Wnt信号通路在衰老造血干细胞中的变化研究
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摘要
第一部分Wnt信号途径在衰老造血干细胞中的变化研究
【目的】研究衰老造血干细胞中Wnt信号途径的变化情况。
【方法】以端粒酶功能缺陷小鼠(TERC-／-)为研究对象，分别分离TERC-／-小鼠及野生型(wide type，WT)小鼠全骨髓细胞，以普通PCR方法对Wnt信号途径的相关分子的表达差异进行初步筛查，并用western blot检测感兴趣分子的蛋白表达。进一步通过磁珠分选及流式细胞仪分别分选TERC-／-小鼠及WT小鼠造血干细胞，对Wnt信号通路中差异表达的相关基因进一步行实时定量PCR检测验证。
【结果】Wnt5b转录本在TERC-／-小鼠全骨髓细胞中表达显著升高；Fzd1、Lef1转录本在TERC-／-小鼠全骨髓细胞及造血干细胞中表达均显著减低。Lef1蛋白表达水平在TERC-／-小鼠全骨髓细胞中显著降低。
【结论】衰老造血干细胞及骨髓细胞中Wnt经典信号途径表达水平显著下调，衰老骨髓细胞Wnt非经典信号途径表达水平显著上调，可能与衰老造血干细胞再生能力下降有关。
第二部分造血干细胞联合AGM基质细胞移植对骨髓移植小鼠造血重建影响
【目的】探讨造血干细胞与主动脉—性腺—中肾(Aorta-gonad-mesonephros，AGM)区来源的基质细胞联合移植对同基因骨髓移植(bone marrow transplantation，BMT)小鼠骨髓造血重建的影响。
【方法】建立同基因骨髓移植小鼠模型，随机分成3组：空白对照组、单纯BMT组、BMT联合AGM基质细胞移植组(联合移植组)，另设正常组小鼠6只。分别于BMT后第7、14、21、28天检测外周血白细胞及血小板、骨髓单个核细胞(bone marrowmono-nuclear cells，BMMNC)的变化，并同时于BMT后第7、10、21天检测骨髓组织学变化。
【结果】联合移植组外周血白细胞及血小板计数、骨髓单个核细胞及骨髓造血组织恢复均较单纯BMT组快，有显著性差异(p＜0.05)。
【结论】BMT联合AGM基质细胞移植对骨髓移植小鼠造血重建具有促进作用。
第三部分三氧化二砷联合全反式维甲酸治疗急性早幼粒细胞白血病的意义研究
【目的】探讨三氧化二砷(As_2O_3)与全反式维甲酸(ATRA)联合治疗急性早幼粒细胞白血病的临床意义。
【方法】对80例急性早幼粒细胞白血病患者回顾性分析，将患者分为单用ATRA组和ATRA与As_2O_3联用组，比较两组间完全缓解(CR)、早期死亡、血象恢复及不良反应发生率等的差异。
【结果】联用组与单用组CR率分别为91.7％和88.2％，无统计学差异；联用组达CR时间、血红蛋白及血小板恢复时间分别为(28±7.8)天、(22.36±8.72)天和(19.38±9.52)天，而单用组分别为(47.7±10.9)天、(28.40±8.95)天和(28.03±7.29)天，联用组与单用组相比均明显缩短：联用组早期死亡率11.1％较单用组20.8％有降低趋势；两组不良反应发生率无显著性差异。
【结论】ATRA与As_2O_3联用治疗初治APL患者较单用ATRA有优势，有望降低早期死亡率，且联用不加重不良反应。
Purpose: To analyze gene expression changes of components of the Wnt signaling pathwayin aging hematopoietic stem cells.
Methods: Use ordinary PCR, real time PCR and western blot to analyze Wnt componentsexpression in bone marrow cells and hematopoietic stem cells isolated from TERC-/- mice(telomerase-deficient mice null for the telomerase RNA component)and wide type mice bymagnetic bead sorting (MACS) and fluorescence activated cell sorting (FACS).
Results: Wnt5b transcripts were significantly upregulated in total bone marrow cells ofTERC -/- mice, while Fzdl and Lefl transcripts were significantly downregulated in totalbone marrow cells as well as hematopoietic stem cells of TERC -/- mice. Lefl was alsodownregulated at protein level in total bone marrow of TERC -/- mice.
Conclusion: The canonical Wnt signaling pathway was downregulated in total bonemarrow cells as well as in hematopoietic stem cells of TERC -/- mice, while thenoncanonical Wnt signaling pathway was upregulated in total bone marrow cells in TERC-/- mice, which might contribute to the impaired regenaration ability of stem cells of theaccelerated aging mice.
