Stromal-derived factor 1 inhibits the cycling of very primitive human hematopoietic cells in vitro and in NOD/SCID mice.
Stromal-derived factor 1 (SDF-1) is a -CXC- chemokine that plays a critical role in embryonic and adult hematopoiesis, and its specific receptor, CXCR4, has been implicated in stem cell homing. In this study, it is shown that the addition of SDF-1 to long-term cultures (LTCs) of normal human marrow can selectively, reversibly, and specifically block the S-phase entry of primitive quiescent erythroid and granulopoietic colony-forming cells (CFCs) present in the adherent layer. Conversely, addition of anti-SDF-1 antibody or SDF-1(G2), a specific CXCR4 antagonist, to preactivated human LTCs prevented both types of primitive CFCs from re-entering a quiescent state, demonstrating that endogenous SDF-1 contributes to the control of primitive CFC proliferation in the LTC system. Interestingly, SDF-1 failed to arrest the proliferation of primitive chronic myeloid leukemia CFCs in the adherent layer of LTCs containing normal marrow stromal cells. In vivo, injection of SDF-1 arrested the cycling of normal human LTC-initiating cells as well as primitive CFCs in the marrow of nonobese diabetic/severe combined immunodeficient mice engrafted with human cord blood cells. Conversely, injection of the antagonist, SDF-1(G2), reactivated the cycling of quiescent primitive human CFCs present in the marrow of mice engrafted with human marrow cells. These studies are the first to demonstrate a potential physiological role of SDF-1 in regulating the cell-cycle status of primitive hematopoietic cells and suggest that the deregulated cycling activity of primitive chronic myeloid leukemia (CML) cells is due to the BCR-ABL-mediated disruption of a pathway shared by multiple chemokine receptors.
Cashman
Johanne
J
Terry Fox Laboratory, British Columbia Cancer Agency, 601 West 10th Ave, Vancouver, BC, V5Z 1L3, Canada.
Clark-Lewis
Ian
I
Eaves
Allen
A
Eaves
Connie
C
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD / Q000097:blood*; D016513:Mice, SCID / Q000097:blood*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D014183:Transplantation, Heterologous
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse