载脂蛋白J对诱导成肌细胞中CXCR4表达和迁移及潜在保护作用机制的研究
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摘要
研究背景
在人体中心肌细胞属于最终分化细胞,一旦损伤只能由疤痕组织代替；如何修复或逆转已经坏死的心肌一直是多年来国内外专家研究的热点。成肌细胞(或肌原细胞,myoblast)来源于中胚层干细胞,具有增殖的潜能,可以相互融合,形成终末分化的肌纤维。现在已有多方研究报道证实,成肌细胞移植可以通过抑制心肌细胞的凋亡,减少心肌梗死面积,并改善受损心肌的功能,用于治疗心肌梗死、心力衰竭等缺血性心脏病。虽然目前还存在许多有待解决的问题,但这种治疗手段将可能成为治疗心肌损害和心力衰竭的重要新途径。
目前由于细胞水平的治疗方案受分离技术、量化和临床应用的限制,使得干细胞移植治疗仍处于初级预备阶段。细胞治疗的一种替代措施就是识别和调控能够介导干细胞归巢移植到缺血的心肌中的某些分子,发展为分子治疗。干细胞的表面受体则是这些分子之一
基质细胞衍生因子-1(SDF-1)是α组趋化因子家族的一个新成员,最早从骨髓的基质细胞中分离出来,其特异性受体CXCR4广泛地表达在许多组织和器官上,SDF-1/CXCR4在定向造血干细胞和间充质干细胞的动员和归巢以及调节免疫和炎症反应、调控造血、恶性肿瘤细胞的浸润转移、内皮细胞的迁移以及心血管发育和生后血管、神经生成等方面发挥着重要的作用,而细胞的归巢(homing)和定植(engraftment)对干细胞治疗方案和效果至关重要。在骨髓造血干细胞治疗局灶性脑缺血的研究中发现,损伤组织可能通过诱导SDF-1正调节表达与CXCR4相互作用使干细胞向损伤部位趋化集中,进而修复组织功能。研究还发现,促分裂原活化蛋白激酶(MAPK)和PI 3-kinase/Akt也在SDF-1/CXCR4介导的细胞迁移中发挥了重要的作用。然而在包括骨髓间充质干细胞在内的多种干细胞在体外培养扩增过程中CXCR4的表达水平显著降低,削弱了干细胞对SDF-1的靶向迁移作用,为干细胞的转移带来了很大的挑战。
存在于血浆中高密度脂蛋白(HDL)和极高密度脂蛋白(vHDL)中的载脂蛋白J (Apolipoprotein-J),也称作丛生蛋白(clusterin),是近年来新发现的一种多功能的蛋白质,当细胞发生损伤、死亡和病理改变时表达增加。其功能主要包括1)调节细胞-细胞、细胞-基质相互作用；2)参与脂类交换和运输3)调节补体作用；4)与细胞凋亡有关；5)参与生殖功能6)参与内分泌、神经系统等疾病的病理生理过程。大量不同的心血管相关病理生理状态比如心肌炎、动脉粥样硬化都暗示了ApoJ的细胞保护作用,但保护的机制不甚明了。潜在的保护机制包括保护干细胞免受氧化损伤；在血管损伤期间调控血管平滑肌细胞和内皮细胞的迁移及增殖。与ApoJ息息相关的HDL一直被认为与冠心病的发病危险呈独立的负相关,因此其降低可以作为重要的预测指标,最近的报道发现HDL在PI3-K/MAPK的介导下通过激活内皮祖细胞向内皮层的募集参与受损内皮的修复,表明调节干细胞的迁移是一种新发重要的血管保护机制。
我们的研究首次发现狗成肌细胞ApoJ的表达可以极大的降低细胞凋亡,稳定线粒体膜电位,阻止细胞色素C向胞浆的释放。然而,ApoJ在组织特异性干细胞迁移中的作用和潜在机制仍然是未知的。那么这个蛋白的表达是否在心脏干细胞增殖和迁移中发挥重要作用以及与SDF-1/CXCR4信号通路的关系是什么呢?对受损的心脏干细胞是否又有直接的保护作用呢?
目的
利用CDNA转染ApoJ到体外培养的成肌细胞中而大大提高ApoJ的表达,探究ApoJ对CXCR4表达水平以及在不改变细胞周期前提下对由SDF-1/CXCR4介导的组织特异性干细胞迁移水平的影响；通过抗逆转录病毒药物体外人为造成对成肌细胞的细胞毒性作用,利用毒理学分析进一步评价ApoJ对细胞的保护作用。
方法
1.分离培养心脏成肌细胞,转染ApoJ基因片段并评价转染后的基因表达：胶原酶消化分离犬胚胎心肌组织,胰酶振荡消化,利用细胞计数器计算细胞数目并按照一定的浓度接种于细胞培养瓶中,加入细胞培养液进行培养放入培养箱培养10-14天。利用HindⅢ和EcoRV双酶切含有人ApoJ cDNA的pCMV-sport 6质粒,得到的目的基因片段,偶联pcDNA3真核表达载体,利用Lipofectamine介导法将pcDNA3-APOJ转染入成肌细胞,转染后的细胞分裂培养48h后进行G418筛选。Western blotting鉴定转染后成肌细胞中ApoJ的表达。BrdU Proliferation Assay检测评价转染与未转染细胞的增殖；流式细胞仪分析细胞周期,450nm波长下酶标仪测定吸光度(OD)。
2.CXCR4表达水平检测和SDF-1对于细胞迁移的影响：实时定量PCR与Western blot测定CXCR4的表达,在成肌细胞中加入PE偶联的CXCR4抗体,通过Becton Dickinson荧光活化细胞流式分选仪(FACS),流式CELLQUEST分析荧光强度检测CXCR4阳性率。将细胞接种于含有SDF-1的培养基中,抚育后再移入含有Calcein-AM的培养基,通过荧光分析仪来检测迁移细胞的荧光活性。为了进一步验证细胞的运动性,在细胞生长至70%融合度时,去除培养液并用无菌的吸管头刮除一部分表面细胞,加入培养液再重新培养。细胞DAPI染色,相差倒置显微镜和荧光显微镜检证实该损伤,随机选取5个视野进行照相和计数。
3.评价ApoJ对受损细胞的保护作用：制备核苷酸逆转录酶抑制剂(NRTI)药物储存溶液,按照人体中血药浓度Cmax配成同等浓度溶液,并按照比例稀释为1：1,1：2,1：4,1：8,分别处理未转染组和转染组细胞。24小时后计数法计算细胞死亡率；利用体外毒理学分析试剂盒(In vitro toxicology assay)检测2种细胞遭到药物破坏后释放于培养液中的乳酸脱氢酶(LDH)活性,以分光光度计测得OD值表示,并在相差显微镜下观察记录细胞形态学变化。为了探讨ApoJ保护受损细胞的机制,采用ELISA法测定受损后细胞的细胞色素C (Cyt-C)含量和罗丹明123检测线粒体膜电位。
结果
1、犬胚胎心脏干细胞或者或者称之为成肌细胞分离提取后,并稳定转染ApoJ cDNA; Western Blot结果证实了转染后成肌细胞中ApoJ的表达显著增加。
由于细胞在不同的周期阶段会表现为不同的迁移能力,ApoJ转染后的成肌细胞通过血清饥饿(serum starvation)使之与对照组细胞同步化。溴脱氧尿嘧啶核苷(BrdU)标记的细胞通过流式细胞仪分析显示2组细胞有相同细胞周期,在Go/Gl, S和M相所占的细胞百分比无明显差异(P>0.05)：G1相分别为ApoJ细胞组73.6%±4.6% vs对照细胞组70.1%±5.1%；S相两组细胞分别为ApoJ细胞组13.8%±5.3% vs.对照组15.4%±4.9%。
