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Animal models of beta-cell
regeneration
L.J. Góñez, A.M. Holland,
G. Naselli, I. Banakh,
L.C. Harrison
The adult pancreas has the capacity to respond to an increased requirement for beta-cell mass/function during pregnancy, obesity or insulin-resistance, and its ability to regenerate endocrine cells has also been documented. Adult stem cells have been difficult to isolate and study, possibly because they reside in a microenvironment or niche that controls their fate. We are investigating the presumptive pancreatic stem cell niche and the cellular and molecular components that regulate beta-cell regeneration using mouse models of accelerated diabetes and conditional regulation of the transcription factor, Pdx1 .
Conditional expression demonstrates the role of the homeodomain transcription factor, Pdx1, in maintenance and regeneration of beta cells in the adult pancreas
A. M. Holland, L. J. Góñez, G. Naselli, L. C. Harrison, in collaboration with R. J. MacDonald, University of Texas Southwestern Medical Center, Dallas, Texas, USA
We generated a mouse in which the transcription factor Pdx1 could be reversibly repressed by doxycycline administration. Repression of Pdx1 impaired insulin expression in pancreatic beta cells leading to diabetes, and was associated with cellular proliferation and up-regulation of genes implicated in pancreas regeneration. After de-repression of Pdx1, diabetes remitted over 28 days, during which time Pdx1+/Ins+ cells were observed associated with duct epithelia. These findings show that Pdx1 is required for beta-cell function in the adult pancreas and that in the absence of Pdx1 a regenerative program is initiated with the potential for Pdx1-dependent beta-cell neogenesis.
Convergence of bone morphogenetic protein and laminin-1 signaling pathways promotes proliferation and colony formation by fetal mouse pancreatic cells
F.-X. Jiang, L. C. Harrison
We previously reported that bone morphogenetic proteins (BMPs), together with laminin-1 (Ln-1), promote formation of foetal mouse pancreatic cell colonies containing insulin-positive cells. In further investigating crosstalk between BMP and Ln-1 signals, we found that specific blocking antibodies to BMP-4 and -6 and selective BMP antagonists partially inhibited colony formation. Colony formation was completely abolished by blocking Ln-1 binding to its alpha-6 integrin and alpha-dystroglycan receptors, or by blocking the Ln-1 signalling molecules, phosphatidyl-inositol-3-kinase (P13K) and MAP kinase kinase-1. These results demonstrate convergence of BMP and Ln-1 signalling through P13K and MAP kinase pathways to induce proliferation and colony formation of foetal mouse pancreatic cells.
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