Transient overexpression of cyclin D2/CDK4/GLP1 genes induces proliferation and differentiation of adult pancreatic progenitors and mediates islet regeneration

The molecular mechanism of beta-cell regeneration remains poorly understood. Cyclin D2/CDK4 expresses in normal beta cells and maintains adult beta-cell growth. We hypothesized that gene therapy with cyclin D2/CDK4/GLP-1 plasmids targeted to the pancreas of STZ-treated rats by ultrasound-targeted microbubble destruction (UTMD) would force cell cycle re-entry of residual G(0)-phase islet cells into G(1)/S phase to regenerate beta cells. A single UTMD treatment induced beta-cell regeneration with reversal of diabetes for 6 mo without evidence of toxicity. We observed that this beta-cell regeneration was not mediated by self-replication of pre-existing beta cells. Instead, cyclin D2/CDK4/GLP-1 initiated robust proliferation of adult pancreatic progenitor cells that exist within islets and terminally differentiate to mature islets with beta cells and a cells.