在流式细胞仪进行BrdU染色标记分析中显示,ApoJ并未改变成肌细胞的增殖,450nm波长下OD值比较无显著差异(对照组1.81±0.03 vs.ApoJ组细胞1.79±0.02.P>0.05)
2、实时定量PCR分析趋化因子受体CXCR4的表达：与未转染基因的对照组成肌细胞相比,ApoJ转染后的细胞表现为CXCR4 mRNA的表达显著提高,琼脂糖凝胶电泳证实在ApoJ阳性的细胞RNA样本中CXCR4 cDNA含量比对照组提高了4倍,而18S rRNA条带并没有明显差别。
利用抗CXCR4抗体标记染色转染组和对照组细胞后流式细胞术测定单细胞水平上CXCR4的表达,结果表明ApoJ表达阳性的转染细胞组细胞表明CXCR4表达是增加的。免疫染色同样显示了CXCR4的高阳性表达率(29.8%±3.4% in ApoJ cells vs.10.5±2.1% in wild type cells, p<0.01).
提取两组细胞总蛋白,应用相同的CXCR4抗体Western blot分析结果显示了转染细胞有明显的蛋白条带,而对照组中没有发现。
对CXCR4/SDF-1介导的细胞迁移的影响：我们观察到ApoJ转染细胞表现为明显增加的对SDF-1的趋化性。在PI3激酶抑制剂作用下,这种迁移则受到影响,增加程度减低,与未转染细胞无明显差异,MAP/ERK激酶抑制剂的干预下不存在这种差异变化。除此之外,封闭CXCR4抗体(10μg/ml)同样导致ApoJ诱导的迁移受到抑制。趋化因子SDF-1对成肌细胞的趋化迁移实验“伤口愈合”(woundhealing)实验显示,在SDF-1的作用下,ApoJ转染的成肌细胞迁移能力得到显著增强,表现出对SDF-1趋化作用的反应性。
3、LDH法分析药物对细胞的破坏作用：10种药物分别干预成肌细胞对照组和ApoJ转染组,24小时后观察到细胞形态的改变：细胞膜破溃,坏死,胞体破碎,碎片融合成片。LDH活性测定结果表明anti-HIV药物对犬胚心来源成肌细胞有一定的细胞毒性作用,随药物浓度的增加LDH释放增多。在其中四种药物去羟肌苷(Didanosine)、司他夫定(Zerit)、拉米夫定(Epivir)和去羟肌苷加(Viread)干预下,24h后与成肌细胞对照组相比,ApoJ阳性细胞的LDH释放有显著差异,表明破坏减轻(P<0.01),对细胞有保护作用。
四种药物以浓度100mM干预对照组细胞和ApoJ组细胞4,8,16,24h后,以酶标仪检测细胞色素c的释放量。4,8,16h药物作用后,两组细胞的细胞色素c释放无显著差别,P>0.01；24h时,与ApoJ组比较,成肌细胞对照组的细胞色素c释放显著增高,有显著差异。P<0.01
罗丹明123检测线粒体膜电位：选用去羟肌苷、司他夫定、拉米夫定、去羟肌苷加四种药物,浓度分别为25,50, and 100 mM,干预犬胚胎成肌细胞4,8,16h后,线粒体膜电位的变化用Rh123的荧光强度表示。在低浓度25mM、50 mM处理组,16h后没有表现为随时间差异而变化P>0.05；在高浓度100 mM时,拉米夫定、去羟肌苷、司他夫定在16h后表现为显著降低P<0.05,去羟肌苷加处理8h后即有显著降低P<0.05。以四种药物浓度为100mM,处理对照组细胞和ApoJ细胞,4,8,16h后,检测Rh123的荧光强度。在4h和8h时,对照组细胞和ApoJ组细胞的Rh123强度对比无明显差异；16h时,对照组的Rh123荧光强度显著降低,与ApoJ组比较有显著差异。P<0.01
结论
1、利用ApoJ cDNA稳定转染的犬胚胎心脏干细胞与未转染的成肌细胞生长周期与增殖相同,排除对细胞迁移速度的影响。
2、ApoJ可以诱导体外心肌干细胞的CXCR4表达增高；通过稳定转染ApoJ导致的高表达也可以导致细胞对SDF-1趋化作用的反应性增强,并且数据表明该迁移作用的增加可以排除MAP/ERK的影响,是CXCR4依赖性的。这种CXCR4/SDF-1诱导的细胞迁移可能是通过PI3-kinase信号转导通路发挥作用。
3、实验中所用核苷酸逆转录酶抑制剂目前广泛应用于临床治疗HIV病毒感染,研究表明此类药物可造成体外成肌细胞的破坏和死亡,载脂蛋白J可以对抗某些药物的破坏作用,其保护机制可能与ApoJ可以减轻药物毒性诱导的细胞凋亡有关。不但可以为AIDS治疗前景提供新思路,亦可作为临床筛选药物的指标之一。
Background
In mature human body, cardiac myocytes belong to the final differentiated cells, once damaged can only be replaced by scar tissue. How to Repair or reversing myocardial necrosis has been a hot spot for domestic and international experts to study for many years. A myoblast is a type of progenitor cell that gives rise to myocytes, Derived from mesodermal, with potential of proliferation, can be integrated with each other to form terminal muscle fibers. Many studies have now been reported to confirm that myoblast transplantation can inhibit the apoptosis of myocardial cells, reduce infarction size,improve cardiac function, participate in the treatment of myocardial infarction, heart failure and other ischemic heart disease. Although there are still many problems need to be solved, but this treatment may become the new method for myocardial damage and heart failure.
