Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Pdx1 maintains ?-cell identity and function by repressing an ?-cell program

ABSTRACT: To get a more complete picture of the transcriptional changes associated with Pdx1 loss in ?-cells, we conducted an mRNA microarray comparing normal islet ?-cells and a-cells to the reprogrammed cells from PKO mice. Islet beta cells are from mice which has a single copy of Pdx1 flox (Pdx1L/+) allele, but is considered normal based on normal islet morphology, gene profiling, and euglycemic status. We chose to use heterozygous mice as control to avoid the litter effect. Islet alpha cells are from normal mice. To enrich for genes directly affected by Pdx1 loss, we chose the early time-point for analysis of PKO mice (5d after TAM administration). Control mRNA profiling was performed on FACS sorted islet YFP+ ?-cells and a-cells obtained from 2 month-old glucagon-Cre; RosaYFP and RIP-CreER; Pdx1fl/+, RosaYFP mice, respectively.

ORGANISM(S): Mus musculus

SUBMITTER: Tao Gao

PROVIDER: E-GEOD-52258 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Expression of CD40 in non-hematopoietic cells has been linked to inflammation. We presented evidence that CD40, a T-cell costimulatory molecule, is expressed in human Î²-cells and the engagement of CD40 in insulinoma cells activated the NFKB and ERK1/2 pathways. CD40 activation in human islets cells induced secretion of IL-8, MCP-1 and MIP-1 Î², which is abrogated by inhibitors of NFkB and ERK1/2 inhibitors. In this study, we have studied gene expression mediated by CD40-CD40L interaction in islet cells. This approach identified 90 genes and transcripts exhibiting at least a 1.7 fold increase in their expression intensity after treatment with soluble CD40L. A significant number of genes were related to inflammation and oxidative stress. We have a strong overexpression of CXCL1 (GroÎ±), CXCL2 (Mif2) and CXCL3; chemokines belonging to CXC family structurally related to Il-8. 11 genes were selected from this group and further quantified by Real Time PCR, including CXCL1. Activation of islet cells with CD40L induced the secretion of CXCL1 in a NFKB dependent manner. Engagement of CD40 in islet cells did not induce apoptosis, neither Î²-cell death and did not enhanced TNF-Î± mediated cell death as observed in insulinoma cells. CD40 activation in insulinoma cells, results in ERK1/2 dependent phsophorylation of synapsin I, a protein associated with the exocytosis machinery in neurons and Î²-cells. However, treatment of islets with soluble CD40L did not affect glucose induced insulin secretion. It has been reported that ductal cells always present in human islet preparations express CD40 constitutively (ref). We found that CD40-CD40L interaction in ductal cells, unlike in Î²-cells, induces secretion of diabetogenic cytokines IFNÎ³ and TNF-Î±. Furthermore, incubation of islets containing ductal cells with CD40L decreased Î²-cells viability as assessed by measurement of their mitochondrial membrane potential Experiment Overall Design: We isolated islet cells from three patients. Part of islet cells from each patient has been treated with CD40L. We compared gene expression in treated cells vs untreated for each patient using dye-swap.

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Pdx1 maintains ?-cell identity and function by repressing an ?-cell program

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