title: P21cip-overexpression in the mouse beta cells leads to the improved recovery from streptozotocin-induced diabetes.
abstract: Under normal conditions, the regeneration of mouse beta cells is mainly dependent on their own duplication. Although there is evidence that pancreatic progenitor cells exist around duct, whether non-beta cells in the islet could also potentially contribute to beta cell regeneration in vivo is still controversial. Here, we developed a novel transgenic mouse model to study the pancreatic beta cell regeneration, which could specifically inhibit beta cell proliferation by overexpressing p21(cip) in beta cells via regulation of the Tet-on system. We discovered that p21 overexpression could inhibit beta-cell duplication in the transgenic mice and these mice would gradually suffer from hyperglycemia. Importantly, the recovery efficiency of the p21-overexpressing mice from streptozotocin-induced diabetes was significantly higher than control mice, which is embodied by better physiological quality and earlier emergence of insulin expressing cells. Furthermore, in the islets of these streptozotocin-treated transgenic mice, we found a large population of proliferating cells which expressed pancreatic duodenal homeobox 1 (PDX1) but not markers of terminally differentiated cells. Transcription factors characteristic of early pancreatic development, such as Nkx2.2 and NeuroD1, and pancreatic progenitor markers, such as Ngn3 and c-Met, could also be detected in these islets. Thus, our work showed for the first time that when beta cell self-duplication is repressed by p21 overexpression, the markers for embryonic pancreatic progenitor cells could be detected in islets, which might contribute to the recovery of these transgenic mice from streptozotocin-induced diabetes. These discoveries could be important for exploring new diabetes therapies that directly promote the regeneration of pancreatic progenitors to differentiate into islet beta cells in vivo.
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Weiqi
authors.initials: W
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Sun
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Han
authors.forename: Mingxiao
authors.initials: M
authors.lastname: Ding
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Hongkui
authors.initials: H
authors.lastname: Deng
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000628:therapy*; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000378:metabolism; D006728:Hormones / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D006728:Hormones; C000715627:Nkx2-2 protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D004318:Doxycycline