Dextran sulfate and stromal cell derived factor-1 enhance the expression of CXCR4 and improve the homing efficiency of hematopoletic stem cells in bone marrow

硫酸葡聚糖和基质细胞衍生因子1增强CXCR4表达并提高骨髓造血干细胞归巢效率

• 批准号: 14570780
• 负责人: FUKUNAGA Yoshitaka
• 金额: $ 1.92万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570780/
• 关键词: Dextran Sulfate; SDF-1; CXCR4; Homing of HSCs; Dextran sulfate; CXCR4; SDF1; 遺伝子導入

Homing of hematopoietic stem cells (HSCs) in bone marrow (BM) is an important step of hematopoietic development and bone marrow repopulation. It is postulated that the circulating HSCs interact with BM endothelial cells, extravasate, and finally reach the specialized BM micrenvironment called "niches'. Although various kinds of chemokines, cytokines, and adhesion molecules supposed to be involved, the mechanism of HSC homing is not fully understood. Recent studies suggested that interaction of the chemokine receptor CXCR4 and its ligand, stromnal derived factor 1 (SDF-1) plays critical roles in multiple steps of HSC homing. In addition, it was reported that dextran sulfate (DEX) increased plasma levels of SDF1 and HSCs in mice and non-human primates. In this study, we examined the effects of preconditioning with SDF1 and DEX on the homing efficiency of HSCs during BM transplantation. SDF-1 (100ng/kg), DEX (100mg/kg), or PBS was injected into donor GFP transgenic mice 4 times for 4 cons … More ecutive days before harvesting BM cells. Quantitative RP-PCR analysis showed CXCR4 expression on GFP+BM cells was increased in both SDF-1 and DEX treated mice. DEX pretreatment also increased the levels of homing related molecules including MMP9, E-selectin, VEGF, VLA5, and LFA1 in BM cells harvested from the donor mice. Flow cytometry analysis demonstrated that the reconstitution efficiencies at 7 days after BM transplantation were significantly higher with BM cells from SDF-1 treated (45.1±10.1%) and DEX6 treated mice (72.3±7.1%) comnpored to control mice (35.2±1.6%)(n=3). The DEX mediated enhancement of reconstitution at an early stage was also observed in peripheral blood, thymus and spleen. However, the differences became not significant 30 days after BM transplantation. These results indicate that both SDF-1 and DEX are capable of enhancement of HSC homing SDF-1 may directly upregulate CXCR4 expression on HSCs, widle DEX appears to multiple functions including induction of SDF-1 and other molecules required for homing. Preconditioning with DEX may offer a novel clinical approach to improve homing and engraftment of HSCs. Less

造血干细胞（hematopoietic stem cells，HSCs）在骨髓中的归巢是造血发育和骨髓再增殖的重要环节。据推测，循环的HSC与BM内皮细胞相互作用，外渗，并最终到达称为“小生境”的特化BM微增强。虽然各种趋化因子、细胞因子和粘附分子可能参与了HSC归巢，但其机制尚未完全清楚。最近的研究表明，趋化因子受体CXCR 4及其配体基质衍生因子1（SDF-1）的相互作用在HSC归巢的多个步骤中起着关键作用。此外，据报道，硫酸葡聚糖（DEX）增加了小鼠和非人灵长类动物中SDF 1和HSC的血浆水平。在这项研究中，我们研究了SDF 1和DEX预处理对骨髓移植过程中HSC归巢效率的影响。将SDF-1（100 ng/kg）、DEX（100 mg/kg）或PBS注射到供体GFP转基因小鼠体内，共4次，持续4周。 ...更多信息 在收获BM细胞之前的连续几天。定量RP-PCR分析显示，在SDF-1和DEX处理的小鼠中，GFP+BM细胞上的CXCR 4表达增加。DEX预处理还增加了从供体小鼠收获的BM细胞中归巢相关分子的水平，包括MMP 9、E-选择素、VEGF、VLA 5和LFA 1。流式细胞术分析表明，骨髓移植后7天，SDF-1处理组和DEX 6处理组小鼠骨髓细胞的重建效率（45.1±10.1%）（72.3±7.1%）显著高于对照组小鼠（35.2±1.6%）（n=3）。在外周血、胸腺和脾脏中也观察到DEX介导的早期重建增强。然而，骨髓移植后30天的差异变得不显著。这些结果表明，SDF-1和DEX都能够增强HSC归巢，SDF-1可能直接上调HSC上CXCR 4的表达，广泛的DEX似乎具有多种功能，包括诱导SDF-1和归巢所需的其他分子。DEX预处理可能为改善HSC归巢和植入提供一种新的临床方法。少

项目成果

Hayakawa J, Migita M, Ueda T, Shimada T, Fukunaga Y: "Generation of a chimeric mouse reconstituted with green fluorescent protein-positive bone marrow cells : a useful model for studying the behavior of bone marrow cells in regeneration in vivo."Int J Hem

Hayakawa J、Migita M、Ueda T、Shimada T、Fukunaga Y：“用绿色荧光蛋白阳性骨髓细胞重建的嵌合小鼠的产生：研究骨髓细胞体内再生行为的有用模型。”Int

Hayakawa J, Migita M et al.: "Generation of a chimeric mouse reconstituted with green fluorescent protein-positive bone marrow cells : a useful model for studying the behavior of bone marrow cells in regeneration in vivo."Int.J.Hematol. 77. 456-462 (2003)

Hayakawa J、Migita M 等人：“用绿色荧光蛋白阳性骨髓细胞重建嵌合小鼠的产生：研究骨髓细胞体内再生行为的有用模型。”Int.J.Hematol。