Treatment of circulating CD34(+) cells with SDF-1alpha or anti-CXCR4 antibody enhances migration and NOD/SCID repopulating potential

• Published in: Experimental hematology 2002-09, Vol.30 (9), p.1061-1069
• Main Authors: Plett, P Artur, Frankovitz, Stacy M, Wolber, Frances M, Abonour, Rafat, Orschell-Traycoff, Christie M
• Format: Article
• Language: English
• Subjects: Adult; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antigens, CD34 - analysis; Blood Cells - cytology; Blood Cells - drug effects; Bone Marrow Cells - cytology; Bone Marrow Cells - drug effects; Cell Adhesion Molecules - biosynthesis; Cell Movement - drug effects; Chemokine CXCL12; Chemokines, CXC - pharmacology; Graft Survival - drug effects; Hematopoietic Stem Cells - drug effects; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Phosphorylation; Protein Processing, Post-Translational - drug effects; Protein-Tyrosine Kinases - metabolism; Radiation Chimera; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - physiology; Signal Transduction; Specific Pathogen-Free Organisms; Stem Cell Transplantation; Transplantation, Heterologous
• ISSN: 0301-472X

Stromal cell-derived factor-1alpha (SDF-1alpha) has been implicated in homing and engraftment of primitive hematopoietic progenitor cells (HPC) in studies demonstrating reduced NOD/SCID repopulating potential of HPC exposed to supra-physiologic concentrations of SDF-1alpha or anti-CXCR4. Outcome of CXCR4 signaling in some cells has been shown to be dependent on the concentration of SDF-1alpha. We aimed to determine whether similar concentration-dependent responses to CXCR4 signaling are present in CD34(+)cells. Human peripheral blood (PB), mobilized PB (MPB), or bone marrow (BM) CD34(+) cells were incubated for 30 minutes with different concentrations of SDF-1alpha or anti-CXCR4, washed, then assessed for in vitro hematopoietic potential, migration, and NOD/SCID repopulating potential. Exposure of MPB or PB CD34(+) cells to 100 ng/mL SDF-1alpha increased tyrosine phosphorylation without subsequent proliferation or apoptosis. Spontaneous and SDF-1alpha-directed migration also increased in pretreated cells, despite previous exposure to SDF-1alpha. Cells exposed to 1 microg anti-CXCR4/10(6) cells displayed similar increases in activation and migration as cells exposed to SDF-1alpha, demonstrating the ability of anti-CXCR4 to activate the CXCR4 receptor. Interestingly, chimerism in NOD/SCID mice transplanted with MPB CD34(+) cells pretreated with SDF-1alpha or anti-CXCR4 was increased, while exposure of these cells to 10- to 100-fold higher concentrations of these proteins inhibited in vitro migration and NOD/SCID repopulating potential. Migration and NOD/SCID repopulating potential of BM CD34(+) cells remained unchanged after treatment with either protein. These results illustrate the ability of SDF-1alpha and anti-CXCR4 to augment repopulating potential of CD34(+) cells, and suggest that HPC function can be favorably modulated through specific CXCR4 signaling.