药物提高骨髓间充质干细胞治疗急性心肌梗死效果的实验研究
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摘要
目的：随着干细胞再生医学不断发展,应用骨髓来源的间充质干细胞(mesenchymal stem cells, MSCs)进行急性心肌梗死(acute myocardial infarction, AMI)后心肌修复成为一种有前景的方法。然而干细胞移植进行梗死心肌修复虽然有效,但是疗效有限。其疗效底下的原因之一是干细胞归巢至梗死心肌的数量较少。基质细胞衍生因子1(stromal cell-derived factor-1, SDF-1)与其特异性受体趋化因子受体4(CXC chemokine receptor4, CXCIR4)构成的SDF-1/CXCR4生物学轴在MSCs归巢、定植到损伤部位参与修复的过程中发挥重要作用。既往研究表明,他汀不但能改善梗死微环境促进MSCs存活,而且能增强MSCs的自身抗凋亡能力。然而,他汀能否促进MSCs的迁移和归巢能力尚无相关研究。因此,我们进行此项研究,拟明确阿托伐他汀(atorvastatin, ATV)预处理能否增加MSCs表面CXCR4的表达,并提高MSCs的归巢能力,进而改善心梗后心功能。
方法：实验分为体外实验和体内实验两部分。体外实验部分：分离并培养Sprague-Dawley大鼠MSCs,将第3代细胞随机分为正常对照组、ATV不同浓度梯度组(0.01μM、0.1μM、1μM、10μM)、ATV不同时间梯度组(1h、3h、6h、12h、24h、36h、48h)；机制探讨部分设MSCs组、最适ATV预处理组(ATV-MSCs). MSCs+CXCR4中和抗体组(MSCs-NA)、ATV-MSCs+CXCR4中和抗体组(ATV-MSCs-NA)。流式细胞术和RT-PCR检测各组CXCR4的表达,Transwell小室评估MSCs的迁移能力。体内实验部分：共108只雌性SD大鼠(6-8周龄),随机分为SDF-1动态测定组(AMI30min、1h、12h、24h、48h、72h、5d、7d)、假手术组(Sham)、心梗对照组AMI)、MSCs移植组(MSCs)、ATV预处理MSCs移植组(ATV-MSCs).采用结扎冠状动脉前降支的方法制作急性心肌梗死模型,梗死后24小时经尾静脉注射MSCs或ATV-MSCs(2x106细胞/只),对照组动物注射等体积PBS。在干细胞移植后3天(基线)及30天(终点)分别行心脏超声检测、病理组织学及分子生物学检测。
结果：体外实验表明,与正常对照组相比,ATV剂量依赖性的增加细胞表面CXCR4表达,以1μM ATV处理组最为明显(14.76±3.05%vs.1.98±0.40%,P<0.001)；与正常对照组相比,ATV处理组CXCR4的表达呈一定的时间依赖性,其中ATV处理12小时CXCR4的表达至峰值(22.77±2.03%vs.2.20±0.18%,P<0.001),24小时仍保持在较高水平(20.34±4.13%vs.2.20±0.18%,P<0.001)。CXCR4mRNA的表达趋势与细胞表面CXCR4的表达趋势相似。‘Transwell迁移结果显示,ATV预处理组MSCs向SDF-1迁移的数量是未处理组的2倍左右(24.65±5.57vs.12.70±2.40,P<0.001),然而加入CXCR4的中和抗体后MSCs的迁移能力被抑制。
体内试验发现,干细胞移植后3天,冰冻切片激光共聚焦显微镜下观察到ATV-MSCs组归巢到梗死心肌区域的细胞数明显高于MSCs组(41.68±10.80vs.65.30±13.37,P<0.05),在非梗死区域未发现移植的干细胞；在细胞移植后30天,ATV-MSCs组和MSCs组的存活率都很低,MSCs组的存活率更低。与AMI组相比,MSCs组的左室收缩末期内径和左室射血分数有适度改善。与MSCs组相比,ATV-MSCs组的左室舒张末期内径和左室收缩末期内径进一步减小,左室射血分数(62.28±3.27%vs.52.77±7.05%,P=0.014)和左室短轴缩短率(27.80±2.16%vs.22.27±3.84%,P=0.015)显著改善。组织学分析显示,与AMI组和MSCs组相比,ATV-MSCs组的心肌纤维化面积显著减小,炎细胞浸润明显减轻。Western blot分析显示,细胞移植后3天,ATV-MSCs组IL-6和TNF-α的表达水平明显降低；细胞移植后30天,其表达水平进一步降低。
结论：ATV预处理可以提高MSCs表面CXCR4的表达,进而增强MSCs的迁移和归巢能力,并通过改善梗死心肌中炎性因子的表达,进一步改善心肌梗死后心功能,ATV预处理MSCs可能成为提高干细胞移植疗效的一有效方法。
目的：骨髓来源的间充质干细胞(mesenchymal stem cells,MSCs)是移植治疗急性心肌梗死的理想种子。目前移植的瓶颈问题是移植后的干细胞在心梗后恶劣的微环境大量凋亡,导致其疗效受限。通心络是一种传统中药,在我国广泛应用于心血管疾病的治疗。我们既往的体内研究表明,中药通心络可以增加MSCs的存活,提高干细胞移植疗效,但是通心络在能否减少MSCs的凋亡及其具体机制尚未明确。单磷酸腺苷活化蛋白激酶(AMP-activated protein kinase,AMPK)是调控细胞能量代谢的核心分子,内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)是AMPK下游的重要分子,AMPK/eNOS通路在调节细胞凋亡中发挥重要作用。因此我们在体外建立缺氧无血清(hypoxia and serum deprivation H/SD)模型来模拟心肌梗死后体内缺血缺氧环境,探讨通心络(tongxinluo,TXL)能否减少MSCs的凋亡,并明确AMPK/eNOS通路在其中发挥的作用。