The application of cell-based therapy for the treatment of heart disease remains in its preliminary phase, because cell therapy encounters significant challenges in isolation techniques, scalability and ease of clinical application. An alternative to cell therapy is to identify and modulate the molecules that mediate homing and engraftment of stem cells to the ischemic myocardium and to develop molecular therapies based on these discoveries. One of these molecules is surface receptor on stem cells. The chemokine, stromal cell-derived factor-1 (SDF-1), and its unique receptor CXCR4, are essential for normal cardiovascular development and play a critical role in postnatal vasculogenesis. Importantly, cell mobilization and homing of hematopoietic and mesenchymal stem cells depend on SDF-1 and CXCR4. Moreover, both MAP kinase (MAPK) and, particularly, phosphatidyl-inositol 3-kinase (PI 3-kinase)/Akt play central roles in SDF-1/CXCR4-mediated cell migration. However, it is still a challenge to enhance stem cell migration through modulating CXCR4/SDF-1, since the expression level of CXCR4 is low on some stem cells.
Apolipoprotein-J (ApoJ, also designated clusterin), found in high-density lipoproteins (HDL), is a stress-responding, chaperone-like protein. The cytoprotection of ApoJ has been suggested in a number of different cardiovascular-related pathophysiological conditions, such as atheroscelrosis and myocarditis, whereas the mechanism of protection of ApoJ requires further study. The potential protective mechanisms of ApoJ include protecting stem cells against oxidative injury, modulating vascular smooth muscle cell and endothelial cell migration and proliferation during vascular injury. HDL, which is associated with ApoJ, is shown to be inversely related to the incidence of coronary heart disease and, hence, could be used as a powerful predictor for future coronary events. Potential protective mechanisms of HDL include reverse cholesterol transport, endothelial protection, anti-oxidation, and anti-inflammation. More recently, it has been reported that HDL promotes the repair of injured endothelium by stimulating the recruitment of endothelial progenitor cells into the endothelial layer. Some effects of HDL are mediated through PI3 kinase and MAPK, including PI3 kinase-dependent endothelial cell migration. These findings suggest that modulating migration of some stem cells is a potentially important atheroprotective mechanism to be added to the other known properties of these lipoproteins.
We have recently shown that expression of ApoJ by cDNA transfection markedly reduces apoptosis in fetal cardiac stem cells or myoblasts, restores the mitochondrial membrane potential, and prevents the release of cytochrome C from the mitochondria into the cytoplasm. However, the effects of ApoJ on tissue-specific stem cell migration and its potential mechanisms are unknown. In this study, we examined the effects of ApoJ on canine fetal cardiac stem cell proliferation and migration, and the relationship of ApoJ with the SDF-1/CXCR4 signaling pathway. Furthermore, we need to know whether ApoJ have a direct protective effect on damaged cardiac stem cells?
Objective
To determine whether ApoJ exerts a protective effect on cardiovascular cells against a toxic agent, such as anti-HIV drug nucleotide analogue reverse transcriptase inhibitors(NRTI), and explore the effect of ApoJ on CXCR4 expression and SDF-1/CXCR4 mediated migration by tissue-specific stem cell without altering the cell cycle, ApoJ expression was induced in canine fetal myoblasts by stable cDNA transfection.
Methods
1. Cardiac stem cell cultures were prepared from myoblasts isolated from fetal dog heart by collagenase digestion. The myoblast tissues were suspended in trypsin and placed in a shaking water bath. After dissociation, the cells were counted using a hemacytometer and plated in tissue culture flasks. The cells were cultured in an incubator for 10-14 days before use. Overexpression of Apo J in stem cells:Human Apo J cDNA corresponding to human ApoJ was isolated from pCMV-sport 6 plasmid by using Hind III and EcoRV. The resulting fragment, containing the full length human ApoJ cDNA, was ligated into the mammalian expression vector pcDNA3, and transfected into stem cells using Lipofectamine2000. Transfected cells were split 48 h later and maintained in medium containing G418. Evaluate the ApoJ expression in the transfected myoblasts with Western blotting analysis. Cell proliferation was assessed with a BrdU Proliferation Assay. the cells were exposed to anti-BrdU monoclonal antibody followed by peroxidase-conjugated goat anti-mouse substrate. The colored reaction product was quantified by measuring absorbance at 450 nm and 595 nm. Cell cycle analysis were analyzed by FACScan flow cytometry.
2. CXCR4 expression and migration to SDF-1:Applying real-time PCR and Western blot analysis to determine the expression of CXCR4.Flow cytometry is for its positive percentage which method is:Myoblast cells were stained with PE-conjugated anti-CXCR4, then sorted with a triple-laser fluorescence-activated cell sorter. The data were collected using a FACSCalibur machine and analyzed by using CELLQUEST. 10,000 events.
