辐射导致长期骨髓抑制的机制及MnTE骨髓辐射保护作用的试验观察
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摘要
目的电离辐射(ionizing radiation, IR)不仅引起急性组织损伤,也可导致长期的组织损伤,如长期骨髓抑制(long-term bone marrow depression)。导致长期骨髓抑制的主要原因是IR诱导的造血干细胞(hematopoietic stem cells, HSCs)衰老。然而,目前不仅IR引起HSCs衰老的分子机制尚未阐明,而且临床上也缺乏治疗长期骨髓抑制的有效手段。本课题对辐射导致的长期骨髓抑制的机制进行了深入研究,并探讨超氧化物歧化酶模拟化合物MnTE对骨髓长期抑制的治疗作用,为开发新的治疗长期骨髓抑制的药物提供实验基础。
方法8-10周雄性C57BL/6-Ly-5.2小鼠分为对照组、照射组(亚致死剂量6.5Gy TBI)和照射后给药组(NADPH氧化酶抑制剂DPI；抗氧化剂MnTE)。给药2个月后取小鼠骨髓,进行以下分析：梯度离心分离小鼠骨髓单个核细胞(bone marrow mononuclear cells, BM-MNCs),进行在体HSCs竞争抑制试验(competitive repopulation assay); BM-MNCs在MethoCult M3434 methylcellulose培养基中培养,11天后收取单个CFU-GEMM集落进行细胞遗传学分析；流式细胞仪分选造血干细胞(hematopoietic progenitor cells, HSCs;或者lin-Sca-1+cKit+,LSK-)、造血祖细胞(lin-Sca-1-cKit+, hematopoietic progenitor cells, HPCs) (LSK+),测定两群细胞内活性氧(Reactive oxygen species, ROS)水平；8-羟基-脱氧鸟嘌呤核苷(8-hydroxydeoxyguanine,8-OH-dG)及y-H2AX免疫荧光染色检测DNA氧化损伤和DNA双链断裂(double-strand breaks, DSBs);细胞集落形成试验(Colony-forming cell assay), Cobblestone Area-Forming Cell assay (CAFC)试验和单细胞CAFC分析检测两群细胞的集落形成能力：Annexin V/PI细胞染色流式细胞仪分析细胞凋亡(apoptosis);半定量逆转录聚合酶链反应(RT-PCR)技术检测两群细胞中NADPH氧化酶(NADPH oxidases, NOX),包括NOX1, NOX2,NOX3和NOX4及P16和p53表达水平,并对两群细胞行NOX3和NOX4免疫荧光染色。
结果在辐射导致骨髓损伤的氧化机制研究中,我们首次发现小鼠接受亚致死剂量全身照射(6.5Gy TBI)后,其造血祖细胞(HPCs)内ROS短暂性升高,之后迅速下降至正常水平；而HSCs内活性氧持续维持在高水平,即处于长期氧化应激状态。TBI诱导的HSCs的慢性氧化应激与持续存在的DNA氧化损伤、DNA双链断裂、HSCs集落形成能力降低及HSCs衰老密切相关,但与细胞凋亡无关。进一步研究发现,TBI所诱导的HSCs长期氧化损伤主要是通过NOX4表达的上调介导的,TBI照射引起HSCs NOX4表达升高,照射后给予diphenylene iodonium(特异性抑制NOXs表达),抑制了NOXs的活性可明显降低TBI诱导HSCs内活性氧的增加,也可减轻DNA氧化损伤和减少DNA双链断裂,并明显提高HSCs的集落形成能力。这些研究结果首次直接证明辐射可能部分通过上调NOX4而选择性提高HSCs慢性氧化应激水平,诱导HSCs衰老,最终导致长期骨髓抑制。
为了有效预防和治疗核辐射暴露或接受放射治疗患者的长期骨髓抑制,基于TBI诱导HSCs慢性氧化应激导致长期骨髓抑制的机制,我们试图寻找新的抗氧化剂,治疗TBI诱导的长期骨髓抑制。Mn (Ⅲ) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE)是一种超氧化物歧化酶模拟化合物,我们应用上述TBI小鼠模型检测了MnTE对长期骨髓抑制的治疗作用。结果发现,照射后使用MnTE可明显抑制TBI所致的HSCs、造血祖细胞活性氧生成和DNA氧化损伤。HSCs内氧化应激水平下降与骨髓中的HSCs数量增加和功能改善有关。照射后使用MnTE治疗小鼠的HSCs功能与未照射作为对照小鼠的HSCs的功能已无明显差异,提示MnTE治疗可抑制TBI造成的HSCs功能损伤。照射后使用MnTE治疗对辐射造成的HSCs保持休眠或静止能力及增殖分化能力损伤具有保护作用,对TBI小鼠HSCs寿命缩短有改善作用。进一步研究发现,MnTE治疗可降低TBI诱导的HSCs中p16 mRNA的表达水平,提示MnTE治疗抑制了TBI诱导的HSCs的衰老,在体内竞争性移植试验中,MnTE治疗明显改善照射后小鼠HSCs长期再植能力和多系细胞造血重建能力。
结论辐射诱导造血干细胞损伤机制研究发现：TBI选择性诱导HSCs内持续性ROS升高；HSCs内ROS的持续升高部分是通过NOX4表达上调介导；TBI所诱导的HSCs慢性氧化应激可通过上调p16导致HSCs丧失自我更新能力、HSCs发生衰老,从而诱发长期骨髓抑制。利用强抗氧化剂MnTE进行试验性治疗,研究发现MnTE可抑制ROS-p16通路,减轻辐射诱发的HSCs衰老,缓解TBI所导致的长期骨髓抑制,可能成为有效的TBI损伤治疗药物。
The mechanism of Long-term Bone Marrow Suppression Induced by Ionizing Radiation and The Radioprotectiveeffects of MnTE on bone marrow Exposure to Ionizing Radition
Objective Ionizing radiation (IR) causes not only acute tissue damage but also late effects including long-term bone marrow (BM) injury. The induction of long-term BM injury is primarily attributable to the induction of hematopoietic stem cells (HSCs) senescence. However, the molecular mechanisms by which IR induces HSCs senescence have not been clearly defined, nor has an effective treatment been developed to ameliorate the injury. Thus, we investigated these mechanisms and the radioprotection of Mn (Ⅲ) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE) on TBI induced BM injury in this study.