方法：分离并培养Sprague-Dawley大鼠MSCs,将第3代细胞随机分为正常对照组、H/SD对照组、通心络不同浓度梯度组(50μg/mL、100μg/mL、200μg/mL、400μg/mL)、 AMPK通路抑制剂Compound C组(10μM)。在荧光显微镜下观察Hocchst33342染色阳性细胞以及TUNEL染色阳性细胞,Annexin V/PI流式细胞术检测各组细胞的凋亡比例,荧光探针JC-1流式细胞术检测线粒体膜电位的变化,并进一步采用westernblot方法检测凋亡相关蛋白细胞色素C、bax、bcl-2水平及AMPK、eNOS及其磷酸化蛋白的水平。
结果：与正常组相比,H/SD条件下细胞凋亡明显增加Annexin V+/PI-细胞：21.91±3.28%vs.2.13±0.33%,P<0.001；JC-1红/绿色荧光比值：5.40±0.43vs.2.34±0.25,P<0.001)。通心络剂量依赖性的降低MSCs凋亡,在400μg/mL浓度时最为明显,表现为nnexin V+/PI-细胞减少(3.47±0.69%vs.21.91±3.28%, P<0.001), JC-1红/绿色荧光比值增高(4.78±0.37vs.2.34±0.25,P<0.001),促凋亡蛋白bax表达降低(1.06±0.24vs.2.92±0.29,P<0.001),抗凋亡蛋白bcl-2表达增高(2.59±0.15vs.1.14±0.09,P<0.001)。而且,通心络各组AMPK和eNOS的磷酸化水平显著升高。加入AMPK抑制剂Compound C后通心络组AMPK和eNOS的磷酸化水平下降,同时减弱了通心络的抗凋亡作用。
结论：通心络可以抑制缺氧无血清培养条件下诱导的MSCs凋亡,其中AMPK/eNOS通路在其中发挥重要作用。这也为通心络在心血管系统中的多效性提供了新的解释。通心络可能成为提高心肌梗死患者MSCs存活的又一有效方法。
Background:With the development of stem cell regenerative medicine, transplantation of bone morrow-derived mesenchymal stem cells (MSCs) into the infarcted heart after acute myocardial infarction (AMI) has emerged as a promising therapy for myocardial repair. However, poor engraftment of donor MSCs limits reparative capability of the therapy. Mobilization and migration of MSCs are mainly controlled by stromal cell-derived factor1(SDF-1) and its receptor CXC chemokine receptor4(CXCR4). Statins can increase the survival of MSCs. However, whether statins could enhance MSCs migration and engraftment is still unknown. Therefore, we designed the study to investigate whether atorvastatin (ATV) could enhance CXCR4expression of MSCs and promote them homing toward the injured myocardium.
Methods:In vitro, MSCs from the Sprague-Dawley rats bone marrow (60-80g, male) were treated with different concentrations of ATV (0.01μM,0.1μM,1μM,10μM) different ATV culture durations (1h,3h,6h,12h,24h,36h,48h). For inhibitory studies, MSCs were incubated with CXCR4neutralizing antibody. Expression of CXCR4was evaluated using flow cytometry and real time PCR. A transwell system was used to assess MSCs migration. In vivo, female Sprague-Dawley rats were randomized into the following groups:SDF-1dynamic groups (AMI30min,1h,12h,24h,48h,72h,5d,7d), Sham group, AMI group, MSCs group, ATV-pretreated-MSCs group (ATV-MSCs). AMI was created by ligating the left anterior descending coronary artery.24h after AMI,2.0×106CM-Dil-labeled MSCs, CM-Dil-labeled ATV-MSCs, or PBS were injected in a total volume of500μL through the tail vein. Cardiac function, histology, inflammation cytokines were examined at3days and30days after MSCs transplantation.
