Methods: A doxycycline (DOX)-inducible transgenic mouse model was used to induce conditional intra-islet hypovascularization. In this model, VEGF-A signaling within pancreatic islets is antagonized through ß-cell-specific overexpression of a VEGF-A decoy receptor, soluble fms-like tyrosine kinase 1 (sFLT1). Cessation of sFLT1 overexpression was induced by DOX withdrawal. sFLT1 expression, vessel kinetics, and ß-proliferation upon DOX treatment and withdrawal were analyzed using RT-qPCR and immunostainings. Single-cell RNA sequencing was used to investigate the effects on the islet cells' transcriptome and perform pathway enrichment analysis. RIP-rtTA;TetO-GFP mice were studied in parallel to assess the dependency of cell cycle induction on vessel manipulation. Additionally, the results were confirmed through in vitro experiments.
Results: Serendipitously, we found that transgene overexpression in β-cells induces endoplasmic reticulum (ER) stress and that subsequent relief from this stress stimulated ß-cell proliferation independent of vessel recovery. Similarly, transient GFP overexpression in vivo and transient chemical induction of ER stress in vitro replicated the increased β-cell cycling response.
Conclusions: Our findings highlight the potential side effects of ER stress due to transgene overexpression in ß-cells and assert that ER stress relief serves as a potent regenerative stimulus.
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