Stromal-derived factor 1 inhibits the cycling of very primitive human hematopoietic cells in vitro and in NOD/SCID mice

Blood. 2002 Feb 1;99(3):792-9. doi: 10.1182/blood.v99.3.792.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Transplantation
  • Cell Cycle / drug effects
  • Cell Division / drug effects
  • Cells, Cultured
  • Chemokine CXCL12
  • Chemokines, CXC / administration & dosage
  • Chemokines, CXC / antagonists & inhibitors
  • Chemokines, CXC / pharmacology*
  • Fetal Blood / cytology
  • Fetal Blood / drug effects
  • Graft Survival / drug effects
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / drug effects*
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice
  • Mice, Inbred NOD / blood*
  • Mice, SCID / blood*
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Transplantation, Heterologous

Substances

  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Cxcl12 protein, mouse