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

Volume 11, Issue 4   February 15, 2012
Pages 695 - 705
http://dx.doi.org/10.4161/cc.11.4.19120
Authors: Shuyuan Chen, Masayuki Shimoda, Jiaxi Chen, Shinichi Matsumoto and Paul A. Grayburn

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Abstract:
The molecular mechanism of β-cell regeneration remains poorly understood. Cyclin D2/CDK4 expresses in normal β cells and maintains adult β-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 G0-phase islet cells into G1/S phase to regenerate β cells. A single UTMD treatment induced β-cell regeneration with reversal of diabetes for 6 mo without evidence of toxicity. We observed that this β-cell regeneration was not mediated by self-replication of pre-existing β 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 β cells and α cells.

Received: October 24, 2011; Accepted: December 19, 2011

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