Transgenic expression of stromal cell-derived factor-1/CXC chemokine ligand 12 enhances myeloid progenitor cell survival/antiapoptosis in vitro in response to growth factor withdrawal and enhances myelopoiesis in vivo.
Hemopoiesis is regulated in part by survival/apoptosis of hemopoietic stem/progenitor cells. Exogenously added stromal cell-derived factor-1 ((SDF-1)/CXC chemokine ligand (CXCL)12) enhances survival/antiapoptosis of myeloid progenitor cells in vitro. To further evaluate SDF-1/CXCL12 effects on progenitor cell survival, transgenic mice endogenously expressing SDF-1/CXCL12 under a Rous sarcoma virus promoter were produced. Myeloid progenitors (CFU-granulocyte-macrophage, burst-forming unit-erythroid, CFU-granulocyte-erythrocyte-megakaryocyte-monocyte) from transgenic mice were studied for in vitro survival in the context of delayed addition of growth factors. SDF-1-expressing transgenic myeloid progenitors were enhanced in survival and antiapoptosis compared with their wild-type littermate counterparts. Survival-enhancing effects were due to release of low levels of SDF-1/CXCL12 and mediated through CXCR4 and G(alpha)i proteins as determined by ELISA, an antagonist to CXCR4, Abs to CXCR4 and SDF-1, and pertussis toxin. Transgenic effects of low SDF-1/CXCR4 may be due to synergy of SDF-1/CXCL12 with other cytokines; low SDF-1/CXCL12 synergizes with low concentrations of other cytokines to enhance survival of normal mouse myeloid progenitors. Consistent with in vitro results, progenitors from SDF-1/CXCL12 transgenic mice displayed enhanced marrow and splenic myelopoiesis: greatly increased progenitor cell cycling and significant increases in progenitor cell numbers. These results substantiate survival effects of SDF-1/CXCL12, now extended to progenitors engineered to endogenously produce low levels of this cytokine, and demonstrate activity in vivo for SDF-1/CXCL12 in addition to cell trafficking.
Broxmeyer
Hal E
HE
Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. hbroxmey@iupui.edu
Cooper
Scott
S
Kohli
Lisa
L
Hangoc
Giao
G
Lee
Younghee
Y
Mantel
Charlie
C
Clapp
D Wade
DW
Kim
Chang H
CH
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000502:physiology; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000276:immunology*; D006133:Growth Substances / Q000378:metabolism*; D007106:Immune Sera / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000166:cytology* / Q000276:immunology; D038042:Myelopoiesis / Q000235:genetics / Q000276:immunology*; D037342:Pertussis Toxin / Q000494:pharmacology; D017154:Stromal Cells / Q000502:physiology; D019076:Transgenes / Q000276:immunology*
D000276:Adjuvants, Immunologic; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D006133:Growth Substances; D007106:Immune Sera; D037342:Pertussis Toxin