ER stress relief drives beta cell proliferation
Bourgeois, S.; Van Mulders, A.; Heremans, Y.; Leuckx, G.; Willems, L.; Coenen, S.; Degroote, L.; Pierreux, J.; Kancheva, D.; Scheyltjens, I.; Movahedi, K.; Carlotti, F.; de Koning, E.; Yi, X.; Vinci, C.; Tong, Y.; Cnop, M.; Heimberg, H.; De Leu, N.; Staels, W.
Show abstract
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 hypovascularization of the endocrine pancreas, achieved by modulating the transgenic production of a VEGF-A blocker in {beta}-cells, could trigger mouse {beta}-cell proliferation. Serendipitously, we found that transgene overexpression in {beta}-cells induces endoplasmic reticulum (ER) stress and that subsequent relief from this stress stimulates {beta}-cell proliferation independent of vessel recovery. Transient GFP overexpression in vivo and chemical induction of ER stress in vitro replicated this {beta}-cell cycling response. Our findings highlight the potential side effects of ER stress due to transgene overexpression in {beta}-cells and assert that ER stress relief serves as a potent regenerative stimulus.
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