Myoblast cells were placed in the culture medium and 100 nM SDF-1 for measuring the migratory capacity of myoblast cells. After incubation the medium was removed, and the insert was transferred to a second plate containing Calcein-AM solution. Then, the fluorescence of migrated cells was read in a fluorescence plate reader with bottom reading capabilities at excitation/emission wavelengths of 485/530 nm. To assess cell motility, cells were seeded at a density of 5×105 cells and grown to 70% confluence. The medium was removed from the plates and a wound was generated in each plate using a sterile pipette tip. Movement across the wound was assessed by microscopic examination and multiple fields were photographed with microscope equipped with a SPOT digital camera. Cells were stained with DAPI.
3. Evaluat the protection of ApoJ to damaged cells:NRTI drug stock solution were made with 5 different NRTI drug and DPBS. Interfere in the wide-type myoblasts and ApoJ transfected myoblasts with concentrations of 1:1,1:2,1:4, andl:8 Cmax.24 hours later,counting method was used for cell mortality; In vitro toxicological analysis suite and spectrophotometry of LDH which was released in the culture medium after cell damage were used to test cell viability. Absorbance was measured at 490 nm. In the phase contrast microscope, cells were observed by morphological changes.
Results:
1. Synchronization of cell cycle in canine wild type and ApoJ-transfected fetal myoblasts. Canine fetal cardiac stem cells or myoblasts were isolated and transfected stably with or without ApoJ cDNA. The stable expression of ApoJ in the transfected cells was confirmed by PCR and Western blot. Because cells at different phases of cell cycle show different capacities of migration, ApoJ-transfected myoblasts were synchronized with wild type control cells through serum starvation. Analysis of myoblasts with BrdU incorporation by flow cytometry revealed that wild type and ApoJ-transfected myoblasts had a similar cell cycle. There were no differences in the percentages of cells in Go/Gl, S and M phases between untransfected myoblasts and ApoJ-transfected. Flow cytometry showed that 73.6%±4.6% of ApoJ-transfected canine fetal myoblasts and 70.1%±5.1% of wild-type myoblasts were in the Gl phase of the cell cycle (Figure 1B). Similarly, we found no substantial differences between the two groups in the percentage of cells in S phase (13.8%±5.3% of ApoJ-transfected fetal myoblasts vs.15.4%±4.9% of wild-type myoblasts). Furthermore, ApoJ did not alter the proliferation of canine fetal myoblasts as determined by BrdU incorporation assay (1.81±0.03 in wild-type myoblasts vs.1.79±0.02 absorbance in ApoJ-transfected myoblasts).
2. After synchronization of cell cycle, expression of the chemokine receptor CXCR4 was analyzed by use of real time quantitative PCR. Compared to untransfected control cells, ApoJ-transfected myoblasts showed markedly increased expression of CXCR4 mRNA. Also, agarose gel electrophoresis demonstrated a four-fold increase in the expression of CXCR4 cDNA in the RNA samples from ApoJ-positive cells. By contrast, no difference in the 18S rRNA bands was found between wild type and ApoJ-expressing cells.
Flow cytometry study clearly illustrates an increased of cell surface expression of CXCR4 in myoblasts transfected with ApoJ. Furthermore, ApoJ-transfected myoblast showed a much higher positivity in CXCR4 immunostaining as compared to wild type cells (29.8%±3.4% in ApoJ cells vs.10.5±2.1% in wild type cells, p< 0.01).
Western blot analysis was conducted using total protein extracts of ApoJ-expressing and wild type cells with the same antibodies for flow cytometry. A single clear CXCR4 protein band was detected in ApoJ-transfected myoblast while this protein band was not found in wild type cells.
In ApoJ-transfected cells, we observed a marked increase in the migratory response of canine fetal myoblasts to SDF-1 (100 nM). The ApoJ-induced increase in canine fetal myoblast migration in response to SDF-1 was attenuated by the addition of the PI3 kinase inhibitor, but not by the mitogen-activated protein/ERK kinase inhibitor,. In addition, the increased migration of ApoJ-transfected canine fetal myoblasts was inhibited by pretreatment with blocking anti-CXCR4 antibody (10μg/ml). The wound healing was increased in ApoJ-transfected myoblasts compared to wild type myoblast
3. After 24 hours of the intervention of five NRTIdrugs(didanosin, Epivir, Zerit, ZIaGen, Viread),the cell morphology:the cell membrane rupture, necrosis, cell body broken, debris fused into pieces. Counting estimate the concentration of dead cells (control group vs ApoJ group) were didanosine 75.25%±9.22% vs70.31%±3.92%, Epivir 53.54%±2.76% vs 58.02%±10.8%, Zerit 62.65%±4.63% vs 32.21%±8.34%, ZIaGen 65.39%±4.75% vs 60.7%±14.6%, Viread 50.65%±2.63% vs 27.12%±5.35%, which Zerit and Viread have significant differences between two group cells (P<0.05). In vitro toxicological analysis showed that the release of LDH by myoblasts in the control group and Apo J transfected group increased with an increase in the drug concentration. Most drugs did not cause LDH release in the two kinds of cultured cells except for Viread (P=0.045) and Zerit (P=0.029), which caused the release of LDH at a low concentration by Apo J transgenic myogenic cells (P<0.05).
Conclusions:
1. ApoJ cDNA stable transfection of canine fetal cardiac stem cells has the same cell cycle and proliferation with non-transfected myoblast can exclude the impact of them to migration.
2. ApoJ induced expression of CXCR4 in cardiac myoblasts. We also have shown that ApoJ overexpression by stable transfection increases SDF-1-induced migration in canine fetal cardiac myoblasts. These data indicate that the ApoJ-induced increase in migration of canine fetal myoblasts is CXCR4 dependent. These data indicate that the ApoJ-induced increase in migration of canine fetal myoblasts is CXCR4 dependent.
3. The NRTIs drugs in our study are widely used in clinical treatment of HIV infection, studies have shown that these drugs can cause myoblasts damaged and death in vitro, meanwhile apolipoprotein J can counter the destructive effects of certain drugs, such as Viread and Zerit. The protection mechanism of ApoJ are perhaps mediated, in part, through attenuating cell apoptosis induced by cytotoxic actions,oxidative stress and altered calcium homeostasis.This study provides the first experimental evidence to the AIDS treatment propects and clinical drug screening.
