人骨髓间充质干细胞对白血病细胞增殖和化疗敏感性的影响及其机制的研究
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摘要
已有研究表明HM除调控正常造血功能外,对白血病细胞的生物学行为和化疗敏感性也有重要影响。本课题以HM的主要成分之一骨髓MSCs为主要研究对象,模拟HM对白血病细胞增殖、化疗敏感性的影响进行研究,并探索MSCs诱导白血病耐药的发生机制,以进一步明确HM与白血病耐药的关系。
本研究把白血病细胞株与MSCs进行黏附共培养,发现如下结果:①U937、K562细胞增殖受抑,细胞周期进程受阻,主要阻滞于G0/G1期,并使U937细胞的自然凋亡率下降;②降低白血病细胞对DNR、Ara-C的敏感性;③采用cDNA芯片技术对细胞凋亡和细胞周期相关基因检测结果显示,黏附共培养后U937细胞出现了表达差异较大的基因,以高表达为主,包括凋亡抑制、促进基因,细胞周期正、负调控基因。其中凋亡抑制基因Bcl-XL上调最明显,可能是耐药逆转剂研究的潜在靶点;④黏附培养并未诱导U937细胞表达MDR1。
本研究于国内外首次提出了MSCs调控白血病细胞增殖及诱导耐药,并采用高通量cDNA芯片技术,突破了以往有关HM调控白血病细胞的研究手段,证明MSCs调控白血病增殖和参与耐药是一个复杂的过程,在U937细胞中凋亡抑制基因Bcl-XL可能起主要作用,而经典多药耐药机制MDR1基因并未直接参与。本研究在基因水平深入探索了HM诱导白血病耐药机制,为寻找特异的耐药逆转剂奠定了理论基础。
Leukemia is one of the most important diseases threatening human life.The most effective treatment of the disease is chemotherapy. But recurrencewill take place finally in most patients after they experience initially effectivechemotherapy, for which the most important reason is chemotherapeutic drugresistance produced by the leukemia cell. Previously, in the study on themechanism of leukemia drug resistance, people often focused their attention onthe change in a single tumor cell, but ignored the role of the hematopoieticmicroenvironment (HM). The tumor microenvironment is one of the keyfactors affecting the outcome of tumor cells. More and more studies found thatin addition to having an important regulating function in normal hematopoiesis,HM has an important effect on the biological behavior of the leukemia cell.HM can protect the leukemia cell, promoting the production of leukemia cellresistance and induce apoptosis resistance, but the mechanisms have not beenidentified completely yet. In this work, the effect of bone marrow derivedmesenchymal stem cells(MSCs), one of the main components of HM, on theproliferation and chemotherapeutic sensitivity of the leukemia cell strain wasobserved and studied and their mechanisms were investigated by simulatingHM through the adhesion coculture of MSCs and the leukemia cell line,and getthe result as follows:
1、MSCs were isolated from the marrow of healthy adults in primary andpassage cultures and the cell surface immune phenotypes were identified byflow cytometry. The results showed that MSCs expressed CD44 while CD45
was negative. Abundant MSCs which express CD44,non-express CD45,can bepurified and amplified from the healthy adults' bone marrows. Theestablishment of this method has settled experimental foundation for advancedresearch on the regulation and control mechanism of HM on malignant tumorsof blood system, and has offered technical method for MSCs' tissueengineering and clinical amplication.2、In the adhesion coculture of MSCs and the leukemia cell strain, wefound that the adhesion rate of K562 cell at 2 hours was 52.2% and U937 was37.5%. And it was found from the leukemia cell growth curve that proliferationof U937 and K562 cells could be inhibited at a certain time during adhesioncoculture. The results of measuring cell cycle after 48-hour coculture by flowcytometry showed that compared with the suspension culture group, theleukemia cell cycle progression was blocked in the adhesion group, U937 cellhad an increase in the percentage of cells in G0/G1 phase (P<0.05) G2/M phase,decrease in the percentage of cells in G2/M phase (P<0.01), no significantchange in S phase and decrease in S+G2/M phase (P<0.05). K562 cell differedfrom U937 cell in the cell cycle change, showing a percentage increase inG0/G1 phase (P<0.05), a percentage increase in G2/M phase (P<0.01) and apercentage decrease in S phase (P<0.05). The above results demonstrated thatafter adhesion culture the proliferative rate of the leukemia cell decreased, thecell cycle progression was blocked, mainly in G0/G1 phase, but the cell cyclechange in various phases differed between leukemia cell lines. At the sametime, it was also founded in the experiment that apoptosis existed in a certainpercentage of U937 under the natural condition, and the natural apoptosis ratealso significantly decreased after adhesion culture (P<0.05), showing