Objective: To explore the effects of cotransplantation of hematopoietic stem cells (HSC)and stromal cells derived from aorta-gonad-mesonephros (AGM) region on hematopoieticreconstitution in mice after bone marrow transplantation.
Methods: The typical model of syngeneic BMT was established and the model mice wererandomly divided into 3 groups: the control group, the BMT group, and the group ofcotransplantation of HSC with AGM stromal cells (the cotransplantation group). Thefollowing factors were measured on day 7, 10, 14, 21 and 28 after BMT: peripheral whiteblood cells(WBC) and platelets(PLT), bone marrow mononuclear cells (BMMNC), andhistology changes of bone marrow.
Results: The levels of peripheral WBC, PLT and BMMNC in the contransplantation groupwere higher than those of the single BMT group and the control group.
Conclusion: Cotransplantation with AGM stromal cells could significantly promotehematopoietic reconstruction in mice after BMT. Cotransplantation may represent apromising means of achieving higher engraftment rate after BMT.
Purpose: This study moves towards this goal in understanding the significance ofcombined therapy of arsenic trioxide (As_2O_3) and all-trans retinoic acid (ATRA) in acutepromyelocytic leukemia (APL).
Methods: Retrospective study of 80 APL patients was performed and the completeremission (CR), the recovery of the hemogram, the early mortality, and the adverse effectrates were analyzed between the ATRA group and the combined group.
Results: CR rates of the two groups were 91.7% and 88.2% respectively, which showsno significant difference; time of reaching CR, hemoglobin recovery, and platelet recoveryfor the combined group were (28±7.8)days, (22.36±8.72)days and (19.38±9.52) daysrespectively, while those were (47.7±10.9) days,(28.40±8.95) days and (28.03±7.29) daysfor the ATRA group, which suggested a significantly shorter period of the combined groupof achieving recovery. With 11.1% compared to 20.8%, the mortality of the combinedgroup seemed lower than that of the ATRA group but no significance was observed. Theadverse effect rates of the two groups also lacked of significant difference.
Conclusions: Compared to using ATRA alone, combined therapy of As_2O_3 and ATRAwas dominant in achieving CR and recovery for APL. Besides, the combined therapycarries the promise of reducing the early mortality with no aggravation of the adverseeffects.
【目的】研究衰老造血干细胞中Wnt信号途径的变化情况。
【方法】以端粒酶功能缺陷小鼠(TERC-／-)为研究对象，分别分离TERC-／-小鼠及野生型(wide type，WT)小鼠全骨髓细胞，以普通PCR方法对Wnt信号途径的相关分子的表达差异进行初步筛查，并用western blot检测感兴趣分子的蛋白表达。进一步通过磁珠分选及流式细胞仪分别分选TERC-／-小鼠及WT小鼠造血干细胞，对Wnt信号通路中差异表达的相关基因进一步行实时定量PCR检测验证。
【结果】Wnt5b转录本在TERC-／-小鼠全骨髓细胞中表达显著升高；Fzd1、Lef1转录本在TERC-／-小鼠全骨髓细胞及造血干细胞中表达均显著减低。Lef1蛋白表达水平在TERC-／-小鼠全骨髓细胞中显著降低。
【结论】衰老造血干细胞及骨髓细胞中Wnt经典信号途径表达水平显著下调，衰老骨髓细胞Wnt非经典信号途径表达水平显著上调，可能与衰老造血干细胞再生能力下降有关。
第二部分造血干细胞联合AGM基质细胞移植对骨髓移植小鼠造血重建影响
【目的】探讨造血干细胞与主动脉—性腺—中肾(Aorta-gonad-mesonephros，AGM)区来源的基质细胞联合移植对同基因骨髓移植(bone marrow transplantation，BMT)小鼠骨髓造血重建的影响。
【方法】建立同基因骨髓移植小鼠模型，随机分成3组：空白对照组、单纯BMT组、BMT联合AGM基质细胞移植组(联合移植组)，另设正常组小鼠6只。分别于BMT后第7、14、21、28天检测外周血白细胞及血小板、骨髓单个核细胞(bone marrowmono-nuclear cells，BMMNC)的变化，并同时于BMT后第7、10、21天检测骨髓组织学变化。
【结果】联合移植组外周血白细胞及血小板计数、骨髓单个核细胞及骨髓造血组织恢复均较单纯BMT组快，有显著性差异(p＜0.05)。
【结论】BMT联合AGM基质细胞移植对骨髓移植小鼠造血重建具有促进作用。
第三部分三氧化二砷联合全反式维甲酸治疗急性早幼粒细胞白血病的意义研究
【目的】探讨三氧化二砷(As_2O_3)与全反式维甲酸(ATRA)联合治疗急性早幼粒细胞白血病的临床意义。
【方法】对80例急性早幼粒细胞白血病患者回顾性分析，将患者分为单用ATRA组和ATRA与As_2O_3联用组，比较两组间完全缓解(CR)、早期死亡、血象恢复及不良反应发生率等的差异。
【结果】联用组与单用组CR率分别为91.7％和88.2％，无统计学差异；联用组达CR时间、血红蛋白及血小板恢复时间分别为(28±7.8)天、(22.36±8.72)天和(19.38±9.52)天，而单用组分别为(47.7±10.9)天、(28.40±8.95)天和(28.03±7.29)天，联用组与单用组相比均明显缩短：联用组早期死亡率11.1％较单用组20.8％有降低趋势；两组不良反应发生率无显著性差异。
【结论】ATRA与As_2O_3联用治疗初治APL患者较单用ATRA有优势，有望降低早期死亡率，且联用不加重不良反应。
Purpose: To analyze gene expression changes of components of the Wnt signaling pathwayin aging hematopoietic stem cells.
