ER stress relief drives ß-cell proliferation

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.