氧化应激诱导间充质干细胞凋亡及磷脂类分子调节血管内皮生长因子分泌研究
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摘要
细胞移植治疗缺血性心肌病已取得较大进展,但由于多种因素的制约限制了其治疗效果。移植骨髓间充质干细胞(MSCs)的低存活率是限制其治疗效果的重要因素之一,梗死心肌微环境中除缺血缺氧外,可能还存在多种因素会诱导MSCs凋亡,其中梗死心脏中由于活性氧(ROS)增高而导致的持续氧化应激可能是诱导MSCs凋亡的另一个重要因素,研究这些因素及作用机制有助于寻找抗凋亡的有效途径。
十细胞的旁分泌是其治疗缺血性心肌病的重要机制之一。MSCs能够分泌多种细胞因子,其中血管内皮生长因子(VEGF)具有促血管生成和心肌保护等多种功能,增加MSCs中VEGF分泌能够显著提高细胞移植的治疗效果。溶血磷脂酸(Lysophospholipids acid,LPA)作为一种内源性磷脂类分子在许多生理和病理过程中都发挥着重要作用。我们前期研究表明LPA预处理的MSCs增加了心肌梗死区毛细血管密度,促进MSCs分泌VEGF,但其具体作用机制尚不明确。作为一种新型磷脂,二酰基甘油焦磷酸(DGPP)常用作LPA1／3受体拮抗剂,目前关于DGPP对MSCs生长调节方面的研究还是空白,我们的前期实验意外发现DGPP能比LPA更为有效地促进VEGF分泌,但其具体的机制还不明确。而这些磷脂分子对MSCs的具体作用效果和机制的阐明将可能为MSCs移植增效提供新的候选药物。
针对上述背景,本论文分析了梗死心肌中增高的活性氧化物对移植MSCs存活的影响以及其作用机制,分别探讨了LPA和DGPP对MSCs旁分泌的作用及其调控机制,研究了LPA对MSCs的增殖调控及其相关信号通路。本研究主要包括以下四部分内容：
1.过氧化氢对MSCs存活的影响及其调节信号通路
为研究活性氧化物对移植十细胞存活的影响,本研究建立了体外氧化应激模型,并对H2O2诱导MSCs凋亡的机制进行了研究。结果表明H2O2浓度等于或高于0.9 mM,作用时间超过12小时,细胞发生明显凋亡。H2O2导致细胞线粒体膜电位降低,细胞色素c从线粒体释放入胞浆,bax从胞浆向线粒体转移。H2O2处理还导致caspase-3和caspase-12的活化,二者的抑制剂不同程度抑制了MSCs的凋亡,而caspase-12抑制剂没有抑制细胞色素c的释放和caspase-3的切割。H2O2增加JNK和p38的磷酸化水平,其中p38抑制剂也阻止了MSCs的早期凋亡,并抑制了细胞色素c的释放及bax的转移,而JNK抑制剂减少了细胞的晚期凋亡。因此,H2O2以浓度和时间依赖性诱导MSCs凋亡,凋亡同时通过线粒体途经和内质网应激途径。H2O2也活化了JNK／p38途经,其中p38通过调节线粒体途经调控MSCs的早期凋亡,而JNK调节细胞的晚期凋亡,并独立于线粒体途径。
2.LPA促进MSCs分泌VEGF及其调节机制
为研究LPA对MSCs分泌VEGFI的调控及其机制,应用LPA处理MSCs,分别检测相关蛋白表达与定位、ATP酶及离子通道的变化情况,结果表明LPA以浓度和时间依赖性促进MSCs分泌VEGF,而对细胞内VEGF蛋白和VEGF mRNA的表达没有影响。LPA抑制了Na+，K+-ATPase活性,上调了150KD氧调控蛋白(ORP150)的表达,并减少了VEGF蛋白在内质网内的驻留。钾离子通道开放剂diazoxide抑制了LPA的诱导ORP150表达增高,同时也抑制了LPA促进的VEGF分泌,增加了VEGF的内质网驻留。因此,上述结果证明LPA在翻译后水平调控VEGF分泌,其调节途径如下：LPA降低了MSCs中Na+, K+-ATPase活性,使ATP/ADP下降,线粒体ATP-敏感型钾离子通道(mitoKATP channel)关闭,进而导致ORP150表达增高,高表达的ORP150促进VEGF从内质网向细胞外运输。
3. DGPP促进MSCs分泌VEGF及其调节机制
为检测(?)3GPP对MSCs分泌VEGF的调节,应用DGPP处理MSCs后,检测VEGF的分泌,并对相关机制进行研究分析,结果显示DGPP显著促进MSCs分泌VEGF,其促VEGF的分泌效果强于LPA。低血清条件下DGPP没有显著改变存活细胞数量,高浓度DGPP抑制了MSCs增殖。DGPP没有影响细胞内VEGF蛋白和VEGF mRNA的表达。钾离子通道开放剂diazoxide没有抑制DGPP导致的VEGF分泌增高。DGPP上调了GRP94 mRNA的表达。Sulfinator分析预测VEGF蛋白存在酪氨酸硫酸化修饰位点。因此,DGPP能够比LPA更为有效促进MSCs中VEGF的分泌,并与细胞数量变化无关。与LPA不同,DGPP调节VEGF可能没有涉及mitoKATP通道的调节。GRP94、VEGFN-糖基化、酪氨酸硫酸化在DGPP促VEGF分泌过程中的作用有待进一步研究。
4.LPA对MSCs增殖的调节作用及其作用机制