Methods 4-8 weeks old 57BL/6-Ly-5.2 were classified into three groups: control group, radiation group and radiation plus drug group, radiation was 6.5 Gy total body irradiation (TBI) and drugs includes diphenylene iodonium and MnTE. Bone marrow mononulcer cells(BM-MNCs) isolated form these mice were used to perform competitive repopulation assay in vivo and CFU-GEMM individual colonies were developed by culturing BM-MNCs in MethoCult GF M3434 methylcellulose medium after 11 days were used to performcytogenetic analyses. and hematopoietic progenitor cells (HPCs) sorted out by flow cytometry were used to examine the following tests:the level of ROS by 2', 7'-dichlorofluorescin diacetate (DCFDA), the DNA damage and DNA double strand breaks by using 8-hydroxydeoxyguanine and H2AX staining, respectively; Colony forming function were analyzed by in vitro colony-forming cell assay, cobblestone area-forming cell assay and single cobblestone area-forming cell assay. Apoptosis was detected by Annexin V/7-AAD; The expression of NOXs, p16 and p53, were assayed by RT-PCR or immunostaining.
Results The results showed that exposure of mice to a sublethal. dose of total body irradiation (TBI) induced a persistent increase in reactive oxygen species (ROS) production in HSCs selectively. The induction of chronic oxidative stress in HSCs was associated with sustained increases in oxidative DNA damage, DNA double-strand breaks (DSBs), inhibition of HSC clonogenic function, and induction of HSC senescence but not apoptosis. The induction of chronic oxidative stress in HSCs by TBI is probably attributable to the up-regulation of NADPH oxidase 4 (NOX4), because irradiated HSCs expressed an increased level of NOX4, and inhibition of NOX activity with diphenylene iodonium but not apocynin significantly reduced TBI-induced increases in ROS production, oxidative DNA damage, and DNA DSBs in HSCs and dramatically improved HSC clonogenic function.
Then, we examined if Mn (Ⅲ) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE), a superoxide dismutase mimetic and potent antioxidant, can mitigate TBI-induced long-term BM injury in a mouse model. Our results showed that post-TBI treatment with MnTE significantly inhibited the increases in ROS production and DNA damage in HSCs and reduction in HSC frequency and clonogenic function induced by TBI. In fact, the clonogenic function of HSCs from irradiated mice after MnTE treatment was comparable to that of HSCs from normal controls on a per HSC basis, suggesting that MnTE treatment inhibited the induction of HSC senescence by TBI. In addition, MnTE treatment can mitigate TBI induced defects in the abilities of HSCs to maitain quiescence, proliferate and survive in vitro. This suggestion is supported by the findings that MnTE treatment also reduced the expression of p16Ink4a (p16) mRNA in HSCs induced by TBI and improved the long-term and multi-lineage engraftment of irradiated HSCs after transplantation.