Methods: Use ordinary PCR, real time PCR and western blot to analyze Wnt componentsexpression in bone marrow cells and hematopoietic stem cells isolated from TERC-/- mice(telomerase-deficient mice null for the telomerase RNA component)and wide type mice bymagnetic bead sorting (MACS) and fluorescence activated cell sorting (FACS).
Results: Wnt5b transcripts were significantly upregulated in total bone marrow cells ofTERC -/- mice, while Fzdl and Lefl transcripts were significantly downregulated in totalbone marrow cells as well as hematopoietic stem cells of TERC -/- mice. Lefl was alsodownregulated at protein level in total bone marrow of TERC -/- mice.
Conclusion: The canonical Wnt signaling pathway was downregulated in total bonemarrow cells as well as in hematopoietic stem cells of TERC -/- mice, while thenoncanonical Wnt signaling pathway was upregulated in total bone marrow cells in TERC-/- mice, which might contribute to the impaired regenaration ability of stem cells of theaccelerated aging mice.
Objective: To explore the effects of cotransplantation of hematopoietic stem cells (HSC)and stromal cells derived from aorta-gonad-mesonephros (AGM) region on hematopoieticreconstitution in mice after bone marrow transplantation.
Methods: The typical model of syngeneic BMT was established and the model mice wererandomly divided into 3 groups: the control group, the BMT group, and the group ofcotransplantation of HSC with AGM stromal cells (the cotransplantation group). Thefollowing factors were measured on day 7, 10, 14, 21 and 28 after BMT: peripheral whiteblood cells(WBC) and platelets(PLT), bone marrow mononuclear cells (BMMNC), andhistology changes of bone marrow.
Results: The levels of peripheral WBC, PLT and BMMNC in the contransplantation groupwere higher than those of the single BMT group and the control group.
Conclusion: Cotransplantation with AGM stromal cells could significantly promotehematopoietic reconstruction in mice after BMT. Cotransplantation may represent apromising means of achieving higher engraftment rate after BMT.
Purpose: This study moves towards this goal in understanding the significance ofcombined therapy of arsenic trioxide (As_2O_3) and all-trans retinoic acid (ATRA) in acutepromyelocytic leukemia (APL).
Methods: Retrospective study of 80 APL patients was performed and the completeremission (CR), the recovery of the hemogram, the early mortality, and the adverse effectrates were analyzed between the ATRA group and the combined group.
Results: CR rates of the two groups were 91.7% and 88.2% respectively, which showsno significant difference; time of reaching CR, hemoglobin recovery, and platelet recoveryfor the combined group were (28±7.8)days, (22.36±8.72)days and (19.38±9.52) daysrespectively, while those were (47.7±10.9) days,(28.40±8.95) days and (28.03±7.29) daysfor the ATRA group, which suggested a significantly shorter period of the combined groupof achieving recovery. With 11.1% compared to 20.8%, the mortality of the combinedgroup seemed lower than that of the ATRA group but no significance was observed. Theadverse effect rates of the two groups also lacked of significant difference.
Conclusions: Compared to using ATRA alone, combined therapy of As_2O_3 and ATRAwas dominant in achieving CR and recovery for APL. Besides, the combined therapycarries the promise of reducing the early mortality with no aggravation of the adverseeffects.
引文
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