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Published 24 November 2003. doi:10.1083/jcb.200304153
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© The Rockefeller University Press, 0021-9525/2003/11/859 $8.00
The Journal of Cell Biology, Volume 163, Number 4, 859-869

Article

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



Ayse G. Kayali1, Kurt Van Gunst1, Iain L. Campbell2, Aleksandr Stotland1, Marcie Kritzik1, Guoxun Liu1, Malin Flodström-Tullberg1, You-Qing Zhang1 and Nora Sarvetnick1

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{alpha}/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{alpha} and CXCR4 expression in fetal pancreas. We have found that SDF-1{alpha} 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) {gamma}–nonobese diabetic mouse. We show that SDF-1{alpha} 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{alpha} on ductal cell migration. Importantly, blocking the SDF-1{alpha}/CXCR4 axis in IFN{gamma}-nonobese diabetic mice resulted in diminished proliferation and increased apoptosis in the pancreatic ductal cells. Together, these data indicate that the SDF-1{alpha}–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

M. Flodström-Tullberg's present address is Center for Infectious Medicine, The Karolinska Institute, SE-171 77 Stockholm, Sweden.

Abbreviations used in this paper: C-10, small inducible cytokine A6; Eotaxin, small inducible chemokine A 11; IP-10, IFN-{gamma}–inducible protein 10 kD; MCP, monocyte chemoattractant protein; MIG, monokine induced by {gamma} 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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