为研究LPA对MSCs增殖的调节作用,用LPA处理MSCs,检测细胞增殖情况,并对其相关信号通路进行分析,结果表明LPA促进MSCs增殖,并呈浓度依赖性。LPA1／3受体特异性抑制剂,ERK信号通路抑制剂都不同程度降低了LPA的促增殖作用。LPA使细胞内c-myc蛋白表达上调,而加入上述抑制剂则下调了c-myc蛋白的表达。因此,LPA能够促进间充质干细胞增殖,这种作用是通过结合LPA1／3受体,活化ERK信号通路,从而上调c-myc蛋白表达实现的。
综上所述,本研究确定了氧化应激对MSCs促凋亡作用及其机制,分析了磷脂分子对MSCs旁分泌和增殖等生物学功能的调节,为提高移植MSCs存活率,促进磷脂分子在MSCs移植治疗心血管疾病方面的应用,改善MSCs移植治疗效果提供了依据。
Although mesenchymal stem cells (MSCs) have great promise in the recovery of damaged myocardium after myocardial infarction, several factors limit therapeutic effect of MSCs transplantation. One of them is low viability of MSCs transplanted into infarcted heart. MSCs apoptosis transplanted into infarcted heart might result from more than one factor besides hypoxia and serum deprivation (Hypoxia/SD). The increase of exogenous reactive oxygen species (ROS) in infracted heart might be another important factor to induce apoptosis of MSCs. Identification of such factors contributes to improvement of the cell viability.
Transplanted MSCs without any modification might be another factor to limit the therapeutic effect. The therapeutic effects of MSCs results partly from release of paracrine factors, among which vascular endothelial growth factor (VEGF) is one of crucial mediators by regulating angiogenesis and protecting myocardium against ischemic injury. Increase of VEGF secreted from MSCs improves the therapeutic effects of MSCs. Lysophosphatidic acid (LPA), as an endogenous lipid messenger, is involved in diverse physiological and pathological processes. Our previous studies indicated that LPA enhanced capillary density after transplantation of MSCs in ischemic myocardium in vivo, and increase VEGF production under hypoxia/SD in vitro, but its mechanism is not known. DGPP is a novel phospholipid, and ofen used as one of LPA1/3 receptor antagonists, but the effect of DGPP on MSCs is not clear. In our previous study, we superisely found that DGPP promote VEGF secretion than LPA in MSCs, but its accurate effect and mechanism are not well understood.
According to the background mentioned above, we investigated the role of reactive oxidative species (ROS) in transplanted MSCs, the effect of LPA and DGPP in paracrine of MSCs and their mechanism, and the regulation of LPA on MSCs proliferation. The study includes four sections.
