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Adenosine signaling promotes regeneration of pancreatic ? cells in vivo.

ABSTRACT: Diabetes can be controlled with insulin injections, but a curative approach that restores the number of insulin-producing ? cells is still needed. Using a zebrafish model of diabetes, we screened ~7,000 small molecules to identify enhancers of ? cell regeneration. The compounds we identified converge on the adenosine signaling pathway and include exogenous agonists and compounds that inhibit degradation of endogenously produced adenosine. The most potent enhancer of ? cell regeneration was the adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA), which, acting through the adenosine receptor A2aa, increased ? cell proliferation and accelerated restoration of normoglycemia in zebrafish. Despite markedly stimulating ? cell proliferation during regeneration, NECA had only a modest effect during development. The proliferative and glucose-lowering effect of NECA was confirmed in diabetic mice, suggesting an evolutionarily conserved role for adenosine in ? cell regeneration. With this whole-organism screen, we identified components of the adenosine pathway that could be therapeutically targeted for the treatment of diabetes.

SUBMITTER: Andersson O

PROVIDER: S-EPMC3372708 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Adenosine signaling promotes regeneration of pancreatic β cells in vivo.

Andersson Olov O Adams Bruce A BA Yoo Daniel D Ellis Gregory C GC Gut Philipp P Anderson Ryan M RM German Michael S MS Stainier Didier Y R DY

Cell metabolism 20120517 6

Diabetes can be controlled with insulin injections, but a curative approach that restores the number of insulin-producing β cells is still needed. Using a zebrafish model of diabetes, we screened ~7,000 small molecules to identify enhancers of β cell regeneration. The compounds we identified converge on the adenosine signaling pathway and include exogenous agonists and compounds that inhibit degradation of endogenously produced adenosine. The most potent enhancer of β cell regeneration was the a ...[more]

PMID: 22608007

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Project description:BackgroundMesenchymal stem cells (MSC) are non-haematopoietic, fibroblast-like multipotent stromal cells. In the injured pancreas, these cells are assumed to secrete growth factors and immunomodulatory molecules, which facilitate the regeneration of pre-existing β-cells. However, when MSC are delivered intravenously, their majority is entrapped in the lungs and does not reach the pancreas. Therefore, the aim of this investigation was to compare the regenerative support of hTERT-MSC (human telomerase reverse transcriptase mesenchymal stem cells) via intrapancreatic (IPR) and intravenous route (IVR).MethodshTERT-MSC were administered by IPR and IVR to 50% pancreatectomized NMRI nude mice. After eight days, blood glucose level, body weight, and residual pancreatic weight were measured. Proliferating pancreatic β-cells were labelled and identified with bromodeoxyuridine (BrdU) in vivo. The number of residual islets and the frequency of proliferating β-cells were compared in different groups with sequential pancreatic sections. The pancreatic insulin content was evaluated by enzyme-linked immunosorbent assay (ELISA) and the presence of hTERT-MSC with human Alu sequence. Murine gene expression of growth factors, β-cell specific molecules and proinflammatory cytokines were inspected by real-time polymerase chain reaction (RT-PCR) and Western blot.ResultsThis study evaluated the regenerative potential of the murine pancreas post-hTERT-MSC administration through the intrapancreatic (IPR) and intravenous route (IVR). Both routes of hTERT-MSC transplantation (IVR and IPR) increased the incorporation of BrdU by pancreatic β-cells compared to control. MSC induced epidermal growth factor (EGF) expression and inhibited proinflammatory cytokines (IFN-γ and TNF-α). FOXA2 and PDX-1 characteristics for pancreatic progenitor cells were activated via AKT/ PDX-1/ FoxO1 signalling pathway.ConclusionThe infusion of hTERT-MSC after partial pancreatectomy (Px) through the IVR and IPR facilitated the proliferation of autochthonous pancreatic β-cells and provided evidence for a regenerative influence of MSC on the endocrine pancreas. Moderate benefit of IPR over IVR was observed which could be a new treatment option for preventing diabetes mellitus after pancreas surgery.

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Adenosine signaling promotes regeneration of pancreatic ? cells in vivo.

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Adenosine signaling promotes regeneration of pancreatic β cells in vivo.

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