Stromal cell-derived factor-1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cells through CXCR4 and G(alpha)i proteins and enhances engraftment of competitive, repopulating stem cells.
Stromal cell-derived factor-1 (SDF-1/CXCL12) enhances survival of myeloid progenitor cells. The two main questions addressed by us were whether these effects on the progenitors were direct-acting and if SDF-1/CXCL12 enhanced engrafting capability of competitive, repopulating mouse stem cells subjected to short-term ex vivo culture with other growth factors. SDF-1/CXCL12 had survival-enhancing/antiapoptosis effects on human bone marrow (BM) and cord blood (CB) and mouse BM colony-forming units (CFU)-granulocyte macrophage, burst-forming units-erythroid, and CFU-granulocyte-erythroid-macrophage-megakaryocyte with similar dose responses. The survival effects were direct-acting, as assessed on colony formation by single isolated human BM and CB CD34(+++) cells. Effects were mediated through CXCR4 and G(alpha)i proteins. Moreover, SDF-1/CXCL12 greatly enhanced the engrafting capability of mouse long-term, marrow-competitive, repopulating stem cells cultured ex vivo with interleukin-6 and steel factor for 48 h. These results extend information on the survival effects mediated through the SDF-1/CXCL12-CXCR4 axis and may be of relevance for ex vivo expansion and gene-transduction procedures.
Broxmeyer
Hal E
HE
Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis 46202, USA. hbroxmey@iupui.edu
Kohli
Lisa
L
Kim
Chang H
CH
Lee
Younghee
Y
Mantel
Charlie
C
Cooper
Scott
S
Hangoc
Giao
G
Shaheen
Montaser
M
Li
Xiaxin
X
Clapp
D Wade
DW
D000818:Animals; D020296:Animals, Congenic; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects*; D037342:Pertussis Toxin / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011828:Radiation Chimera; D019718:Receptors, CXCR4 / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D037342:Pertussis Toxin; C498015:GNAI2 protein, human; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498016:Gnai2 protein, mouse