1. The role of hydrogen peroxides in the viability of MSCs and its mechanism
To identify the role of hydrogen peroxide, a model of oxidative stress was established to mimic the environment in vivo, and the mechanism of H2O2 on MSC apoptosis was investigated. Obvious apoptosis of MSCs resulted from a certain concentration of H2O2 (≧0.9 mM) and treatment time (≧12 h). H2O2 treatment resulted into loss of mitochondrialΔΨm, release of cytochrome C released from mitochondria to cytosol and bax translocation from the cytosol to the mitochondria in MSCs.Caspase-3 and caspase-12 were activated after H2O2 treatment, and their inhibitors prevented apoptosis of MSCs.However, the caspase-12 inhibitor had no effect on cytochrome C release and cleavage of caspase-3 caused by H2O2. Transient phosphorylation of JNK/p38 increased after H2O2 treatment. P38 inhibitor prevented the early apoptosis of MSCs, accompanied by the decrease of cytochrome C release and bax translocation, while JNK inhibitor inhibited the late apoptosis. In conclusion, H2O2 induced apoptosis of MSCs in a dose and time dependent way. Apoptosis of the cells involved both mitochondrial death pathway and ER stress which were parallel. H2O2 activated the JNK/p-38 pathway, among which p-38 contributed to the early apoptosis of MSCs by regulating mitochondrial pathway, and JNK was involved in the late apoptosis independent of mitochondrial pathway. 2.The effect of LPA on VEGF secretion in MSCs and its mechanism
To identify the effect of LPA on VEGF secretion, MSCs were treated with LPA, and the relative signaling pathways were detected. The results indicated that LPA promoted VEGF secretion in a dose and time manner in MSCs, but had no effect on expression of VEGF protein and VEGF mRNA in the cells. LPA inhibited Na+, K+-ATPase activity, upgraded the expression of ORP150, and decreased the resident of VEGF in endoplasmic reticulum(ER).Diazoxide, the mitochondrial KATP channel opener, inhibited both the expression of ORP150, the secretion of VEGF, and the resident of VEGF in ER induced by LPA. In conclusion, LPA promoted VEGF secretion in MSCs through the post-translation level. LPA stimulated VEGF secretion by upgrading ORP150 expression, and the increase of ORP150 expression resulted from inhibition of Na+, K+-ATPase activity and mitoKATP channels induced by LPA.
3.The role of DGPP in VEGF secretion in MSCs and its mechanism
To investigate the role of DGPP in VEGF secrection, MSCs were treated with DGPP, VEGF secretion was detected, and the relative mechanism was investigated. The results indicated that DGPP promoted more VEGF production secreted to extracellular supernatant than LPA, and it did not change the amount of the apoptosis cells at the same condition, but high concentration of DGPP inhibited MSCs proliferation. DGPP had no effect on the expression of VEGF protein and VEGF mRNA in the cells.The mitochondrial KATP channel opener diazoxide failed to inhibit VEGF secretion induced by VEGF.DGPP increased the expression of GRP94 mRNA. The Sulfinator software predicted the tyrosine sulfation sites of VEGF.In conclusion, DGPP had better effect in VEGF secretion than LPA in MSCs, and the increase VEGF production did not result from the amount of the cells.The mitochondrial KATP channel was not involved in VEGF secretion induced by DGPP, thus, it was different between DGPP and LPA in the regulation of VEGF secretion. The roles of GRP94, N-glycosylation and tyrosine sulfation of VEGF in VEGF secretion were worth to further explore.
4.The effect of LPA on MSCs proliferation and its mechanism
MSCs were treated with LPA, and proliferation of the cells was detected and its mechanism was investigated. The results demonstrated that LPA promoted MSCs proliferation in a dose-dependent manner. The inhibitors for LPA1/3 receptor and ERK prevented the cell proliferation. LPA also increased the expression of c-myc,which was inhibited by the inhibitors of LPA1/3 receptor and ERK. In conclusion, LPA promoted proliferation of MSCs by binding LPA1/3 receptor, activating ERK pathway and increasing the expression of c-myc.