Results:Cell surface expression of CXCR4assessed by flow cytometry showed that ATV enhanced CXCR4expression in a dose-dependent manner, especially in the1μM ATV group (14.76±3.05%vs.1.98±0.40%, P<0.001). Then the time-course experiments at1μM ATV concentration revealed that, compared with the control group, CXCR4expression was significantly increased with ATV treatment (1to48h), peaking at12h (22.77±2.03%vs.2.20±0.18%, P<0.001) and maintaining at a high level within 24h (20.34±4.13%vs.2.20±0.18%, P<0.001). CXCR4mRNA expression showed the same tendency as the cell surface expression in each group. As expected, MSCs pretreated with ATV showed enhanced migration ability demonstrated by the increased number of cells migrating toward SDF-1compared with untreated MSCs (24.65±5.57vs.12.70±2.40, P<0.001). However, the effect was largely abolished by CXCR4neutralizing antibody, indicating that the benefit was mediated by CXCR4expression.
In AMI model of Sprague-Dawley rats, we found much more ATV-pretreated MSCs homing toward the infarcted myocardium than non-treated cells (41.68±10.80vs.65.30±13.37, P<0.05). In addition, almost no MSCs were detected in the non-infarcted myocardium. At30days after cell injection, the survival rate in both ATV-MSCs and MSCs groups were low, fewer cells can be seen in the MSCs group. Compared with AMI group, left ventricular end-diastolic diameter and left ventricular ejection fraction were slightly improved in MSCs group. Cardiac performance was further improved in ATV-MSCs group than MSCs group, evidenced by increased left ventricular ejection fraction (62.28±3.27%vs.52.77±7.05%, P=0.014) and left ventricular fractional shortening (27.80±2.16%vs.22.27±3.84%, P=0.015). Histology analysis showed that compared with AMI and MSCs groups, the left ventricular fibrotic area was markedly reduced in ATV-MSCs group, and the inflammation was obviously attenuated. Western Blot analysis demonstrated that the expression of inflammation cytokines IL-6and TNF-a were decreased in ATV-MSCs group at3days and30days.
Conclusions:ATV increases MSCs migration ability and improves cardiac performance due to up-regulated expression of CXCR4. These results suggest that ATV pretreatment of donor MSCs is an effective way to promote cell therapeutic potential for AMI.
Background:Bone morrow-derived mesenchymal stem cells (MSCs) are the optimal candidate cells for acute myocardial infarction. However, the poor survival of the implanted cells because of the harsh environment hampered the therapeutic potential of the treatment. Tongxinluo (TXL), a traditional Chinese medicine, is widely used to treat cardiovascular diseases in China. Our previous study has demonstrated the pro-survival role of TXL on mesenchymal stem cells (MSCs) in vivo. But whether TXL could decrease apoptosis of MSCs in vitro and the underlying mechanism are still unknown. Moreover, AMPK/eNOS pathway is crucial in regulating cell apoptosis. Therefore, we designed the study to investigate whether TXL could decrease MSCs apoptosis under hypoxia and serum deprivation (H/SD) conditions and to determine the role of AMPK/eNOS pathway.
Methods:MSCs from the Sprague-Dawley rats bone marrow (60-80g, male) were treated with TXL (50μg/mL,100μg/mL,200μg/mL,400μg/mL) for6h under H/SD conditions. For inhibitor studies, the cells were preincubated with AMPK inhibitor compound C (10μM) prior to the addition of TXL (400μg/mL). Cell apoptosis was assessed using Hocchst33342and TUNEL by Fluorescence microscope, Annexin V/PI by flow cytometry, mitochondrial membrane potential using fluorescent dye JC-1by flow cytometry, and apoptosis related protein cytochrome C, bax and bcl-2by western blot. The expression of AMPK and eNOS were measured by western blot.
Results:Cell apoptosis was significantly upregulated under H/SD conditions compared with the normal (Annexin V+/PI-cells:21.91±3.28%vs.2.13±0.33%, P<0.001; JC-1red/green signal ratio:5.40±0.43vs.2.34±0.25, P<0.001)。TXL decreased the apoptosis level in a dose-dependent manner especially in the400μg/mL group, demonstrated by reduced Annexin V+/PI-cells (3.47±0.69%vs.21.91±3.28%in H/SD, P<0.001), increased ratio of JC-1red/green signal (4.78±0.37vs.2.34±0.25, P<0.001), decreased expression of bax(1.06±0.24vs.2.92±0.29, P<0.001) and cytochrome C, and incerased expression of bcl-2(2.59±0.15vs1.14±0.09, P<0.001). Further, TXL upregulated the phosphorylation of AMPK and eNOS. While, treatment with compound C decreased the phosphorylation of AMPK and eNOS and was accompanied by attenuated anti-apoptotic effect of TXL.
Conclusions:TXL protected MSCs against H/SD-induced injury at least in part through the AMPK/eNOS signal pathway, which provides a novel explanation for the multi-effect of TXL on cardiovascular system. And TXL administration may be a useful method to improve MSCs survival for myocardial infarction patients.
