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CXCR1/2 inhibition enhances pancreatic islet survival after transplantation.

ABSTRACT: Although long considered a promising treatment option for type 1 diabetes, pancreatic islet cell transformation has been hindered by immune system rejection of engrafted tissue. The identification of pathways that regulate post-transplant detrimental inflammatory events would improve management and outcome of transplanted patients. Here, we found that CXCR1/2 chemokine receptors and their ligands are crucial negative determinants for islet survival after transplantation. Pancreatic islets released abundant CXCR1/2 ligands (CXCL1 and CXCL8). Accordingly, intrahepatic CXCL1 and circulating CXCL1 and CXCL8 were strongly induced shortly after islet infusion. Genetic and pharmacological blockade of the CXCL1-CXCR1/2 axis in mice improved intrahepatic islet engraftment and reduced intrahepatic recruitment of polymorphonuclear leukocytes and NKT cells after islet infusion. In humans, the CXCR1/2 allosteric inhibitor reparixin improved outcome in a phase 2 randomized, open-label pilot study with a single infusion of allogeneic islets. These findings indicate that the CXCR1/2-mediated pathway is a regulator of islet damage and should be a target for intervention to improve the efficacy of transplantation.

SUBMITTER: Citro A

PROVIDER: S-EPMC3461913 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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CXCR1/2 inhibition enhances pancreatic islet survival after transplantation.

Citro Antonio A Cantarelli Elisa E Maffi Paola P Nano Rita R Melzi Raffaella R Mercalli Alessia A Dugnani Erica E Sordi Valeria V Magistretti Paola P Daffonchio Luisa L Ruffini Pier Adelchi PA Allegretti Marcello M Secchi Antonio A Bonifacio Ezio E Piemonti Lorenzo L

The Journal of clinical investigation 20120917 10

Although long considered a promising treatment option for type 1 diabetes, pancreatic islet cell transformation has been hindered by immune system rejection of engrafted tissue. The identification of pathways that regulate post-transplant detrimental inflammatory events would improve management and outcome of transplanted patients. Here, we found that CXCR1/2 chemokine receptors and their ligands are crucial negative determinants for islet survival after transplantation. Pancreatic islets releas ...[more]

PMID: 22996693

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Project description:BackgroundType 1 diabetes mellitus (T1D) is characterized by the autoimmune destruction of the pancreatic β cells. The transplantation of mesenchymal stromal/stem cells (MSC) was reported to rescue the damaged pancreatic niche. However, there is an ongoing discussion on whether direct physical contact between MSC and pancreatic islets results in a superior outcome as opposed to indirect effects of soluble factors released from the MSC entrapped in the lung microvasculature after systemic administration. Hence, MSC were studied in direct contact (DC) and indirect contact (IDC) with murine pancreatic β cell line MIN6-cells damaged by nitrosourea derivative streptozotocin (STZ) in vitro. Further, the protective and antidiabetic outcome of MSC transplantation was evaluated through the intrapancreatic route (IPR) and intravenous route (IVR) in STZ-induced diabetic NMRI nude mice.MethodsMSC were investigated in culture with STZ-damaged MIN6-cells, either under direct contact (DC) or separated through a semi-permeable membrane (IDC). Moreover, multiple low doses of STZ were administered to NMRI nude mice for the induction of hyperglycemia. 0.5 × 106 adipose-derived mesenchymal stem cells (ADMSC) were transferred through direct injection into the pancreas (IPR) or the tail vein (IVR), respectively. Bromodeoxyuridine (BrdU) was injected for the detection of proliferating islet cells in vivo, and real-time polymerase chain reaction (RT-PCR) was employed for the measurement of the expression of growth factor and immunomodulatory genes in the murine pancreas and human MSC. Phosphorylation of AKT and ERK was analyzed with Western blotting.ResultsThe administration of MSC through IPR ameliorated hyperglycemia in contrast to IVR, STZ, and non-diabetic control in a 30-day window. IPR resulted in a higher number of replicating islet cells, number of islets, islet area, growth factor (EGF), and balancing of the Th1/Th2 response in vivo. Physical contact also provided a superior protection to MIN6-cells from STZ through the AKT and ERK pathway in vitro in comparison with IDC.ConclusionOur study suggests that the physical contact between MSC and pancreatic islet cells is required to fully unfold their protective potential.

Project description:Islet transplantation is a promising therapy for diabetes, yet the limited survival and functionality of transplanted islet grafts hinder optimal outcomes. Glucagon-like peptide-1 (GLP-1), an endogenous hormone, has shown potential to enhance islet survival and function; however, its systemic administration can result in poor localization and undesirable side effects. To address these challenges, we developed a novel peptide-based nanofiber hydrogel incorporating GLP-1 functionality for localized delivery. By conjugating the FFG tripeptide (a self-assembling motif derived from phenylalanine-phenylalanine-glycine) to the C-terminus of native GLP-1, we engineered GLP-1-FFG, a self-assembling peptide that forms a robust nanofiber structure resistant to enzymatic degradation. When GLP-1-FFG co-assembles with the biotin-DFYIGSRGD peptide (referred to as SupraGel), a self-assembling supramolecular polypeptide hydrogel we previously identified containing motifs derived from extracellular matrix components, the resulting hydrogel (SupraGel + GLP-1-FFG) creates a stable nanofibrous network with excellent rheological properties. In vitro, this nanofiber hydrogel significantly improves islet function and survival. Bulk RNA sequencing results demonstrate that the hydrogel suppresses the expression of hypoxia-related genes, downregulates pro-inflammatory genes, and upregulates genes associated with islet function. Further analysis reveals that these effects are related to the activation of the AKT signaling pathway. In a syngeneic mouse islet transplantation model, the localized application of SupraGel + GLP-1-FFG at the renal subcapsular islet transplant site significantly enhanced the efficacy of marginal-dose islet transplantation, as shown by improved glycemic control, faster and higher rates of diabetes reversal, better glucose tolerance, and greater islet graft survival in diabetic recipient mice. This innovative nanotechnology-based hydrogel offers a promising strategy for enhancing the efficacy of islet grafts in transplantation therapy.

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CXCR1/2 inhibition enhances pancreatic islet survival after transplantation.

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CXCR1/2 inhibition enhances pancreatic islet survival after transplantation.

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