Local In Vivo GSK3β Knockdown Promotes Pancreatic β Cell and Acinar Cell Regeneration in 90% Pancreatectomized Rat

Abstract

Endocrine and exocrine insufficiencies are associated with serious diseases such as diabetes and pancreatitis, respectively. Pancreatic cells retain the capacity to regenerate in the context of cell deficiency. The remnant pancreas after pancreatectomy (Px) is a valuable target for testing the efficiency of pharmacological interventions to stimulate cell regeneration. Here, we tested the ability of GSK3β downregulation on the stimulation of β- and acinar cell regeneration after 90% Px in adult rats. We developed an in vivo approach based on local silencing of GSK3β, by delivering antisense morpholino-oligonucleotides within the remnant pancreas of 90% pancreatectomized rats, and evaluated its impact on the regenerative potential of pancreatic β and exocrine cells. β-Cell (BC) mass was evaluated by morphometry. Cell proliferation and apoptosis were assessed by 5'bromo 2'deoxyuridine (BrdU) incorporation method and TUNEL assay, respectively. The expression of Sox9, Neurogenin-3 (Ngn3), and PDX1 was evaluated by immunohistochemistry. We show that intrapancreatic GSK3β knockdown leads to increased BC mass (BCM) in 90% pancreatectomized rats by promoting both BC proliferation and differentiation. Moreover, downregulation of GSK3β significantly improves exocrine growth and prevents acinar cell apoptosis in vivo. Our study designates GSK3β as a viable drug target for therapeutic intervention on diseases of endocrine and exocrine pancreas associated with cell deficiency.