Conclusions TBI selectively induces a persistent increase in reactive oxygen species (ROS) production in HSCs only. The induction of chronic oxidative stress in HSCs by TBI is probably attributable to the up-regulation of NADPH oxidase 4 (NOX4)。Chronic oxidative stress in HSCs leads to the loss of HSCs self-renewal and the induction of HSC senescence via up-regulation of p16, which leads to long-term bone marrow suppression. TBI-induced long-term BM suppression can be mitigated by antioxidant treanment. We found MnTE can mitigate IR-induced HSC senescence inhibiting the ROS-p16 pathway and be used to a therapeutic agent to mitigate TBI-induced long-term BM suppression by TBI.
方法8-10周雄性C57BL/6-Ly-5.2小鼠分为对照组、照射组(亚致死剂量6.5Gy TBI)和照射后给药组(NADPH氧化酶抑制剂DPI；抗氧化剂MnTE)。给药2个月后取小鼠骨髓,进行以下分析：梯度离心分离小鼠骨髓单个核细胞(bone marrow mononuclear cells, BM-MNCs),进行在体HSCs竞争抑制试验(competitive repopulation assay); BM-MNCs在MethoCult M3434 methylcellulose培养基中培养,11天后收取单个CFU-GEMM集落进行细胞遗传学分析；流式细胞仪分选造血干细胞(hematopoietic progenitor cells, HSCs;或者lin-Sca-1+cKit+,LSK-)、造血祖细胞(lin-Sca-1-cKit+, hematopoietic progenitor cells, HPCs) (LSK+),测定两群细胞内活性氧(Reactive oxygen species, ROS)水平；8-羟基-脱氧鸟嘌呤核苷(8-hydroxydeoxyguanine,8-OH-dG)及y-H2AX免疫荧光染色检测DNA氧化损伤和DNA双链断裂(double-strand breaks, DSBs);细胞集落形成试验(Colony-forming cell assay), Cobblestone Area-Forming Cell assay (CAFC)试验和单细胞CAFC分析检测两群细胞的集落形成能力：Annexin V/PI细胞染色流式细胞仪分析细胞凋亡(apoptosis);半定量逆转录聚合酶链反应(RT-PCR)技术检测两群细胞中NADPH氧化酶(NADPH oxidases, NOX),包括NOX1, NOX2,NOX3和NOX4及P16和p53表达水平,并对两群细胞行NOX3和NOX4免疫荧光染色。
结果在辐射导致骨髓损伤的氧化机制研究中,我们首次发现小鼠接受亚致死剂量全身照射(6.5Gy TBI)后,其造血祖细胞(HPCs)内ROS短暂性升高,之后迅速下降至正常水平；而HSCs内活性氧持续维持在高水平,即处于长期氧化应激状态。TBI诱导的HSCs的慢性氧化应激与持续存在的DNA氧化损伤、DNA双链断裂、HSCs集落形成能力降低及HSCs衰老密切相关,但与细胞凋亡无关。进一步研究发现,TBI所诱导的HSCs长期氧化损伤主要是通过NOX4表达的上调介导的,TBI照射引起HSCs NOX4表达升高,照射后给予diphenylene iodonium(特异性抑制NOXs表达),抑制了NOXs的活性可明显降低TBI诱导HSCs内活性氧的增加,也可减轻DNA氧化损伤和减少DNA双链断裂,并明显提高HSCs的集落形成能力。这些研究结果首次直接证明辐射可能部分通过上调NOX4而选择性提高HSCs慢性氧化应激水平,诱导HSCs衰老,最终导致长期骨髓抑制。
为了有效预防和治疗核辐射暴露或接受放射治疗患者的长期骨髓抑制,基于TBI诱导HSCs慢性氧化应激导致长期骨髓抑制的机制,我们试图寻找新的抗氧化剂,治疗TBI诱导的长期骨髓抑制。Mn (Ⅲ) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE)是一种超氧化物歧化酶模拟化合物,我们应用上述TBI小鼠模型检测了MnTE对长期骨髓抑制的治疗作用。结果发现,照射后使用MnTE可明显抑制TBI所致的HSCs、造血祖细胞活性氧生成和DNA氧化损伤。HSCs内氧化应激水平下降与骨髓中的HSCs数量增加和功能改善有关。照射后使用MnTE治疗小鼠的HSCs功能与未照射作为对照小鼠的HSCs的功能已无明显差异,提示MnTE治疗可抑制TBI造成的HSCs功能损伤。照射后使用MnTE治疗对辐射造成的HSCs保持休眠或静止能力及增殖分化能力损伤具有保护作用,对TBI小鼠HSCs寿命缩短有改善作用。进一步研究发现,MnTE治疗可降低TBI诱导的HSCs中p16 mRNA的表达水平,提示MnTE治疗抑制了TBI诱导的HSCs的衰老,在体内竞争性移植试验中,MnTE治疗明显改善照射后小鼠HSCs长期再植能力和多系细胞造血重建能力。
结论辐射诱导造血干细胞损伤机制研究发现：TBI选择性诱导HSCs内持续性ROS升高；HSCs内ROS的持续升高部分是通过NOX4表达上调介导；TBI所诱导的HSCs慢性氧化应激可通过上调p16导致HSCs丧失自我更新能力、HSCs发生衰老,从而诱发长期骨髓抑制。利用强抗氧化剂MnTE进行试验性治疗,研究发现MnTE可抑制ROS-p16通路,减轻辐射诱发的HSCs衰老,缓解TBI所导致的长期骨髓抑制,可能成为有效的TBI损伤治疗药物。
The mechanism of Long-term Bone Marrow Suppression Induced by Ionizing Radiation and The Radioprotectiveeffects of MnTE on bone marrow Exposure to Ionizing Radition
Objective Ionizing radiation (IR) causes not only acute tissue damage but also late effects including long-term bone marrow (BM) injury. The induction of long-term BM injury is primarily attributable to the induction of hematopoietic stem cells (HSCs) senescence. However, the molecular mechanisms by which IR induces HSCs senescence have not been clearly defined, nor has an effective treatment been developed to ameliorate the injury. Thus, we investigated these mechanisms and the radioprotection of Mn (Ⅲ) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE) on TBI induced BM injury in this study.