方法：实验分为体外实验和体内实验两部分。体外实验部分：分离并培养Sprague-Dawley大鼠MSCs,将第3代细胞随机分为正常对照组、ATV不同浓度梯度组(0.01μM、0.1μM、1μM、10μM)、ATV不同时间梯度组(1h、3h、6h、12h、24h、36h、48h)；机制探讨部分设MSCs组、最适ATV预处理组(ATV-MSCs). MSCs+CXCR4中和抗体组(MSCs-NA)、ATV-MSCs+CXCR4中和抗体组(ATV-MSCs-NA)。流式细胞术和RT-PCR检测各组CXCR4的表达,Transwell小室评估MSCs的迁移能力。体内实验部分：共108只雌性SD大鼠(6-8周龄),随机分为SDF-1动态测定组(AMI30min、1h、12h、24h、48h、72h、5d、7d)、假手术组(Sham)、心梗对照组AMI)、MSCs移植组(MSCs)、ATV预处理MSCs移植组(ATV-MSCs).采用结扎冠状动脉前降支的方法制作急性心肌梗死模型,梗死后24小时经尾静脉注射MSCs或ATV-MSCs(2x106细胞/只),对照组动物注射等体积PBS。在干细胞移植后3天(基线)及30天(终点)分别行心脏超声检测、病理组织学及分子生物学检测。
结果：体外实验表明,与正常对照组相比,ATV剂量依赖性的增加细胞表面CXCR4表达,以1μM ATV处理组最为明显(14.76±3.05%vs.1.98±0.40%,P<0.001)；与正常对照组相比,ATV处理组CXCR4的表达呈一定的时间依赖性,其中ATV处理12小时CXCR4的表达至峰值(22.77±2.03%vs.2.20±0.18%,P<0.001),24小时仍保持在较高水平(20.34±4.13%vs.2.20±0.18%,P<0.001)。CXCR4mRNA的表达趋势与细胞表面CXCR4的表达趋势相似。‘Transwell迁移结果显示,ATV预处理组MSCs向SDF-1迁移的数量是未处理组的2倍左右(24.65±5.57vs.12.70±2.40,P<0.001),然而加入CXCR4的中和抗体后MSCs的迁移能力被抑制。
体内试验发现,干细胞移植后3天,冰冻切片激光共聚焦显微镜下观察到ATV-MSCs组归巢到梗死心肌区域的细胞数明显高于MSCs组(41.68±10.80vs.65.30±13.37,P<0.05),在非梗死区域未发现移植的干细胞；在细胞移植后30天,ATV-MSCs组和MSCs组的存活率都很低,MSCs组的存活率更低。与AMI组相比,MSCs组的左室收缩末期内径和左室射血分数有适度改善。与MSCs组相比,ATV-MSCs组的左室舒张末期内径和左室收缩末期内径进一步减小,左室射血分数(62.28±3.27%vs.52.77±7.05%,P=0.014)和左室短轴缩短率(27.80±2.16%vs.22.27±3.84%,P=0.015)显著改善。组织学分析显示,与AMI组和MSCs组相比,ATV-MSCs组的心肌纤维化面积显著减小,炎细胞浸润明显减轻。Western blot分析显示,细胞移植后3天,ATV-MSCs组IL-6和TNF-α的表达水平明显降低；细胞移植后30天,其表达水平进一步降低。
结论：ATV预处理可以提高MSCs表面CXCR4的表达,进而增强MSCs的迁移和归巢能力,并通过改善梗死心肌中炎性因子的表达,进一步改善心肌梗死后心功能,ATV预处理MSCs可能成为提高干细胞移植疗效的一有效方法。
目的：骨髓来源的间充质干细胞(mesenchymal stem cells,MSCs)是移植治疗急性心肌梗死的理想种子。目前移植的瓶颈问题是移植后的干细胞在心梗后恶劣的微环境大量凋亡,导致其疗效受限。通心络是一种传统中药,在我国广泛应用于心血管疾病的治疗。我们既往的体内研究表明,中药通心络可以增加MSCs的存活,提高干细胞移植疗效,但是通心络在能否减少MSCs的凋亡及其具体机制尚未明确。单磷酸腺苷活化蛋白激酶(AMP-activated protein kinase,AMPK)是调控细胞能量代谢的核心分子,内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)是AMPK下游的重要分子,AMPK/eNOS通路在调节细胞凋亡中发挥重要作用。因此我们在体外建立缺氧无血清(hypoxia and serum deprivation H/SD)模型来模拟心肌梗死后体内缺血缺氧环境,探讨通心络(tongxinluo,TXL)能否减少MSCs的凋亡,并明确AMPK/eNOS通路在其中发挥的作用。
方法：分离并培养Sprague-Dawley大鼠MSCs,将第3代细胞随机分为正常对照组、H/SD对照组、通心络不同浓度梯度组(50μg/mL、100μg/mL、200μg/mL、400μg/mL)、 AMPK通路抑制剂Compound C组(10μM)。在荧光显微镜下观察Hocchst33342染色阳性细胞以及TUNEL染色阳性细胞,Annexin V/PI流式细胞术检测各组细胞的凋亡比例,荧光探针JC-1流式细胞术检测线粒体膜电位的变化,并进一步采用westernblot方法检测凋亡相关蛋白细胞色素C、bax、bcl-2水平及AMPK、eNOS及其磷酸化蛋白的水平。
结果：与正常组相比,H/SD条件下细胞凋亡明显增加Annexin V+/PI-细胞：21.91±3.28%vs.2.13±0.33%,P<0.001；JC-1红/绿色荧光比值：5.40±0.43vs.2.34±0.25,P<0.001)。通心络剂量依赖性的降低MSCs凋亡,在400μg/mL浓度时最为明显,表现为nnexin V+/PI-细胞减少(3.47±0.69%vs.21.91±3.28%, P<0.001), JC-1红/绿色荧光比值增高(4.78±0.37vs.2.34±0.25,P<0.001),促凋亡蛋白bax表达降低(1.06±0.24vs.2.92±0.29,P<0.001),抗凋亡蛋白bcl-2表达增高(2.59±0.15vs.1.14±0.09,P<0.001)。而且,通心络各组AMPK和eNOS的磷酸化水平显著升高。加入AMPK抑制剂Compound C后通心络组AMPK和eNOS的磷酸化水平下降,同时减弱了通心络的抗凋亡作用。
结论：通心络可以抑制缺氧无血清培养条件下诱导的MSCs凋亡,其中AMPK/eNOS通路在其中发挥重要作用。这也为通心络在心血管系统中的多效性提供了新的解释。通心络可能成为提高心肌梗死患者MSCs存活的又一有效方法。
Background:With the development of stem cell regenerative medicine, transplantation of bone morrow-derived mesenchymal stem cells (MSCs) into the infarcted heart after acute myocardial infarction (AMI) has emerged as a promising therapy for myocardial repair. However, poor engraftment of donor MSCs limits reparative capability of the therapy. Mobilization and migration of MSCs are mainly controlled by stromal cell-derived factor1(SDF-1) and its receptor CXC chemokine receptor4(CXCR4). Statins can increase the survival of MSCs. However, whether statins could enhance MSCs migration and engraftment is still unknown. Therefore, we designed the study to investigate whether atorvastatin (ATV) could enhance CXCR4expression of MSCs and promote them homing toward the injured myocardium.
