Mechanism of human stem cell migration and repopulation of NOD/SCID and B2mnull NOD/SCID mice. The role of SDF-1/CXCR4 interactions

• Published in: Annals of the New York Academy of Sciences 2001-06, Vol.938 (1), p.83-95
• Main Author: Lapidot, T
• Format: Article
• Language: English
• Subjects: Animals; beta 2-Microglobulin - deficiency; beta 2-Microglobulin - genetics; Bone Marrow - pathology; Bone Marrow Cells - metabolism; Cell Adhesion; Cell Adhesion Molecules - physiology; Cell Movement; Chemokine CXCL12; Chemokines, CXC - physiology; Chemotaxis - physiology; DNA Damage; Endothelium, Vascular - physiology; Gels; Graft Survival - physiology; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - cytology; Hemorheology; Humans; Integrins - physiology; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Protein Kinase C - physiology; Receptors, CXCR4 - physiology; Severe Combined Immunodeficiency - pathology; Severe Combined Immunodeficiency - therapy; Spleen - pathology; Transplantation, Heterologous
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/j.1749-6632.2001.tb03577.x

The mechanism of hematopoietic stem cell migration and repopulation is not fully understood. Murine fetuses that lack the chemokine stromal-derived factor one (SDF-1null) or its receptor CXCR4 (CXCR4null) have multiple defects that are lethal, including impaired bone marrow hematopoiesis. These results suggest a major role for SDF-1/CXCR4 interactions in murine stem cell homing from the fetal liver into the bone marrow and its repopulation during development. SDF-1 is highly conserved between different species. Human and murine SDF-1 are cross-reactive and differ in one amino acid. Recently, we reported that SDF-1 and CXCR4 are essential for homing and repopulation of immune-deficient NOD/SCID and B2mnull NOD/SCID mice by human stem cells. In addition, immature human CD34+ cells and primitive CD34+/CD38-/low cells, which do not migrate toward a gradient of SDF-1 in vitro, and do not home and repopulate in vivo the murine bone marrow, can become functional repopulating cells by short-term 16-48 hr in vitro stimulation with cytokines such as SCF and IL-6 prior to transplantation. These cytokines increase surface CXCR4 expression, migration toward SDF-1, and in vivo homing and repopulation. We discuss the pleiotropic roles of SDF-1/CXCR4 interactions in human stem cell migration, development, and repopulation in transplanted immune-deficient mice.