In sum, the study identified the effect of ROS in MSCs viability and its signaling pathway, analyzed the role of the phospholipids in MSCs paracrine and proliferation and their mechanism. The data would improve the viability of transplanted MSCs, facilitate application of the phospholipids in cell transplantation, and enhance the therapeutic effects of transplanted MSCs.
十细胞的旁分泌是其治疗缺血性心肌病的重要机制之一。MSCs能够分泌多种细胞因子,其中血管内皮生长因子(VEGF)具有促血管生成和心肌保护等多种功能,增加MSCs中VEGF分泌能够显著提高细胞移植的治疗效果。溶血磷脂酸(Lysophospholipids acid,LPA)作为一种内源性磷脂类分子在许多生理和病理过程中都发挥着重要作用。我们前期研究表明LPA预处理的MSCs增加了心肌梗死区毛细血管密度,促进MSCs分泌VEGF,但其具体作用机制尚不明确。作为一种新型磷脂,二酰基甘油焦磷酸(DGPP)常用作LPA1／3受体拮抗剂,目前关于DGPP对MSCs生长调节方面的研究还是空白,我们的前期实验意外发现DGPP能比LPA更为有效地促进VEGF分泌,但其具体的机制还不明确。而这些磷脂分子对MSCs的具体作用效果和机制的阐明将可能为MSCs移植增效提供新的候选药物。
针对上述背景,本论文分析了梗死心肌中增高的活性氧化物对移植MSCs存活的影响以及其作用机制,分别探讨了LPA和DGPP对MSCs旁分泌的作用及其调控机制,研究了LPA对MSCs的增殖调控及其相关信号通路。本研究主要包括以下四部分内容：
1.过氧化氢对MSCs存活的影响及其调节信号通路
为研究活性氧化物对移植十细胞存活的影响,本研究建立了体外氧化应激模型,并对H2O2诱导MSCs凋亡的机制进行了研究。结果表明H2O2浓度等于或高于0.9 mM,作用时间超过12小时,细胞发生明显凋亡。H2O2导致细胞线粒体膜电位降低,细胞色素c从线粒体释放入胞浆,bax从胞浆向线粒体转移。H2O2处理还导致caspase-3和caspase-12的活化,二者的抑制剂不同程度抑制了MSCs的凋亡,而caspase-12抑制剂没有抑制细胞色素c的释放和caspase-3的切割。H2O2增加JNK和p38的磷酸化水平,其中p38抑制剂也阻止了MSCs的早期凋亡,并抑制了细胞色素c的释放及bax的转移,而JNK抑制剂减少了细胞的晚期凋亡。因此,H2O2以浓度和时间依赖性诱导MSCs凋亡,凋亡同时通过线粒体途经和内质网应激途径。H2O2也活化了JNK／p38途经,其中p38通过调节线粒体途经调控MSCs的早期凋亡,而JNK调节细胞的晚期凋亡,并独立于线粒体途径。
2.LPA促进MSCs分泌VEGF及其调节机制
为研究LPA对MSCs分泌VEGFI的调控及其机制,应用LPA处理MSCs,分别检测相关蛋白表达与定位、ATP酶及离子通道的变化情况,结果表明LPA以浓度和时间依赖性促进MSCs分泌VEGF,而对细胞内VEGF蛋白和VEGF mRNA的表达没有影响。LPA抑制了Na+，K+-ATPase活性,上调了150KD氧调控蛋白(ORP150)的表达,并减少了VEGF蛋白在内质网内的驻留。钾离子通道开放剂diazoxide抑制了LPA的诱导ORP150表达增高,同时也抑制了LPA促进的VEGF分泌,增加了VEGF的内质网驻留。因此,上述结果证明LPA在翻译后水平调控VEGF分泌,其调节途径如下：LPA降低了MSCs中Na+, K+-ATPase活性,使ATP/ADP下降,线粒体ATP-敏感型钾离子通道(mitoKATP channel)关闭,进而导致ORP150表达增高,高表达的ORP150促进VEGF从内质网向细胞外运输。
3. DGPP促进MSCs分泌VEGF及其调节机制
为检测(?)3GPP对MSCs分泌VEGF的调节,应用DGPP处理MSCs后,检测VEGF的分泌,并对相关机制进行研究分析,结果显示DGPP显著促进MSCs分泌VEGF,其促VEGF的分泌效果强于LPA。低血清条件下DGPP没有显著改变存活细胞数量,高浓度DGPP抑制了MSCs增殖。DGPP没有影响细胞内VEGF蛋白和VEGF mRNA的表达。钾离子通道开放剂diazoxide没有抑制DGPP导致的VEGF分泌增高。DGPP上调了GRP94 mRNA的表达。Sulfinator分析预测VEGF蛋白存在酪氨酸硫酸化修饰位点。因此,DGPP能够比LPA更为有效促进MSCs中VEGF的分泌,并与细胞数量变化无关。与LPA不同,DGPP调节VEGF可能没有涉及mitoKATP通道的调节。GRP94、VEGFN-糖基化、酪氨酸硫酸化在DGPP促VEGF分泌过程中的作用有待进一步研究。
4.LPA对MSCs增殖的调节作用及其作用机制
