title: Transient overexpression of cyclin D2/CDK4/GLP1 genes induces proliferation and differentiation of adult pancreatic progenitors and mediates islet regeneration.
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 G(0)-phase islet cells into G(1)/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.
authors.affiliation: Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Chen
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimoda
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Chen
authors.forename: Shinichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Paul A
authors.initials: PA
authors.lastname: Grayburn
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000166:cytology*; D010957:Plasmids; D051381:Rats; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: D056742:Cyclin D2; D052216:Glucagon-Like Peptide 1; D051358:Cyclin-Dependent Kinase 4