thatMSCs induced U937 cell resistance to natural apoptosis. The cell in G0/G1phase was insensitive to chemotherapeutic drugs and at the same time thenatural apoptosis rate decreased. These changes may be one of the importantreasons for MSCs to induce the drug resistance in the leukemia cell.3、In the experiment, DNR and Ara-C, the commonly used drugs for thetreatment of leukemia, acted on U937 cell in the suspension culture group andadhesion culture group at different concentrations and the survival rates wereobserved at 24h. When the concentrations of DNR were respectively 0.5μg/mland 1.0μg/ml, the survival rates in the suspension culture group and adhesionculture group were 48.3%/71.5% and 28.3%/48.1% respectively, with all thep-values less than 0.05. When the concentrations of Ara-C were respectively2.0μg/ml and 4.0μg/ml, the survival rates in the suspension culture group andadhesion culture group were 52.0%/71.7% and 38.9%/57.1% respectively, withall the p-values also less than 0.05. It showed that the adhesion coculture of
U937 and MSCs decreased the sensitivity of DNR and Ara-C to U937 andinduced the production of the drug resistance in U937. When DNR at differentconcentrations acted on K562 cell in the suspension culture group and theadhesion culture group and the concentrations of DNR were respectively 0.8μg/ml and 1.6μg/ml, the cell survival rates at 24h were 65.3%/83% and40.7%/60.5% respectively, showing that MSCs could also induce theproduction of the drug resistance in K562 cell to DNR. Sepharoseelectrophoresis and flow cytometry (Annexin V/PI double-staining method)were used to detect the change in cell apoptosis after DNR acted on U937 andK562 cells. It showed that adhesion culture induced the resistance of theleukemia cell to the chemotherapeutic drug induced apoptosis. The aboveresults showed that MSCs adhesion coculture could induce the production ofthe drug resistance in the leukemia cell and its mechanism is closely related tothe above-mentioned changes in the cell cycle and natural apoptosis rate of theleukemia cell after adhesion culture. The results above have proved thatadhesion and co-culturing with MSCs could induce drug resistance of leukemiacells,whose mechanism has something to do with the inhibition of leukemiacell proliferation induced by MSCs, the change of cell cycle, the decrease ofapoptosis ratio. These have also furtherly proved that the resistance mediatedby adhesion of MSCs and leukemia cells probably plays an important part inthe HM induced drug resistance.Because of protection of MSCs on leukemiacells ,this is probably important in the bone marrow minimal residualdiseases,and promotes the secondary drug resistance of leukemia cells,and alsocan be the root of treatment failure and recrudescence of leukemia。4、The cell apoptosis and cell cycle related genes of U937 cell werestudied by using the cDNA chip technology. The hybrid results of the gene chip(containing 486 genes) showed that compared with those in the adhesionculture group, most genes after adhesion coculture had close abundance ofexpression in the two cells, but after adhesion culture U937 cell also hadlargely differentially expressed genes, including 37 highly expressed genes and2 low expressed genes. Based on bioinformatics analysis, the upregulatedgenes among the above differentially expressed genes are mainly divided intothe following categories: ① 10 kinds of apoptosis inhibiting genes, whichwere Bcl-XL, CDC25C, IGFBP2, PTGS2, LTB, MAPK8, MCL1, DNASE1L1,PSEN2 and BCL-3, in which Bcl-XL was upregulated most significantly, 7times that in the suspension culture group;② apoptosis promoting genes,which were DAPK2, E2F1, NGFRAP1, TNFRSF1A, PPP1R15A, NGFRAP1,LTA, FASTK and DNASE1;③ positively regulating cell cycle genes, which
