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The stromal cell–derived factor-1/CXCR4 ligand–receptor axis is critical for progenitor survival and migration in the pancreas

¹ Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
² Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037

Address correspondence to Nora Sarvetnick, Dept. of Immunology (IMM-23), The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: (858) 784-9066. Fax: (858) 784-9083. email: noras{at}scripps.edu

The SDF-1/CXCR4 ligand/chemokine receptor pair is required for appropriate patterning during ontogeny and stimulates the growth and differentiation of critical cell types. Here, we demonstrate SDF-1 and CXCR4 expression in fetal pancreas. We have found that SDF-1 and its receptor CXCR4 are expressed in islets, also CXCR4 is expressed in and around the proliferating duct epithelium of the regenerating pancreas of the interferon (IFN) –nonobese diabetic mouse. We show that SDF-1 stimulates the phosphorylation of Akt, mitogen-activated protein kinase, and Src in pancreatic duct cells. Furthermore, migration assays indicate a stimulatory effect of SDF-1 on ductal cell migration. Importantly, blocking the SDF-1/CXCR4 axis in IFN-nonobese diabetic mice resulted in diminished proliferation and increased apoptosis in the pancreatic ductal cells. Together, these data indicate that the SDF-1–CXCR4 ligand receptor axis is an obligatory component in the maintenance of duct cell survival, proliferation, and migration during pancreatic regeneration.

Key Words: chemokines; proliferation; regeneration; duct; interferon

Abbreviations used in this paper: C-10, small inducible cytokine A6; Eotaxin, small inducible chemokine A 11; IP-10, IFN-–inducible protein 10 kD; MCP, monocyte chemoattractant protein; MIG, monokine induced by IFN; MIP, macrophage inflammatory protein; NOD, nonobese diabetic; PDX1, pancreatic duodenal homeobox 1; RANTES, regulated on activation normal T-cell expressed and secreted; TCA-4, thymus-derived chemotactic agent 4.

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