为研究LPA对MSCs增殖的调节作用,用LPA处理MSCs,检测细胞增殖情况,并对其相关信号通路进行分析,结果表明LPA促进MSCs增殖,并呈浓度依赖性。LPA1／3受体特异性抑制剂,ERK信号通路抑制剂都不同程度降低了LPA的促增殖作用。LPA使细胞内c-myc蛋白表达上调,而加入上述抑制剂则下调了c-myc蛋白的表达。因此,LPA能够促进间充质干细胞增殖,这种作用是通过结合LPA1／3受体,活化ERK信号通路,从而上调c-myc蛋白表达实现的。
综上所述,本研究确定了氧化应激对MSCs促凋亡作用及其机制,分析了磷脂分子对MSCs旁分泌和增殖等生物学功能的调节,为提高移植MSCs存活率,促进磷脂分子在MSCs移植治疗心血管疾病方面的应用,改善MSCs移植治疗效果提供了依据。
Although mesenchymal stem cells (MSCs) have great promise in the recovery of damaged myocardium after myocardial infarction, several factors limit therapeutic effect of MSCs transplantation. One of them is low viability of MSCs transplanted into infarcted heart. MSCs apoptosis transplanted into infarcted heart might result from more than one factor besides hypoxia and serum deprivation (Hypoxia/SD). The increase of exogenous reactive oxygen species (ROS) in infracted heart might be another important factor to induce apoptosis of MSCs. Identification of such factors contributes to improvement of the cell viability.
Transplanted MSCs without any modification might be another factor to limit the therapeutic effect. The therapeutic effects of MSCs results partly from release of paracrine factors, among which vascular endothelial growth factor (VEGF) is one of crucial mediators by regulating angiogenesis and protecting myocardium against ischemic injury. Increase of VEGF secreted from MSCs improves the therapeutic effects of MSCs. Lysophosphatidic acid (LPA), as an endogenous lipid messenger, is involved in diverse physiological and pathological processes. Our previous studies indicated that LPA enhanced capillary density after transplantation of MSCs in ischemic myocardium in vivo, and increase VEGF production under hypoxia/SD in vitro, but its mechanism is not known. DGPP is a novel phospholipid, and ofen used as one of LPA1/3 receptor antagonists, but the effect of DGPP on MSCs is not clear. In our previous study, we superisely found that DGPP promote VEGF secretion than LPA in MSCs, but its accurate effect and mechanism are not well understood.
According to the background mentioned above, we investigated the role of reactive oxidative species (ROS) in transplanted MSCs, the effect of LPA and DGPP in paracrine of MSCs and their mechanism, and the regulation of LPA on MSCs proliferation. The study includes four sections.
