ER stress relief drives ß-cell proliferation

Stephanie Bourgeois; Willem Staels; Mulders Annelore Van; Lien Willems; Sophie Coenen; Laure Degroote; Julie Pierreux; Gunter Leuckx; Yves Heremans; Leu Nico De; Harry Heimberg; Miriam Cnop; Xiaoyan Yi; Kiavash Movahedi; Daliya Kancheva; Isabelle Scheyltjens; Koning Eelco de; Françoise Carlotti

P1-304

Prev Next

Section Contents Cite

ESPE Abstracts (2024) 98 P1-304

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

Views

Author affiliations

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.