were CDK7 and CDC27;④ negatively regulating cell cycle genes, whichwere CCNG2, CDKN2D, NUMA1, DDIT3, MNAT1 and QSCN6;⑤ genesthat participated in signal transduction or whose functions have not beenidentified completely in cell cycle and apoptosis, which were SREBF1,IGFBP4, KIAA0720, MAPK3, SDC1, HLA-C, CBLB, CBL, MAP3K1 andJUN. There were only two kinds of downregulated genes, which were TOSOand MGST1, the former being the apoptosis promoting gene. The changes inthose genes mainly participated in the change in cell kinetics of U937 cell andthe mechanism of the production of drug resistance after MSCs adhesioncoculture, in which Bcl-XL may play the most important role, and is the latenttarget of inversio dose to drug resistance. Among the initiation factors inducing geneexpression changes, in addition to the MSCs-U937cell-cell adhesion as themain initiation mechanism, the autocrine or paracrine effect of MSCs and theleukemia cell may also participate in it. Among the above genes, some genesregulated both cell apoptosis and cell cycle. For example, CDC25C andCDKN2D were the apoptosis inhibiting gene and negatively regulating genefor cell cycle, showing that there existed a cross regulating path between cellapoptosis and cell cycle, and their functions had effect on each other, so closelyrelated that they cannot be divided.5、In this work, MDR1 gene expression in the mechanism of the classicalmultidrug resistance (MDR) of U937 cell after adhesion culture was detectedby using the RT-PCR technology. It showed that adhesion culture did notinduce MDR1 expression in U937 cell, indicating that MDR1 did notparticipate in the adhesion mediated drug resistance, possibly becauseshort-term adhesion coculture cannot induce MDR1 expression or the latter isnot directly related to the cell adhesion mediated drug resistance.In this work, we first put forward in the country from the view of MSCs thatHM regulate the proliferation of the leukemia cell and induce drug resistanceand made a breakthrough in the research method related to HM regulation ofthe leukemia cell by using the high throughput cDNA chip technology, makingthe study results more comprehensive and in-depth, laying a theoreticalfoundation for further exploration and study of the mechanism of HM inducingleukemia drug resistance at gene levels, and developing a new ideology forsearch effective inversio dose of drug resistance.
本研究把白血病细胞株与MSCs进行黏附共培养,发现如下结果:①U937、K562细胞增殖受抑,细胞周期进程受阻,主要阻滞于G0/G1期,并使U937细胞的自然凋亡率下降;②降低白血病细胞对DNR、Ara-C的敏感性;③采用cDNA芯片技术对细胞凋亡和细胞周期相关基因检测结果显示,黏附共培养后U937细胞出现了表达差异较大的基因,以高表达为主,包括凋亡抑制、促进基因,细胞周期正、负调控基因。其中凋亡抑制基因Bcl-XL上调最明显,可能是耐药逆转剂研究的潜在靶点;④黏附培养并未诱导U937细胞表达MDR1。
本研究于国内外首次提出了MSCs调控白血病细胞增殖及诱导耐药,并采用高通量cDNA芯片技术,突破了以往有关HM调控白血病细胞的研究手段,证明MSCs调控白血病增殖和参与耐药是一个复杂的过程,在U937细胞中凋亡抑制基因Bcl-XL可能起主要作用,而经典多药耐药机制MDR1基因并未直接参与。本研究在基因水平深入探索了HM诱导白血病耐药机制,为寻找特异的耐药逆转剂奠定了理论基础。
Leukemia is one of the most important diseases threatening human life.The most effective treatment of the disease is chemotherapy. But recurrencewill take place finally in most patients after they experience initially effectivechemotherapy, for which the most important reason is chemotherapeutic drugresistance produced by the leukemia cell. Previously, in the study on themechanism of leukemia drug resistance, people often focused their attention onthe change in a single tumor cell, but ignored the role of the hematopoieticmicroenvironment (HM). The tumor microenvironment is one of the keyfactors affecting the outcome of tumor cells. More and more studies found thatin addition to having an important regulating function in normal hematopoiesis,HM has an important effect on the biological behavior of the leukemia cell.HM can protect the leukemia cell, promoting the production of leukemia cellresistance and induce apoptosis resistance, but the mechanisms have not beenidentified completely yet. In this work, the effect of bone marrow derivedmesenchymal stem cells(MSCs), one of the main components of HM, on theproliferation and chemotherapeutic sensitivity of the leukemia cell strain wasobserved and studied and their mechanisms were investigated by simulatingHM through the adhesion coculture of MSCs and the leukemia cell line,and getthe result as follows:
1、MSCs were isolated from the marrow of healthy adults in primary andpassage cultures and the cell surface immune phenotypes were identified byflow cytometry. The results showed that MSCs expressed CD44 while CD45