1. The role of hydrogen peroxides in the viability of MSCs and its mechanism
To identify the role of hydrogen peroxide, a model of oxidative stress was established to mimic the environment in vivo, and the mechanism of H2O2 on MSC apoptosis was investigated. Obvious apoptosis of MSCs resulted from a certain concentration of H2O2 (≧0.9 mM) and treatment time (≧12 h). H2O2 treatment resulted into loss of mitochondrialΔΨm, release of cytochrome C released from mitochondria to cytosol and bax translocation from the cytosol to the mitochondria in MSCs.Caspase-3 and caspase-12 were activated after H2O2 treatment, and their inhibitors prevented apoptosis of MSCs.However, the caspase-12 inhibitor had no effect on cytochrome C release and cleavage of caspase-3 caused by H2O2. Transient phosphorylation of JNK/p38 increased after H2O2 treatment. P38 inhibitor prevented the early apoptosis of MSCs, accompanied by the decrease of cytochrome C release and bax translocation, while JNK inhibitor inhibited the late apoptosis. In conclusion, H2O2 induced apoptosis of MSCs in a dose and time dependent way. Apoptosis of the cells involved both mitochondrial death pathway and ER stress which were parallel. H2O2 activated the JNK/p-38 pathway, among which p-38 contributed to the early apoptosis of MSCs by regulating mitochondrial pathway, and JNK was involved in the late apoptosis independent of mitochondrial pathway. 2.The effect of LPA on VEGF secretion in MSCs and its mechanism
To identify the effect of LPA on VEGF secretion, MSCs were treated with LPA, and the relative signaling pathways were detected. The results indicated that LPA promoted VEGF secretion in a dose and time manner in MSCs, but had no effect on expression of VEGF protein and VEGF mRNA in the cells. LPA inhibited Na+, K+-ATPase activity, upgraded the expression of ORP150, and decreased the resident of VEGF in endoplasmic reticulum(ER).Diazoxide, the mitochondrial KATP channel opener, inhibited both the expression of ORP150, the secretion of VEGF, and the resident of VEGF in ER induced by LPA. In conclusion, LPA promoted VEGF secretion in MSCs through the post-translation level. LPA stimulated VEGF secretion by upgrading ORP150 expression, and the increase of ORP150 expression resulted from inhibition of Na+, K+-ATPase activity and mitoKATP channels induced by LPA.
3.The role of DGPP in VEGF secretion in MSCs and its mechanism
To investigate the role of DGPP in VEGF secrection, MSCs were treated with DGPP, VEGF secretion was detected, and the relative mechanism was investigated. The results indicated that DGPP promoted more VEGF production secreted to extracellular supernatant than LPA, and it did not change the amount of the apoptosis cells at the same condition, but high concentration of DGPP inhibited MSCs proliferation. DGPP had no effect on the expression of VEGF protein and VEGF mRNA in the cells.The mitochondrial KATP channel opener diazoxide failed to inhibit VEGF secretion induced by VEGF.DGPP increased the expression of GRP94 mRNA. The Sulfinator software predicted the tyrosine sulfation sites of VEGF.In conclusion, DGPP had better effect in VEGF secretion than LPA in MSCs, and the increase VEGF production did not result from the amount of the cells.The mitochondrial KATP channel was not involved in VEGF secretion induced by DGPP, thus, it was different between DGPP and LPA in the regulation of VEGF secretion. The roles of GRP94, N-glycosylation and tyrosine sulfation of VEGF in VEGF secretion were worth to further explore.
4.The effect of LPA on MSCs proliferation and its mechanism
MSCs were treated with LPA, and proliferation of the cells was detected and its mechanism was investigated. The results demonstrated that LPA promoted MSCs proliferation in a dose-dependent manner. The inhibitors for LPA1/3 receptor and ERK prevented the cell proliferation. LPA also increased the expression of c-myc,which was inhibited by the inhibitors of LPA1/3 receptor and ERK. In conclusion, LPA promoted proliferation of MSCs by binding LPA1/3 receptor, activating ERK pathway and increasing the expression of c-myc.
In sum, the study identified the effect of ROS in MSCs viability and its signaling pathway, analyzed the role of the phospholipids in MSCs paracrine and proliferation and their mechanism. The data would improve the viability of transplanted MSCs, facilitate application of the phospholipids in cell transplantation, and enhance the therapeutic effects of transplanted MSCs.
引文
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