Transient ER stress cell-autonomously promotes beta cell cycling in mice.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:41537777", "kind": "science-record", "revision": 4, "content_hash": "sha256:1262577e50c935df7464f48e057813ac7879d24e9a57296e6d21466bc973ab7e", "created_at": "2026-11-01T20:31:30Z", "updated_at": "2026-11-01T22:57:44Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Transient ER stress cell-autonomously promotes beta cell cycling in mice.", "doi": "10.1007/s00125-025-06649-3", "pmid": "41537777", "authors": ["Stephanie Bourgeois", "Annelore Van Mulders", "Yves Heremans", "Gunter Leuckx", "Lien Willems", "Sophie Coenen", "Laure Degroote", "Julie Pierreux", "Daliya Kancheva", "Isabelle Scheyltjens", "Kiavash Movahedi", "Françoise Carlotti", "Eelco de Koning", "Xiaoyan Yi", "Chiara Vinci", "Yue Tong", "Miriam Cnop", "Harry Heimberg", "Nico De Leu", "Willem Staels"], "journal": "Diabetologia", "year": 2026, "abstract": "AIMS/HYPOTHESIS: Regenerating endogenous pancreatic beta cells is a potentially curative yet currently elusive strategy for diabetes therapy. Mimicking the microenvironment of the developing pancreas and leveraging vascular signals that support pancreatic endocrinogenesis may promote beta cell regeneration. We aimed to investigate whether recovery from experimental hypovascularisation of the endocrine pancreas could trigger mouse beta cell proliferation.\nMETHODS: A doxycycline (DOX)-inducible transgenic mouse model was used to induce conditional intra-islet hypovascularisation. In this model, vascular endothelial growth factor (VEGF)-A signalling within pancreatic islets is antagonised through beta 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 beta cell proliferation upon DOX administration and withdrawal were analysed using quantitative RT-PCR and immunostaining. Single-cell RNA-seq 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, in vitro experiments were conducted to further elucidate and validate our in vivo findings.\nRESULTS: Serendipitously, we discovered that sFLT1 overexpression in beta cells induces endoplasmic reticulum (ER) stress and activates proliferation-associated pathways. Upon cessation of sFLT1 overexpression, ER stress decreased and beta cell proliferation was promoted independently of vessel recovery, as shown by cumulative BrdU labelling over 7 days (mean ± SEM vs control: 14.3 ± 1.3% vs 5.2 ± 0.6%) during the DOX withdrawal period. Transient GFP overexpression also induced ER stress and a subsequent reduction thereof resulted in increased beta cell proliferation (mean ± SEM vs control: 7.2 ± 0.4% vs 5.1 ± 0.5%). Chemical, transient induction of ER stress in vitro by ER-stress-inducing compounds reproduced this beta cell cycling response, as assessed by cumulative EdU labelling during a 3 day washout period (mean ± SEM vs control: 2.6 ± 0.4% vs 0.8 ± 0.2% for thapsigargin and 3.8 ± 0.9% vs 1.0 ± 0.2% for tunicamycin), which further increased under high-glucose conditions when islets were exposed to thapsigargin (mean ± SEM vs control: 9.0 ± 1.2% vs 2.0 ± 0.4%).\nCONCLUSIONS/INTERPRETATION: Our findings uncover a link between transgene (over)expression, ER stress, glucose and cell cycle activation in mouse beta cells.\nDATA AND CODE AVAILABILITY: The single-cell RNA-seq data generated in this study are deposited at GEO (NCBI) with accession code GSE274443.", "claims": [{"id": "claim-method", "statement": "Data were analysed in GraphPad Prism v9.1.0 using unpaired t tests, one- or two-way ANOVA, or mixed-model analysis with Tukey’s post hoc test as appropriate.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41537777", "locator": "sections[12] \"Statistics\" paragraph 2", "quote": "Data were analysed in GraphPad Prism v9.1.0 using unpaired t tests, one- or two-way ANOVA, or mixed-model analysis with Tukey’s post hoc test as appropriate."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The single-cell RNA-seq data generated in this study are deposited at GEO (NCBI) with accession code GSE274443. Other data that support the findings of this study are available from the corresponding author upon request. There are no restrictions on data availability.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41537777", "locator": "sections[26] \"notes\" paragraph 1", "quote": "The single-cell RNA-seq data generated in this study are deposited at GEO (NCBI) with accession code GSE274443. Other data that support the findings of this study are available from the corresponding author upon request. 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