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Identification of adult pancreatic ß precursor cells and their role in islet neogenesis.
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Teitelman, Gladys
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Spring 2009
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2009-01-15
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Doctoral Dissertation
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Two of the fundamental issues in diabetes research are whether beta precursor cells populate islets of adult mammals and the identity of the signals leading to their differentiation. In this study, we sought to answer these questions by using a double transgenic mouse model (RipCre-ER/ZAP mice) that harbors one transgene which has a rat insulin promoter linked to a tamoxifen-dependent Cre-recombinase (RipCre-ER). The Cre-oestrogen receptor (ER) fusion gene is expressed in the cells with an active insulin promoter (Rip), but excluded from the nucleus. The second transgene is comprised of the beta-actin promoter linked to a floxed reporter gene encoding human placental alkaline phosphatase (PLAP). In these double transgenic mice, injection of Tamoxifen results in the activation of Cre-recombinase, which leads to the deletion of two loxP sites and to the expression of a reporter gene PLAP. The expression of the transgene was specific for beta cells. Due to the dose of TM used, only 30% of the islet bet cells expressed PLAP.
We found that islets of RipCre-ER/ZAP control mice contained ß cells that expressed PLAP (PLAP+IN+), ß cells that lacked PLAP expression (PLAP+IN) and also PLAP+ cells that did not express insulin (PLAP+IN). PLAP+IN cells did not proliferate and expressed transcription factors characteristic of cells in the early stage of endocrine cell differentiation. To determine the fate of the PLAP+INcells, RipCre-ER/ZAP mice that received TM were later injected with streptozotocin (STZ), a beta cell toxin that partially ablated the resident population of beta cells. Animals were examined following the end of the treatment. It was found that PLAP+IN cells of STZ treated mice were mitotically active and differentiated into insulin expressing cells (PLAP+IN+).
Our results strongly suggest the presence of a population of ß precursor cells in adult control mice. Those ß precursor cells replicate and initiate insulin synthesis following islet injury, partially replenishing the depleted beta cell population in STZ-treated animals. These islet-resident ß precursor cells could become an important source of new beta cells for therapy in type I diabetes.
Citation
Liu, Heng (2009). Identification of adult pancreatic ß precursor cells and their role in islet neogenesis. [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/16000