Methods:In vitro, MSCs from the Sprague-Dawley rats bone marrow (60-80g, male) were treated with different concentrations of ATV (0.01μM,0.1μM,1μM,10μM) different ATV culture durations (1h,3h,6h,12h,24h,36h,48h). For inhibitory studies, MSCs were incubated with CXCR4neutralizing antibody. Expression of CXCR4was evaluated using flow cytometry and real time PCR. A transwell system was used to assess MSCs migration. In vivo, female Sprague-Dawley rats were randomized into the following groups:SDF-1dynamic groups (AMI30min,1h,12h,24h,48h,72h,5d,7d), Sham group, AMI group, MSCs group, ATV-pretreated-MSCs group (ATV-MSCs). AMI was created by ligating the left anterior descending coronary artery.24h after AMI,2.0×106CM-Dil-labeled MSCs, CM-Dil-labeled ATV-MSCs, or PBS were injected in a total volume of500μL through the tail vein. Cardiac function, histology, inflammation cytokines were examined at3days and30days after MSCs transplantation.
Results:Cell surface expression of CXCR4assessed by flow cytometry showed that ATV enhanced CXCR4expression in a dose-dependent manner, especially in the1μM ATV group (14.76±3.05%vs.1.98±0.40%, P<0.001). Then the time-course experiments at1μM ATV concentration revealed that, compared with the control group, CXCR4expression was significantly increased with ATV treatment (1to48h), peaking at12h (22.77±2.03%vs.2.20±0.18%, P<0.001) and maintaining at a high level within 24h (20.34±4.13%vs.2.20±0.18%, P<0.001). CXCR4mRNA expression showed the same tendency as the cell surface expression in each group. As expected, MSCs pretreated with ATV showed enhanced migration ability demonstrated by the increased number of cells migrating toward SDF-1compared with untreated MSCs (24.65±5.57vs.12.70±2.40, P<0.001). However, the effect was largely abolished by CXCR4neutralizing antibody, indicating that the benefit was mediated by CXCR4expression.
In AMI model of Sprague-Dawley rats, we found much more ATV-pretreated MSCs homing toward the infarcted myocardium than non-treated cells (41.68±10.80vs.65.30±13.37, P<0.05). In addition, almost no MSCs were detected in the non-infarcted myocardium. At30days after cell injection, the survival rate in both ATV-MSCs and MSCs groups were low, fewer cells can be seen in the MSCs group. Compared with AMI group, left ventricular end-diastolic diameter and left ventricular ejection fraction were slightly improved in MSCs group. Cardiac performance was further improved in ATV-MSCs group than MSCs group, evidenced by increased left ventricular ejection fraction (62.28±3.27%vs.52.77±7.05%, P=0.014) and left ventricular fractional shortening (27.80±2.16%vs.22.27±3.84%, P=0.015). Histology analysis showed that compared with AMI and MSCs groups, the left ventricular fibrotic area was markedly reduced in ATV-MSCs group, and the inflammation was obviously attenuated. Western Blot analysis demonstrated that the expression of inflammation cytokines IL-6and TNF-a were decreased in ATV-MSCs group at3days and30days.
