Lapidot T
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Ann N Y Acad Sci. 2001 Jun;938:83-95. 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.
造血干细胞迁移和再增殖的机制尚未完全明确。缺乏趋化因子基质衍生因子-1（SDF-1基因敲除）或其受体CXCR4（CXCR4基因敲除）的小鼠胎儿存在多种致命缺陷，包括骨髓造血功能受损。这些结果表明，SDF-1/CXCR4相互作用在小鼠干细胞从胎儿肝脏归巢至骨髓及其发育过程中的再增殖中起主要作用。SDF-1在不同物种间高度保守。人和小鼠的SDF-1具有交叉反应性，仅一个氨基酸不同。最近，我们报道SDF-1和CXCR4对人干细胞在免疫缺陷的NOD/SCID和B2m基因敲除的NOD/SCID小鼠中的归巢和再增殖至关重要。此外，未成熟的人CD34+细胞和原始CD34+/CD38-/低细胞在体外不向SDF-1梯度迁移，在体内也不能归巢至小鼠骨髓并进行再增殖，但在移植前通过用细胞因子如SCF和IL-6进行短期16 - 48小时的体外刺激，可成为有功能的再增殖细胞。这些细胞因子可增加表面CXCR4表达、向SDF-1的迁移以及体内归巢和再增殖。我们讨论了SDF-1/CXCR4相互作用在人干细胞迁移、发育以及在移植的免疫缺陷小鼠中的再增殖中的多效性作用。