在人体中心肌细胞属于最终分化细胞,一旦损伤只能由疤痕组织代替；如何修复或逆转已经坏死的心肌一直是多年来国内外专家研究的热点。成肌细胞(或肌原细胞,myoblast)来源于中胚层干细胞,具有增殖的潜能,可以相互融合,形成终末分化的肌纤维。现在已有多方研究报道证实,成肌细胞移植可以通过抑制心肌细胞的凋亡,减少心肌梗死面积,并改善受损心肌的功能,用于治疗心肌梗死、心力衰竭等缺血性心脏病。虽然目前还存在许多有待解决的问题,但这种治疗手段将可能成为治疗心肌损害和心力衰竭的重要新途径。
目前由于细胞水平的治疗方案受分离技术、量化和临床应用的限制,使得干细胞移植治疗仍处于初级预备阶段。细胞治疗的一种替代措施就是识别和调控能够介导干细胞归巢移植到缺血的心肌中的某些分子,发展为分子治疗。干细胞的表面受体则是这些分子之一
基质细胞衍生因子-1(SDF-1)是α组趋化因子家族的一个新成员,最早从骨髓的基质细胞中分离出来,其特异性受体CXCR4广泛地表达在许多组织和器官上,SDF-1/CXCR4在定向造血干细胞和间充质干细胞的动员和归巢以及调节免疫和炎症反应、调控造血、恶性肿瘤细胞的浸润转移、内皮细胞的迁移以及心血管发育和生后血管、神经生成等方面发挥着重要的作用,而细胞的归巢(homing)和定植(engraftment)对干细胞治疗方案和效果至关重要。在骨髓造血干细胞治疗局灶性脑缺血的研究中发现,损伤组织可能通过诱导SDF-1正调节表达与CXCR4相互作用使干细胞向损伤部位趋化集中,进而修复组织功能。研究还发现,促分裂原活化蛋白激酶(MAPK)和PI 3-kinase/Akt也在SDF-1/CXCR4介导的细胞迁移中发挥了重要的作用。然而在包括骨髓间充质干细胞在内的多种干细胞在体外培养扩增过程中CXCR4的表达水平显著降低,削弱了干细胞对SDF-1的靶向迁移作用,为干细胞的转移带来了很大的挑战。
存在于血浆中高密度脂蛋白(HDL)和极高密度脂蛋白(vHDL)中的载脂蛋白J (Apolipoprotein-J),也称作丛生蛋白(clusterin),是近年来新发现的一种多功能的蛋白质,当细胞发生损伤、死亡和病理改变时表达增加。其功能主要包括1)调节细胞-细胞、细胞-基质相互作用；2)参与脂类交换和运输3)调节补体作用；4)与细胞凋亡有关；5)参与生殖功能6)参与内分泌、神经系统等疾病的病理生理过程。大量不同的心血管相关病理生理状态比如心肌炎、动脉粥样硬化都暗示了ApoJ的细胞保护作用,但保护的机制不甚明了。潜在的保护机制包括保护干细胞免受氧化损伤；在血管损伤期间调控血管平滑肌细胞和内皮细胞的迁移及增殖。与ApoJ息息相关的HDL一直被认为与冠心病的发病危险呈独立的负相关,因此其降低可以作为重要的预测指标,最近的报道发现HDL在PI3-K/MAPK的介导下通过激活内皮祖细胞向内皮层的募集参与受损内皮的修复,表明调节干细胞的迁移是一种新发重要的血管保护机制。
我们的研究首次发现狗成肌细胞ApoJ的表达可以极大的降低细胞凋亡,稳定线粒体膜电位,阻止细胞色素C向胞浆的释放。然而,ApoJ在组织特异性干细胞迁移中的作用和潜在机制仍然是未知的。那么这个蛋白的表达是否在心脏干细胞增殖和迁移中发挥重要作用以及与SDF-1/CXCR4信号通路的关系是什么呢?对受损的心脏干细胞是否又有直接的保护作用呢?
目的
利用CDNA转染ApoJ到体外培养的成肌细胞中而大大提高ApoJ的表达,探究ApoJ对CXCR4表达水平以及在不改变细胞周期前提下对由SDF-1/CXCR4介导的组织特异性干细胞迁移水平的影响；通过抗逆转录病毒药物体外人为造成对成肌细胞的细胞毒性作用,利用毒理学分析进一步评价ApoJ对细胞的保护作用。
方法
1.分离培养心脏成肌细胞,转染ApoJ基因片段并评价转染后的基因表达：胶原酶消化分离犬胚胎心肌组织,胰酶振荡消化,利用细胞计数器计算细胞数目并按照一定的浓度接种于细胞培养瓶中,加入细胞培养液进行培养放入培养箱培养10-14天。利用HindⅢ和EcoRV双酶切含有人ApoJ cDNA的pCMV-sport 6质粒,得到的目的基因片段,偶联pcDNA3真核表达载体,利用Lipofectamine介导法将pcDNA3-APOJ转染入成肌细胞,转染后的细胞分裂培养48h后进行G418筛选。Western blotting鉴定转染后成肌细胞中ApoJ的表达。BrdU Proliferation Assay检测评价转染与未转染细胞的增殖；流式细胞仪分析细胞周期,450nm波长下酶标仪测定吸光度(OD)。
2.CXCR4表达水平检测和SDF-1对于细胞迁移的影响：实时定量PCR与Western blot测定CXCR4的表达,在成肌细胞中加入PE偶联的CXCR4抗体,通过Becton Dickinson荧光活化细胞流式分选仪(FACS),流式CELLQUEST分析荧光强度检测CXCR4阳性率。将细胞接种于含有SDF-1的培养基中,抚育后再移入含有Calcein-AM的培养基,通过荧光分析仪来检测迁移细胞的荧光活性。为了进一步验证细胞的运动性,在细胞生长至70%融合度时,去除培养液并用无菌的吸管头刮除一部分表面细胞,加入培养液再重新培养。细胞DAPI染色,相差倒置显微镜和荧光显微镜检证实该损伤,随机选取5个视野进行照相和计数。
3.评价ApoJ对受损细胞的保护作用：制备核苷酸逆转录酶抑制剂(NRTI)药物储存溶液,按照人体中血药浓度Cmax配成同等浓度溶液,并按照比例稀释为1：1,1：2,1：4,1：8,分别处理未转染组和转染组细胞。24小时后计数法计算细胞死亡率；利用体外毒理学分析试剂盒(In vitro toxicology assay)检测2种细胞遭到药物破坏后释放于培养液中的乳酸脱氢酶(LDH)活性,以分光光度计测得OD值表示,并在相差显微镜下观察记录细胞形态学变化。为了探讨ApoJ保护受损细胞的机制,采用ELISA法测定受损后细胞的细胞色素C (Cyt-C)含量和罗丹明123检测线粒体膜电位。
结果
1、犬胚胎心脏干细胞或者或者称之为成肌细胞分离提取后,并稳定转染ApoJ cDNA; Western Blot结果证实了转染后成肌细胞中ApoJ的表达显著增加。
由于细胞在不同的周期阶段会表现为不同的迁移能力,ApoJ转染后的成肌细胞通过血清饥饿(serum starvation)使之与对照组细胞同步化。溴脱氧尿嘧啶核苷(BrdU)标记的细胞通过流式细胞仪分析显示2组细胞有相同细胞周期,在Go/Gl, S和M相所占的细胞百分比无明显差异(P>0.05)：G1相分别为ApoJ细胞组73.6%±4.6% vs对照细胞组70.1%±5.1%；S相两组细胞分别为ApoJ细胞组13.8%±5.3% vs.对照组15.4%±4.9%。