Conclusions:ATV increases MSCs migration ability and improves cardiac performance due to up-regulated expression of CXCR4. These results suggest that ATV pretreatment of donor MSCs is an effective way to promote cell therapeutic potential for AMI.
Background:Bone morrow-derived mesenchymal stem cells (MSCs) are the optimal candidate cells for acute myocardial infarction. However, the poor survival of the implanted cells because of the harsh environment hampered the therapeutic potential of the treatment. Tongxinluo (TXL), a traditional Chinese medicine, is widely used to treat cardiovascular diseases in China. Our previous study has demonstrated the pro-survival role of TXL on mesenchymal stem cells (MSCs) in vivo. But whether TXL could decrease apoptosis of MSCs in vitro and the underlying mechanism are still unknown. Moreover, AMPK/eNOS pathway is crucial in regulating cell apoptosis. Therefore, we designed the study to investigate whether TXL could decrease MSCs apoptosis under hypoxia and serum deprivation (H/SD) conditions and to determine the role of AMPK/eNOS pathway.
Methods:MSCs from the Sprague-Dawley rats bone marrow (60-80g, male) were treated with TXL (50μg/mL,100μg/mL,200μg/mL,400μg/mL) for6h under H/SD conditions. For inhibitor studies, the cells were preincubated with AMPK inhibitor compound C (10μM) prior to the addition of TXL (400μg/mL). Cell apoptosis was assessed using Hocchst33342and TUNEL by Fluorescence microscope, Annexin V/PI by flow cytometry, mitochondrial membrane potential using fluorescent dye JC-1by flow cytometry, and apoptosis related protein cytochrome C, bax and bcl-2by western blot. The expression of AMPK and eNOS were measured by western blot.
Results:Cell apoptosis was significantly upregulated under H/SD conditions compared with the normal (Annexin V+/PI-cells:21.91±3.28%vs.2.13±0.33%, P<0.001; JC-1red/green signal ratio:5.40±0.43vs.2.34±0.25, P<0.001)。TXL decreased the apoptosis level in a dose-dependent manner especially in the400μg/mL group, demonstrated by reduced Annexin V+/PI-cells (3.47±0.69%vs.21.91±3.28%in H/SD, P<0.001), increased ratio of JC-1red/green signal (4.78±0.37vs.2.34±0.25, P<0.001), decreased expression of bax(1.06±0.24vs.2.92±0.29, P<0.001) and cytochrome C, and incerased expression of bcl-2(2.59±0.15vs1.14±0.09, P<0.001). Further, TXL upregulated the phosphorylation of AMPK and eNOS. While, treatment with compound C decreased the phosphorylation of AMPK and eNOS and was accompanied by attenuated anti-apoptotic effect of TXL.
Conclusions:TXL protected MSCs against H/SD-induced injury at least in part through the AMPK/eNOS signal pathway, which provides a novel explanation for the multi-effect of TXL on cardiovascular system. And TXL administration may be a useful method to improve MSCs survival for myocardial infarction patients.
引文
[1]Moran AE, Forouzanfar MH, Roth G, Mensah GA, Ezzati M, Flaxman A, Murray CJ, Naghavi M. The Global Burden of Ischemic Heart Disease in 1990 and 2010: The Global Burden of Disease 2010 Study [J]. Circulation 2014; 129 (14):1493-501.
[2]Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics [J]. Circ Res 2004;95(1):9-20.
[3]Nesselmann C, Ma N, Bieback K, Wagner W, Ho A, Konttinen YT, Zhang H, Hinescu ME, Steinhoff G. Mesenchymal stem cells and cardiac repair [J]. J Cell Mol Med 2008;12(5B):1795-1810.
[4]Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RC. Xenotransplant cardiac chimera:immune tolerance of adult stem cells [J]. Ann Thorac Surg 2002;74(1): 19-24; discussion 24.
[5]Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, Durand DJ, Fitton T, Kuang JQ, Stewart G, Lehrke S, Baumgartner WW, Martin BJ, Heldman AW, Hare JM. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction [J]. Proc Natl Acad Sci U S A 2005;102(32):11474-11479.
[6]Choi SH, Jung SY, Kwon SM, Baek SH. Perspectives on stem cell therapy for cardiac regeneration. Advances and challenges [J]. Circ J 2012;76(6):1307-1312.
[7]Leistner DM, Fischer-Rasokat U, Honold J, Seeger FH, Schachinger V, Lehmann R, Martin H, Burck I, Urbich C, Dimmeler S, Zeiher AM, Assmus B. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI):final 5-year results suggest long-term safety and efficacy [J]. Clin Res Cardiol 2011;100(10):925-934.
