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Extracellular Matrix Protects Pancreatic ß-Cells Against Apoptosis

Role of Short- and Long-Term Signaling Pathways

¹ Department of Genetic Medicine and Development, University Medical Center, University Hospital, Geneva, Switzerland
² Cell Isolation and Transplantation Center, University Hospital, Geneva, Switzerland
³ Division of Endocrinology and Diabetes, University Hospital, Zurich, Switzerland

We have shown previously that culture of ß-cells on matrix derived from 804G cells and rich in laminin-5 improves their function. The purpose of this study was to investigate whether this matrix protects ß-cells against apoptosis and to elucidate signaling pathways involved. Matrix protected sorted rat ß-cells against apoptosis under standard conditions (11.2 mmol/l glucose, 10% serum), after serum deprivation (1% serum), and in response to interleukin-1ß (IL-1ß; 2 ng/ml), compared with control (poly-L-lysine [pLL]). Caspase-8 activity was reduced in cells cultured on matrix, whereas focal adhesion kinase (FAK), protein kinase B (PKB, or Akt), and extracellular signal–regulated kinase (ERK) phosphorylation was augmented. Treatment (4 h) with an anti-ß1 integrin antibody, with the ERK pathway inhibitor PD98059, and/or with the phosphatidylinositol 3-kinase inhibitor LY294002 augmented cell death on 804G matrix but not on pLL. In long-term assays (48 h), PD98059 but not LY294002 drastically augmented cell death on 804G matrix but did so to a lesser extent on pLL. The protein inhibitor of nuclear factor-B (IB) was overexpressed in cells cultured 18 h on matrix with partial blockade by PD98059. In summary, this study provides evidence for activation of signaling pathways and gene expression by extracellular matrix leading to improved ß-cell survival.

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