The stromal cell-derived factor-1alpha/CXCR4 ligand-receptor axis is critical for progenitor survival and migration in the pancreas.
The SDF-1alpha/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-1alpha and CXCR4 expression in fetal pancreas. We have found that SDF-1alpha 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-1alpha stimulates the phosphorylation of Akt, mitogen-activated protein kinase, and Src in pancreatic duct cells. Furthermore, migration assays indicate a stimulatory effect of SDF-1alpha on ductal cell migration. Importantly, blocking the SDF-1alpha/CXCR4 axis in IFNgamma-nonobese diabetic mice resulted in diminished proliferation and increased apoptosis in the pancreatic ductal cells. Together, these data indicate that the SDF-1alpha-CXCR4 ligand receptor axis is an obligatory component in the maintenance of duct cell survival, proliferation, and migration during pancreatic regeneration.
Kayali
Ayse G
AG
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Van Gunst
Kurt
K
Campbell
Iain L
IL
Stotland
Aleksandr
A
Kritzik
Marcie
M
Liu
Guoxun
G
Flodström-Tullberg
Malin
M
Zhang
You-Qing
YQ
Sarvetnick
Nora
N
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005333:Fetus; D008024:Ligands; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D008024:Ligands; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases