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

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.

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%).

Our findings uncover a link between transgene (over)expression, ER stress, glucose and cell cycle activation in mouse beta cells.

The single-cell RNA-seq data generated in this study are deposited at GEO (NCBI) with accession code GSE274443.

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