Mechanism of human stem cell migration and repopulation of NOD/SCID and B2mnull NOD/SCID mice. The role of SDF-1/CXCR4 interactions.
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.
Lapidot
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Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Tsvee.Lapidot@weizmann.ac.il
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000502:physiology; D002465:Cell Movement; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology*; D004249:DNA Damage; D004730:Endothelium, Vascular / Q000502:physiology; D005782:Gels; D006085:Graft Survival / Q000502:physiology*; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D018056:Hemorheology; D006801:Humans; D016023:Integrins / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011493:Protein Kinase C / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology*; D016511:Severe Combined Immunodeficiency / Q000473:pathology / Q000628:therapy; D013154:Spleen / Q000473:pathology; D014183:Transplantation, Heterologous; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics; D000099221:Protein Kinase C zeta
D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D005782:Gels; D016023:Integrins; D011493:Protein Kinase C; D019718:Receptors, CXCR4; D001613:beta 2-Microglobulin; D000099221:Protein Kinase C zeta; C515255:CXCL12 protein, human; C515256:Cxcl12 protein, mouse