was negative. Abundant MSCs which express CD44,non-express CD45,can bepurified and amplified from the healthy adults' bone marrows. Theestablishment of this method has settled experimental foundation for advancedresearch on the regulation and control mechanism of HM on malignant tumorsof blood system, and has offered technical method for MSCs' tissueengineering and clinical amplication.2、In the adhesion coculture of MSCs and the leukemia cell strain, wefound that the adhesion rate of K562 cell at 2 hours was 52.2% and U937 was37.5%. And it was found from the leukemia cell growth curve that proliferationof U937 and K562 cells could be inhibited at a certain time during adhesioncoculture. The results of measuring cell cycle after 48-hour coculture by flowcytometry showed that compared with the suspension culture group, theleukemia cell cycle progression was blocked in the adhesion group, U937 cellhad an increase in the percentage of cells in G0/G1 phase (P<0.05) G2/M phase,decrease in the percentage of cells in G2/M phase (P<0.01), no significantchange in S phase and decrease in S+G2/M phase (P<0.05). K562 cell differedfrom U937 cell in the cell cycle change, showing a percentage increase inG0/G1 phase (P<0.05), a percentage increase in G2/M phase (P<0.01) and apercentage decrease in S phase (P<0.05). The above results demonstrated thatafter adhesion culture the proliferative rate of the leukemia cell decreased, thecell cycle progression was blocked, mainly in G0/G1 phase, but the cell cyclechange in various phases differed between leukemia cell lines. At the sametime, it was also founded in the experiment that apoptosis existed in a certainpercentage of U937 under the natural condition, and the natural apoptosis ratealso significantly decreased after adhesion culture (P<0.05), showing thatMSCs induced U937 cell resistance to natural apoptosis. The cell in G0/G1phase was insensitive to chemotherapeutic drugs and at the same time thenatural apoptosis rate decreased. These changes may be one of the importantreasons for MSCs to induce the drug resistance in the leukemia cell.3、In the experiment, DNR and Ara-C, the commonly used drugs for thetreatment of leukemia, acted on U937 cell in the suspension culture group andadhesion culture group at different concentrations and the survival rates wereobserved at 24h. When the concentrations of DNR were respectively 0.5μg/mland 1.0μg/ml, the survival rates in the suspension culture group and adhesionculture group were 48.3%/71.5% and 28.3%/48.1% respectively, with all thep-values less than 0.05. When the concentrations of Ara-C were respectively2.0μg/ml and 4.0μg/ml, the survival rates in the suspension culture group andadhesion culture group were 52.0%/71.7% and 38.9%/57.1% respectively, withall the p-values also less than 0.05. It showed that the adhesion coculture of
U937 and MSCs decreased the sensitivity of DNR and Ara-C to U937 andinduced the production of the drug resistance in U937. When DNR at differentconcentrations acted on K562 cell in the suspension culture group and theadhesion culture group and the concentrations of DNR were respectively 0.8μg/ml and 1.6μg/ml, the cell survival rates at 24h were 65.3%/83% and40.7%/60.5% respectively, showing that MSCs could also induce theproduction of the drug resistance in K562 cell to DNR. Sepharoseelectrophoresis and flow cytometry (Annexin V/PI double-staining method)were used to detect the change in cell apoptosis after DNR acted on U937 andK562 cells. It showed that adhesion culture induced the resistance of theleukemia cell to the chemotherapeutic drug induced apoptosis. The aboveresults showed that MSCs adhesion coculture could induce the production ofthe drug resistance in the leukemia cell and its mechanism is closely related tothe above-mentioned changes in the cell cycle and natural apoptosis rate of theleukemia cell after adhesion culture. The results above have proved thatadhesion and co-culturing with MSCs could induce drug