[8]Schachinger V, Assmus B, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Yu J, Corti R, Mathey DG, Hamm CW, Tonn T, Dimmeler S, Zeiher AM. Intracoronary infusion of bone marrow-derived mononuclear cells abrogates adverse left ventricular remodelling post-acute myocardial infarction:insights from the reinfusion of enriched progenitor cells and infarct remodelling in acute myocardial infarction (REPAIR-AMI) trial [J]. Eur J Heart Fail 2009;11(10): 973-979.
[9]Meyer GP, Wollert KC, Lotz J, Pirr J, Rager U, Lippolt P, Hahn A, Fichtner S, Schaefer A, Arseniev L, Ganser A, Drexler H. Intracoronary bone marrow cell transfer after myocardial infarction:5-year follow-up from the randomized-controlled BOOST trial [J]. Eur Heart J 2009;30(24):2978-2984.
[10]Beitnes JO, Hopp E, Lunde K, Solheim S, Arnesen H, Brinchmann JE, Forfang K, Aakhus S. Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction:the ASTAMI randomised, controlled study [J]. Heart 2009;95(24):1983-1989.
[11]Clifford DM, Fisher SA, Brunskill SJ, Doree C, Mathur A, Watt S, Martin-Rendon E. Stem cell treatment for acute myocardial infarction [J]. Cochrane Database Syst Rev 2012;2:CD006536.
[12]Delewi R, Andriessen A, Tijssen JG, Zijlstra F, Piek JJ, Hirsch A. Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction:a meta-analysis of randomised controlled clinical trials [J]. Heart 2013;99(4):225-232.
[13]Brunskill SJ, Hyde CJ, Doree CJ, Watt SM, Martin-Rendon E. Route of delivery and baseline left ventricular ejection fraction, key factors of bone-marrow-derived cell therapy for ischaemic heart disease [J]. Eur J Heart Fail 2009; 11(9):887-896.
[14]Qian H, Yang Y, Huang J, Gao R, Dou K, Yang G, Li J, Shen R, He Z, Lu M, Zhao S. Intracoronary delivery of autologous bone marrow mononuclear cells radiolabeled by 18F-fluoro-deoxy-glucose:tissue distribution and impact on post-infarct swine hearts [J]. J Cell Biochem 2007;102(1):64-74.
[15]Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, Ganser A, Knapp WH, Drexler H. Monitoring of bone marrow cell homing into the infarcted human myocardium [J]. Circulation 2005;111(17):2198-2202.
[16]Freyman T, Polin G, Osman H, Crary J, Lu M, Cheng L, Palasis M, Wilensky RL. A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction [J]. Eur Heart J 2006;27(9): 1114-1122.
[17]Wu J, Li J, Zhang N, Zhang C. Stem cell-based therapies in ischemic heart diseases:a focus on aspects of microcirculation and inflammation [J]. Basic Res Cardiol 2011;106(3):317-324.
[18]Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts [J]. Nat Med 2003;9(9):1195-1201.
[19]Zhang Z, Li S, Cui M, Gao X, Sun D, Qin X, Narsinh K, Li C, Jia H, Han Y, Wang H, Cao F. Rosuvastatin enhances the therapeutic efficacy of adipose-derived mesenchymal stem cells for myocardial infarction via PI3K/Akt and MEK/ERK pathways [J]. Basic Res Cardiol 2013;108(2):333.
[20]Wassmann S, Laufs U, Muller K, Konkol C, Ahlbory K, Baumer AT, Linz W, Bohm M, Nickenig G. Cellular antioxidant effects of atorvastatin in vitro and in vivo [J]. Arterioscler Thromb Vasc Biol 2002;22(2):300-305.
[21]Liao JK, Laufs U. Pleiotropic effects of statins [J]. Annu Rev Pharmacol Toxicol 2005;45:89-118.
[22]Yang YJ, Qian HY, Huang J, Geng YJ, Gao RL, Dou KF, Yang GS, Li JJ, Shen R, He ZX, Lu MJ, Zhao SH. Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts [J]. Eur Heart J 2008;29(12):1578-1590.
[23]Yang YJ, Qian HY, Huang J, Li JJ, Gao RL, Dou KF, Yang GS, Willerson JT, Geng YJ. Combined therapy with simvastatin and bone marrow-derived mesenchymal stem cells increases benefits in infarcted swine hearts [J]. Arterioscler Thromb Vasc Biol 2009;29(12):2076-2082.
[24]Dong Q, Yang Y, Song L, Qian H, Xu Z. Atorvastatin prevents mesenchymal stem cells from hypoxia and serum-free injury through activating AMP-activated protein kinase [J]. Int J Cardiol 2011;153(3):311-316.