在流式细胞仪进行BrdU染色标记分析中显示,ApoJ并未改变成肌细胞的增殖,450nm波长下OD值比较无显著差异(对照组1.81±0.03 vs.ApoJ组细胞1.79±0.02.P>0.05)
2、实时定量PCR分析趋化因子受体CXCR4的表达：与未转染基因的对照组成肌细胞相比,ApoJ转染后的细胞表现为CXCR4 mRNA的表达显著提高,琼脂糖凝胶电泳证实在ApoJ阳性的细胞RNA样本中CXCR4 cDNA含量比对照组提高了4倍,而18S rRNA条带并没有明显差别。
利用抗CXCR4抗体标记染色转染组和对照组细胞后流式细胞术测定单细胞水平上CXCR4的表达,结果表明ApoJ表达阳性的转染细胞组细胞表明CXCR4表达是增加的。免疫染色同样显示了CXCR4的高阳性表达率(29.8%±3.4% in ApoJ cells vs.10.5±2.1% in wild type cells, p<0.01).
提取两组细胞总蛋白,应用相同的CXCR4抗体Western blot分析结果显示了转染细胞有明显的蛋白条带,而对照组中没有发现。
对CXCR4/SDF-1介导的细胞迁移的影响：我们观察到ApoJ转染细胞表现为明显增加的对SDF-1的趋化性。在PI3激酶抑制剂作用下,这种迁移则受到影响,增加程度减低,与未转染细胞无明显差异,MAP/ERK激酶抑制剂的干预下不存在这种差异变化。除此之外,封闭CXCR4抗体(10μg/ml)同样导致ApoJ诱导的迁移受到抑制。趋化因子SDF-1对成肌细胞的趋化迁移实验“伤口愈合”(woundhealing)实验显示,在SDF-1的作用下,ApoJ转染的成肌细胞迁移能力得到显著增强,表现出对SDF-1趋化作用的反应性。
3、LDH法分析药物对细胞的破坏作用：10种药物分别干预成肌细胞对照组和ApoJ转染组,24小时后观察到细胞形态的改变：细胞膜破溃,坏死,胞体破碎,碎片融合成片。LDH活性测定结果表明anti-HIV药物对犬胚心来源成肌细胞有一定的细胞毒性作用,随药物浓度的增加LDH释放增多。在其中四种药物去羟肌苷(Didanosine)、司他夫定(Zerit)、拉米夫定(Epivir)和去羟肌苷加(Viread)干预下,24h后与成肌细胞对照组相比,ApoJ阳性细胞的LDH释放有显著差异,表明破坏减轻(P<0.01),对细胞有保护作用。
四种药物以浓度100mM干预对照组细胞和ApoJ组细胞4,8,16,24h后,以酶标仪检测细胞色素c的释放量。4,8,16h药物作用后,两组细胞的细胞色素c释放无显著差别,P>0.01；24h时,与ApoJ组比较,成肌细胞对照组的细胞色素c释放显著增高,有显著差异。P<0.01
罗丹明123检测线粒体膜电位：选用去羟肌苷、司他夫定、拉米夫定、去羟肌苷加四种药物,浓度分别为25,50, and 100 mM,干预犬胚胎成肌细胞4,8,16h后,线粒体膜电位的变化用Rh123的荧光强度表示。在低浓度25mM、50 mM处理组,16h后没有表现为随时间差异而变化P>0.05；在高浓度100 mM时,拉米夫定、去羟肌苷、司他夫定在16h后表现为显著降低P<0.05,去羟肌苷加处理8h后即有显著降低P<0.05。以四种药物浓度为100mM,处理对照组细胞和ApoJ细胞,4,8,16h后,检测Rh123的荧光强度。在4h和8h时,对照组细胞和ApoJ组细胞的Rh123强度对比无明显差异；16h时,对照组的Rh123荧光强度显著降低,与ApoJ组比较有显著差异。P<0.01
结论
1、利用ApoJ cDNA稳定转染的犬胚胎心脏干细胞与未转染的成肌细胞生长周期与增殖相同,排除对细胞迁移速度的影响。
2、ApoJ可以诱导体外心肌干细胞的CXCR4表达增高；通过稳定转染ApoJ导致的高表达也可以导致细胞对SDF-1趋化作用的反应性增强,并且数据表明该迁移作用的增加可以排除MAP/ERK的影响,是CXCR4依赖性的。这种CXCR4/SDF-1诱导的细胞迁移可能是通过PI3-kinase信号转导通路发挥作用。
3、实验中所用核苷酸逆转录酶抑制剂目前广泛应用于临床治疗HIV病毒感染,研究表明此类药物可造成体外成肌细胞的破坏和死亡,载脂蛋白J可以对抗某些药物的破坏作用,其保护机制可能与ApoJ可以减轻药物毒性诱导的细胞凋亡有关。不但可以为AIDS治疗前景提供新思路,亦可作为临床筛选药物的指标之一。
Background
In mature human body, cardiac myocytes belong to the final differentiated cells, once damaged can only be replaced by scar tissue. How to Repair or reversing myocardial necrosis has been a hot spot for domestic and international experts to study for many years. A myoblast is a type of progenitor cell that gives rise to myocytes, Derived from mesodermal, with potential of proliferation, can be integrated with each other to form terminal muscle fibers. Many studies have now been reported to confirm that myoblast transplantation can inhibit the apoptosis of myocardial cells, reduce infarction size,improve cardiac function, participate in the treatment of myocardial infarction, heart failure and other ischemic heart disease. Although there are still many problems need to be solved, but this treatment may become the new method for myocardial damage and heart failure.