resistance of leukemiacells,whose mechanism has something to do with the inhibition of leukemiacell proliferation induced by MSCs, the change of cell cycle, the decrease ofapoptosis ratio. These have also furtherly proved that the resistance mediatedby adhesion of MSCs and leukemia cells probably plays an important part inthe HM induced drug resistance.Because of protection of MSCs on leukemiacells ,this is probably important in the bone marrow minimal residualdiseases,and promotes the secondary drug resistance of leukemia cells,and alsocan be the root of treatment failure and recrudescence of leukemia。4、The cell apoptosis and cell cycle related genes of U937 cell werestudied by using the cDNA chip technology. The hybrid results of the gene chip(containing 486 genes) showed that compared with those in the adhesionculture group, most genes after adhesion coculture had close abundance ofexpression in the two cells, but after adhesion culture U937 cell also hadlargely differentially expressed genes, including 37 highly expressed genes and2 low expressed genes. Based on bioinformatics analysis, the upregulatedgenes among the above differentially expressed genes are mainly divided intothe following categories: ① 10 kinds of apoptosis inhibiting genes, whichwere Bcl-XL, CDC25C, IGFBP2, PTGS2, LTB, MAPK8, MCL1, DNASE1L1,PSEN2 and BCL-3, in which Bcl-XL was upregulated most significantly, 7times that in the suspension culture group;② apoptosis promoting genes,which were DAPK2, E2F1, NGFRAP1, TNFRSF1A, PPP1R15A, NGFRAP1,LTA, FASTK and DNASE1;③ positively regulating cell cycle genes, which
were CDK7 and CDC27;④ negatively regulating cell cycle genes, whichwere CCNG2, CDKN2D, NUMA1, DDIT3, MNAT1 and QSCN6;⑤ genesthat participated in signal transduction or whose functions have not beenidentified completely in cell cycle and apoptosis, which were SREBF1,IGFBP4, KIAA0720, MAPK3, SDC1, HLA-C, CBLB, CBL, MAP3K1 andJUN. There were only two kinds of downregulated genes, which were TOSOand MGST1, the former being the apoptosis promoting gene. The changes inthose genes mainly participated in the change in cell kinetics of U937 cell andthe mechanism of the production of drug resistance after MSCs adhesioncoculture, in which Bcl-XL may play the most important role, and is the latenttarget of inversio dose to drug resistance. Among the initiation factors inducing geneexpression changes, in addition to the MSCs-U937cell-cell adhesion as themain initiation mechanism, the autocrine or paracrine effect of MSCs and theleukemia cell may also participate in it. Among the above genes, some genesregulated both cell apoptosis and cell cycle. For example, CDC25C andCDKN2D were the apoptosis inhibiting gene and negatively regulating genefor cell cycle, showing that there existed a cross regulating path between cellapoptosis and cell cycle, and their functions had effect on each other, so closelyrelated that they cannot be divided.5、In this work, MDR1 gene expression in the mechanism of the classicalmultidrug resistance (MDR) of U937 cell after adhesion culture was detectedby using the RT-PCR technology. It showed that adhesion culture did notinduce MDR1 expression in U937 cell, indicating that MDR1 did notparticipate in the adhesion mediated drug resistance, possibly becauseshort-term adhesion coculture cannot induce MDR1 expression or the latter isnot directly related to the cell adhesion mediated drug resistance.In this work, we first put forward in the country from the view of MSCs thatHM regulate the proliferation of the leukemia cell and induce drug resistanceand made a breakthrough in the research method related to HM regulation ofthe leukemia cell by using the high throughput cDNA chip technology, makingthe study results more comprehensive and in-depth, laying a theoreticalfoundation for further exploration and study of the mechanism of HM inducingleukemia drug resistance at gene levels, and developing a new ideology forsearch effective inversio dose of drug resistance.
引文
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