Methods 4-8 weeks old 57BL/6-Ly-5.2 were classified into three groups: control group, radiation group and radiation plus drug group, radiation was 6.5 Gy total body irradiation (TBI) and drugs includes diphenylene iodonium and MnTE. Bone marrow mononulcer cells(BM-MNCs) isolated form these mice were used to perform competitive repopulation assay in vivo and CFU-GEMM individual colonies were developed by culturing BM-MNCs in MethoCult GF M3434 methylcellulose medium after 11 days were used to performcytogenetic analyses. and hematopoietic progenitor cells (HPCs) sorted out by flow cytometry were used to examine the following tests:the level of ROS by 2', 7'-dichlorofluorescin diacetate (DCFDA), the DNA damage and DNA double strand breaks by using 8-hydroxydeoxyguanine and H2AX staining, respectively; Colony forming function were analyzed by in vitro colony-forming cell assay, cobblestone area-forming cell assay and single cobblestone area-forming cell assay. Apoptosis was detected by Annexin V/7-AAD; The expression of NOXs, p16 and p53, were assayed by RT-PCR or immunostaining.
Results The results showed that exposure of mice to a sublethal. dose of total body irradiation (TBI) induced a persistent increase in reactive oxygen species (ROS) production in HSCs selectively. The induction of chronic oxidative stress in HSCs was associated with sustained increases in oxidative DNA damage, DNA double-strand breaks (DSBs), inhibition of HSC clonogenic function, and induction of HSC senescence but not apoptosis. The induction of chronic oxidative stress in HSCs by TBI is probably attributable to the up-regulation of NADPH oxidase 4 (NOX4), because irradiated HSCs expressed an increased level of NOX4, and inhibition of NOX activity with diphenylene iodonium but not apocynin significantly reduced TBI-induced increases in ROS production, oxidative DNA damage, and DNA DSBs in HSCs and dramatically improved HSC clonogenic function.
Then, we examined if Mn (Ⅲ) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE), a superoxide dismutase mimetic and potent antioxidant, can mitigate TBI-induced long-term BM injury in a mouse model. Our results showed that post-TBI treatment with MnTE significantly inhibited the increases in ROS production and DNA damage in HSCs and reduction in HSC frequency and clonogenic function induced by TBI. In fact, the clonogenic function of HSCs from irradiated mice after MnTE treatment was comparable to that of HSCs from normal controls on a per HSC basis, suggesting that MnTE treatment inhibited the induction of HSC senescence by TBI. In addition, MnTE treatment can mitigate TBI induced defects in the abilities of HSCs to maitain quiescence, proliferate and survive in vitro. This suggestion is supported by the findings that MnTE treatment also reduced the expression of p16Ink4a (p16) mRNA in HSCs induced by TBI and improved the long-term and multi-lineage engraftment of irradiated HSCs after transplantation.
Conclusions TBI selectively induces a persistent increase in reactive oxygen species (ROS) production in HSCs only. The induction of chronic oxidative stress in HSCs by TBI is probably attributable to the up-regulation of NADPH oxidase 4 (NOX4)。Chronic oxidative stress in HSCs leads to the loss of HSCs self-renewal and the induction of HSC senescence via up-regulation of p16, which leads to long-term bone marrow suppression. TBI-induced long-term BM suppression can be mitigated by antioxidant treanment. We found MnTE can mitigate IR-induced HSC senescence inhibiting the ROS-p16 pathway and be used to a therapeutic agent to mitigate TBI-induced long-term BM suppression by TBI.
引文
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