The application of cell-based therapy for the treatment of heart disease remains in its preliminary phase, because cell therapy encounters significant challenges in isolation techniques, scalability and ease of clinical application. An alternative to cell therapy is to identify and modulate the molecules that mediate homing and engraftment of stem cells to the ischemic myocardium and to develop molecular therapies based on these discoveries. One of these molecules is surface receptor on stem cells. The chemokine, stromal cell-derived factor-1 (SDF-1), and its unique receptor CXCR4, are essential for normal cardiovascular development and play a critical role in postnatal vasculogenesis. Importantly, cell mobilization and homing of hematopoietic and mesenchymal stem cells depend on SDF-1 and CXCR4. Moreover, both MAP kinase (MAPK) and, particularly, phosphatidyl-inositol 3-kinase (PI 3-kinase)/Akt play central roles in SDF-1/CXCR4-mediated cell migration. However, it is still a challenge to enhance stem cell migration through modulating CXCR4/SDF-1, since the expression level of CXCR4 is low on some stem cells.
Apolipoprotein-J (ApoJ, also designated clusterin), found in high-density lipoproteins (HDL), is a stress-responding, chaperone-like protein. The cytoprotection of ApoJ has been suggested in a number of different cardiovascular-related pathophysiological conditions, such as atheroscelrosis and myocarditis, whereas the mechanism of protection of ApoJ requires further study. The potential protective mechanisms of ApoJ include protecting stem cells against oxidative injury, modulating vascular smooth muscle cell and endothelial cell migration and proliferation during vascular injury. HDL, which is associated with ApoJ, is shown to be inversely related to the incidence of coronary heart disease and, hence, could be used as a powerful predictor for future coronary events. Potential protective mechanisms of HDL include reverse cholesterol transport, endothelial protection, anti-oxidation, and anti-inflammation. More recently, it has been reported that HDL promotes the repair of injured endothelium by stimulating the recruitment of endothelial progenitor cells into the endothelial layer. Some effects of HDL are mediated through PI3 kinase and MAPK, including PI3 kinase-dependent endothelial cell migration. These findings suggest that modulating migration of some stem cells is a potentially important atheroprotective mechanism to be added to the other known properties of these lipoproteins.
We have recently shown that expression of ApoJ by cDNA transfection markedly reduces apoptosis in fetal cardiac stem cells or myoblasts, restores the mitochondrial membrane potential, and prevents the release of cytochrome C from the mitochondria into the cytoplasm. However, the effects of ApoJ on tissue-specific stem cell migration and its potential mechanisms are unknown. In this study, we examined the effects of ApoJ on canine fetal cardiac stem cell proliferation and migration, and the relationship of ApoJ with the SDF-1/CXCR4 signaling pathway. Furthermore, we need to know whether ApoJ have a direct protective effect on damaged cardiac stem cells?
Objective
To determine whether ApoJ exerts a protective effect on cardiovascular cells against a toxic agent, such as anti-HIV drug nucleotide analogue reverse transcriptase inhibitors(NRTI), and explore the effect of ApoJ on CXCR4 expression and SDF-1/CXCR4 mediated migration by tissue-specific stem cell without altering the cell cycle, ApoJ expression was induced in canine fetal myoblasts by stable cDNA transfection.
Methods
1. Cardiac stem cell cultures were prepared from myoblasts isolated from fetal dog heart by collagenase digestion. The myoblast tissues were suspended in trypsin and placed in a shaking water bath. After dissociation, the cells were counted using a hemacytometer and plated in tissue culture flasks. The cells were cultured in an incubator for 10-14 days before use. Overexpression of Apo J in stem cells:Human Apo J cDNA corresponding to human ApoJ was isolated from pCMV-sport 6 plasmid by using Hind III and EcoRV. The resulting fragment, containing the full length human ApoJ cDNA, was ligated into the mammalian expression vector pcDNA3, and transfected into stem cells using Lipofectamine2000. Transfected cells were split 48 h later and maintained in medium containing G418. Evaluate the ApoJ expression in the transfected myoblasts with Western blotting analysis. Cell proliferation was assessed with a BrdU Proliferation Assay. the cells were exposed to anti-BrdU monoclonal antibody followed by peroxidase-conjugated goat anti-mouse substrate. The colored reaction product was quantified by measuring absorbance at 450 nm and 595 nm. Cell cycle analysis were analyzed by FACScan flow cytometry.
2. CXCR4 expression and migration to SDF-1:Applying real-time PCR and Western blot analysis to determine the expression of CXCR4.Flow cytometry is for its positive percentage which method is:Myoblast cells were stained with PE-conjugated anti-CXCR4, then sorted with a triple-laser fluorescence-activated cell sorter. The data were collected using a FACSCalibur machine and analyzed by using CELLQUEST. 10,000 events.
