髓腔内途径输注脐带血造血干/祖细胞能有效提高其于异种移植NOD/SCID小鼠体内的植活能力
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摘要
脐带血(UCB)因其来源丰富且制备便利，已成为可供临床移植用造血干／祖细胞(HS／PCs)的重要替代来源。UCB及UCB移植(UCBT)正日益受到国内外学者的高度重视，迄今全球逾4，000例患者接受UCBT。累积的临床研究结果显示，与动员外周血干细胞移植(mPBSCT)及骨髓移植(BMT)受者比较，高达10％～20％UCBT受者未植活，且植活者外周血中性粒细胞及血小板水平恢复明显延迟，二者显著增加了UCBT后移植相关死亡率(TRM)。新近的研究报道证实导致上述负面疗效的主要因素为UCBT受者低CD34~+细胞输注剂量。
UCB HS／PCs体外SDF-1α／CXCR-4介导的迁移能力低下，若采用高效的髓腔内途径(iBMI)输注UCB HS／PCs(iBMT-UCBT)可能有助于提高其于异种移植NOD／SCID小鼠体内植活能力。将不同数量UCB HS／PCs经iBMT方式移植入亚致死剂量照射NOD／SCID小鼠体内，移植后8周人造血细胞于受鼠体内植活良好，包括输注部位右侧胫骨(R-tibia)，非输注部位右侧股骨(R-femur)、左侧胫骨(L-tibia)、左侧股骨(L-femur)、脾脏及外周血。剂量依赖实验证实将同一来源1×10~4 CD34~+细胞分别经常规静脉输注法(iVI)及iBMI途径移植于照射NOD／SCID小鼠体内，移植后8周人造血细胞于iBMI-UCBT受鼠植活度优于iVI-UCBT受鼠；输注HS／PCs数量降至1×10~3 CD34~+细胞时，移植后8周人造血细胞仅于iBMI-UCBT受鼠体内植活。动态移植实验显示将适宜数量HS／PCs(0.5×10~4 CD34~+细胞)分别经iVI及iBMI途径移植入照射NOD／SCID小鼠体内，移植后3周及8周iBMI-UCBT受鼠体内人造血细胞植活度较iVI-UCBT受鼠分别高达3～20倍。碳青花(Dil-CM)标记实验及流式细胞术(FACS)分析研究进一步分别证实CD34~+细胞及CD34~+AC133~+CD38~-细胞经iBMI方式输注于R-tibia后可迅速分布于iBMI-UCBT受鼠全身各部位造血微环境。体内归巢研究结果颇有意义，移植后60小时CFSE标记的UCB CD34~+细胞于iBMI-UCBT受鼠的骨髓种植
Umbilical cord blood (UCB) has been proved to be an alternative source of hematopoietic stem/progenitor cells (HS/PCs) for patients without matched sibling donors due to their main practical advantages of relatively ease of procurement and available for immediate use. Clinical experience provides further evidence to increase awareness of hematologists worldwide to use UCB transplantation (UCBT) to treat patients with hematological malignancies, more than 4,000 UCBTs have been performed worldwide to date. But compared with bone marrow transplantation (BMT) and mobilized peripheral blood stem cell transplantation (mPBSCT) recipients, UCBT recipients have the severely delayed neutrophil and platelet recoveries due to their slow engraftment leading to high risks of infectious and bleeding complications together with a documented 10 to 15 percent graft failure rate increased dramatically post-UCBT transplantation-related mortality (TRM). Recently, the importance of low graft CD34 cell dose has been clarified in determining poor outcome after unrelated donor UCBTs. Introducing limited number of hematopoietic stem/progenitor cells (HS/PCs) from UCB directly into bone marrow microenvironment by efficient use of intra-bone marrow injection (iBMI) strategy might produce desirable human cell engraftment in xenotransplanted NOD/SCID mouse model. Superior
8-week-engraftment was observed in injected bone (R-tibia) as well as non-injected bones (including R-femur, L-tibia and L-femur), spleen and peripheral blood in iBMI-UCBT recipients. More superior 8-week-engraftment was observed in
UCB HS／PCs体外SDF-1α／CXCR-4介导的迁移能力低下，若采用高效的髓腔内途径(iBMI)输注UCB HS／PCs(iBMT-UCBT)可能有助于提高其于异种移植NOD／SCID小鼠体内植活能力。将不同数量UCB HS／PCs经iBMT方式移植入亚致死剂量照射NOD／SCID小鼠体内，移植后8周人造血细胞于受鼠体内植活良好，包括输注部位右侧胫骨(R-tibia)，非输注部位右侧股骨(R-femur)、左侧胫骨(L-tibia)、左侧股骨(L-femur)、脾脏及外周血。剂量依赖实验证实将同一来源1×10~4 CD34~+细胞分别经常规静脉输注法(iVI)及iBMI途径移植于照射NOD／SCID小鼠体内，移植后8周人造血细胞于iBMI-UCBT受鼠植活度优于iVI-UCBT受鼠；输注HS／PCs数量降至1×10~3 CD34~+细胞时，移植后8周人造血细胞仅于iBMI-UCBT受鼠体内植活。动态移植实验显示将适宜数量HS／PCs(0.5×10~4 CD34~+细胞)分别经iVI及iBMI途径移植入照射NOD／SCID小鼠体内，移植后3周及8周iBMI-UCBT受鼠体内人造血细胞植活度较iVI-UCBT受鼠分别高达3～20倍。碳青花(Dil-CM)标记实验及流式细胞术(FACS)分析研究进一步分别证实CD34~+细胞及CD34~+AC133~+CD38~-细胞经iBMI方式输注于R-tibia后可迅速分布于iBMI-UCBT受鼠全身各部位造血微环境。体内归巢研究结果颇有意义，移植后60小时CFSE标记的UCB CD34~+细胞于iBMI-UCBT受鼠的骨髓种植
Umbilical cord blood (UCB) has been proved to be an alternative source of hematopoietic stem/progenitor cells (HS/PCs) for patients without matched sibling donors due to their main practical advantages of relatively ease of procurement and available for immediate use. Clinical experience provides further evidence to increase awareness of hematologists worldwide to use UCB transplantation (UCBT) to treat patients with hematological malignancies, more than 4,000 UCBTs have been performed worldwide to date. But compared with bone marrow transplantation (BMT) and mobilized peripheral blood stem cell transplantation (mPBSCT) recipients, UCBT recipients have the severely delayed neutrophil and platelet recoveries due to their slow engraftment leading to high risks of infectious and bleeding complications together with a documented 10 to 15 percent graft failure rate increased dramatically post-UCBT transplantation-related mortality (TRM). Recently, the importance of low graft CD34 cell dose has been clarified in determining poor outcome after unrelated donor UCBTs. Introducing limited number of hematopoietic stem/progenitor cells (HS/PCs) from UCB directly into bone marrow microenvironment by efficient use of intra-bone marrow injection (iBMI) strategy might produce desirable human cell engraftment in xenotransplanted NOD/SCID mouse model. Superior
8-week-engraftment was observed in injected bone (R-tibia) as well as non-injected bones (including R-femur, L-tibia and L-femur), spleen and peripheral blood in iBMI-UCBT recipients. More superior 8-week-engraftment was observed in
引文
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