Myoblast cells were placed in the culture medium and 100 nM SDF-1 for measuring the migratory capacity of myoblast cells. After incubation the medium was removed, and the insert was transferred to a second plate containing Calcein-AM solution. Then, the fluorescence of migrated cells was read in a fluorescence plate reader with bottom reading capabilities at excitation/emission wavelengths of 485/530 nm. To assess cell motility, cells were seeded at a density of 5×105 cells and grown to 70% confluence. The medium was removed from the plates and a wound was generated in each plate using a sterile pipette tip. Movement across the wound was assessed by microscopic examination and multiple fields were photographed with microscope equipped with a SPOT digital camera. Cells were stained with DAPI.
3. Evaluat the protection of ApoJ to damaged cells:NRTI drug stock solution were made with 5 different NRTI drug and DPBS. Interfere in the wide-type myoblasts and ApoJ transfected myoblasts with concentrations of 1:1,1:2,1:4, andl:8 Cmax.24 hours later,counting method was used for cell mortality; In vitro toxicological analysis suite and spectrophotometry of LDH which was released in the culture medium after cell damage were used to test cell viability. Absorbance was measured at 490 nm. In the phase contrast microscope, cells were observed by morphological changes.
Results:
1. Synchronization of cell cycle in canine wild type and ApoJ-transfected fetal myoblasts. Canine fetal cardiac stem cells or myoblasts were isolated and transfected stably with or without ApoJ cDNA. The stable expression of ApoJ in the transfected cells was confirmed by PCR and Western blot. Because cells at different phases of cell cycle show different capacities of migration, ApoJ-transfected myoblasts were synchronized with wild type control cells through serum starvation. Analysis of myoblasts with BrdU incorporation by flow cytometry revealed that wild type and ApoJ-transfected myoblasts had a similar cell cycle. There were no differences in the percentages of cells in Go/Gl, S and M phases between untransfected myoblasts and ApoJ-transfected. Flow cytometry showed that 73.6%±4.6% of ApoJ-transfected canine fetal myoblasts and 70.1%±5.1% of wild-type myoblasts were in the Gl phase of the cell cycle (Figure 1B). Similarly, we found no substantial differences between the two groups in the percentage of cells in S phase (13.8%±5.3% of ApoJ-transfected fetal myoblasts vs.15.4%±4.9% of wild-type myoblasts). Furthermore, ApoJ did not alter the proliferation of canine fetal myoblasts as determined by BrdU incorporation assay (1.81±0.03 in wild-type myoblasts vs.1.79±0.02 absorbance in ApoJ-transfected myoblasts).
2. After synchronization of cell cycle, expression of the chemokine receptor CXCR4 was analyzed by use of real time quantitative PCR. Compared to untransfected control cells, ApoJ-transfected myoblasts showed markedly increased expression of CXCR4 mRNA. Also, agarose gel electrophoresis demonstrated a four-fold increase in the expression of CXCR4 cDNA in the RNA samples from ApoJ-positive cells. By contrast, no difference in the 18S rRNA bands was found between wild type and ApoJ-expressing cells.
Flow cytometry study clearly illustrates an increased of cell surface expression of CXCR4 in myoblasts transfected with ApoJ. Furthermore, ApoJ-transfected myoblast showed a much higher positivity in CXCR4 immunostaining as compared to wild type cells (29.8%±3.4% in ApoJ cells vs.10.5±2.1% in wild type cells, p< 0.01).
Western blot analysis was conducted using total protein extracts of ApoJ-expressing and wild type cells with the same antibodies for flow cytometry. A single clear CXCR4 protein band was detected in ApoJ-transfected myoblast while this protein band was not found in wild type cells.
In ApoJ-transfected cells, we observed a marked increase in the migratory response of canine fetal myoblasts to SDF-1 (100 nM). The ApoJ-induced increase in canine fetal myoblast migration in response to SDF-1 was attenuated by the addition of the PI3 kinase inhibitor, but not by the mitogen-activated protein/ERK kinase inhibitor,. In addition, the increased migration of ApoJ-transfected canine fetal myoblasts was inhibited by pretreatment with blocking anti-CXCR4 antibody (10μg/ml). The wound healing was increased in ApoJ-transfected myoblasts compared to wild type myoblast
3. After 24 hours of the intervention of five NRTIdrugs(didanosin, Epivir, Zerit, ZIaGen, Viread),the cell morphology:the cell membrane rupture, necrosis, cell body broken, debris fused into pieces. Counting estimate the concentration of dead cells (control group vs ApoJ group) were didanosine 75.25%±9.22% vs70.31%±3.92%, Epivir 53.54%±2.76% vs 58.02%±10.8%, Zerit 62.65%±4.63% vs 32.21%±8.34%, ZIaGen 65.39%±4.75% vs 60.7%±14.6%, Viread 50.65%±2.63% vs 27.12%±5.35%, which Zerit and Viread have significant differences between two group cells (P<0.05). In vitro toxicological analysis showed that the release of LDH by myoblasts in the control group and Apo J transfected group increased with an increase in the drug concentration. Most drugs did not cause LDH release in the two kinds of cultured cells except for Viread (P=0.045) and Zerit (P=0.029), which caused the release of LDH at a low concentration by Apo J transgenic myogenic cells (P<0.05).
Conclusions:
1. ApoJ cDNA stable transfection of canine fetal cardiac stem cells has the same cell cycle and proliferation with non-transfected myoblast can exclude the impact of them to migration.
2. ApoJ induced expression of CXCR4 in cardiac myoblasts. We also have shown that ApoJ overexpression by stable transfection increases SDF-1-induced migration in canine fetal cardiac myoblasts. These data indicate that the ApoJ-induced increase in migration of canine fetal myoblasts is CXCR4 dependent. These data indicate that the ApoJ-induced increase in migration of canine fetal myoblasts is CXCR4 dependent.
3. The NRTIs drugs in our study are widely used in clinical treatment of HIV infection, studies have shown that these drugs can cause myoblasts damaged and death in vitro, meanwhile apolipoprotein J can counter the destructive effects of certain drugs, such as Viread and Zerit. The protection mechanism of ApoJ are perhaps mediated, in part, through attenuating cell apoptosis induced by cytotoxic actions,oxidative stress and altered calcium homeostasis.This study provides the first experimental evidence to the AIDS treatment propects and clinical drug screening.
引文
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