[25]Xu R, Chen J, Cong X, Hu S, Chen X. Lovastatin protects mesenchymal stem cells against hypoxia-and serum deprivation-induced apoptosis by activation of PI3K/Akt and ERK1/2 [J]. J Cell Biochem 2008;103(1):256-269.
[26]Qian HY, Yang YJ, Huang J, Gao RL, Dou KF, Yang GS, Li JJ, Shen R, He ZX, Lu MJ, Zhao SH. Effects of Tongxinluo-facilitated cellular cardiomyoplasty with autologous bone marrow-mesenchymal stem cells on postinfarct swine hearts [J]. Chin Med J (Engl) 2007;120(16):1416-1425.
[27]Wu T, Harrison RA, Chen X, Ni J, Zhou L, Qiao J, Wang Q, Wei J, Xin D, Zheng J. Tongxinluo (Tong xin luo or Tong-xin-luo) capsule for unstable angina pectoris [J]. Cochrane Database Syst Rev 2006(4):CD004474.
[28]Chen WQ, Zhong L, Zhang L, Ji XP, Zhao YX, Zhang C, Jiang H, Wu YL, Zhang Y. Chinese medicine tongxinluo significantly lowers serum lipid levels and stabilizes vulnerable plaques in a rabbit model [J]. J Ethnopharmacol 2009;124(1):103-110.
[29]Zhang L, Liu Y, Lu XT, Wu YL, Zhang C, Ji XP, Wang R, Liu CX, Feng JB, Jiang H, Xu XS, Zhao YX, Zhang Y. Traditional Chinese medication Tongxinluo dose-dependently enhances stability of vulnerable plaques:a comparison with a high-dose simvastatin therapy [J]. Am J Physiol Heart Circ Physiol 2009;297(6): H2004-2014.
[30]Fukuda K, Yuasa S. Stem cells as a source of regenerative cardiomyocytes [J]. Circ Res 2006;98(8):1002-1013.
[31]Xu X, Zhu F, Zhang M, Zeng D, Luo D, Liu G, Cui W, Wang S, Guo W, Xing W, Liang H, Li L, Fu X, Jiang J, Huang H. Stromal cell-derived factor-1 enhances wound healing through recruiting bone marrow-derived mesenchymal stem cells to the wound area and promoting neovascularization [J]. Cells Tissues Organs 2013;197(2):103-113.
[32]Kitaori T, Ito H, Schwarz EM, Tsutsumi R, Yoshitomi H, Oishi S, Nakano M, Fujii N, Nagasawa T, Nakamura T. Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model [J]. Arthritis Rheum 2009;60(3): 813-823.
[33]Son BR, Marquez-Curtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J, Ratajczak MZ, Janowska-Wieczorek A. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases [J]. Stem Cells 2006;24(5):1254-1264.
[34]Abbott JD, Huang Y, Liu D, Hickey R, Krause DS, Giordano FJ. Stromal cell-derived factor-lalpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury [J]. Circulation 2004; 110(21):3300-3305.
[35]Yang D, Sun S, Wang Z, Zhu P, Yang Z, Zhang B. Stromal cell-derived factor-1 receptor CXCR4-overexpressing bone marrow mesenchymal stem cells accelerate wound healing by migrating into skin injury areas [J]. Cell Reprogram 2013;15(3): 206-215.
[36]Bhakta S, Hong P, Koc O. The surface adhesion molecule CXCR4 stimulates mesenchymal stem cell migration to stromal cell-derived factor-1 in vitro but does not decrease apoptosis under serum deprivation [J]. Cardiovasc Revasc Med 2006;7(1):19-24.
[37]Wynn RF, Hart CA, Corradi-Perini C, O'Neill L, Evans CA, Wraith JE, Fairbairn LJ, Bellantuono I. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow [J]. Blood 2004;104(9):2643-2645.
[38]Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors [J]. Stem Cells 2006;24(4):1030-1041
[39]Xu H, Yang YJ, Qian HY, Tang YD, Wang H, Zhang Q. Rosuvastatin treatment activates JAK-STAT pathway and increases efficacy of allogeneic mesenchymal stem cell transplantation in infarcted hearts [J]. Circ J 2011;75(6):1476-1485.
[40]Song L, Yang YJ, Dong QT, Qian HY, Gao RL, Qiao SB, Shen R, He ZX, Lu MJ, Zhao SH, Geng YJ, Gersh BJ. Atorvastatin enhance efficacy of mesenchymal stem cells treatment for swine myocardial infarction via activation of nitric oxide synthase [J]. PLoS One 2013;8(5):e65702.
[41]Foster LJ, Zeemann PA, Li C, Mann M, Jensen ON, Kassem M. Differential expression profiling of membrane proteins by quantitative proteomics in a human mesenchymal stem cell line undergoing osteoblast differentiation [J]. Stem Cells 2005;23(9):1367-1377.
[42]Deans RJ, Moseley AB. Mesenchymal stem cells:biology and potential clinical uses [J]. Exp Hematol 2000;28(8):875-884.
[43]De Ugarte DA, Alfonso Z, Zuk PA, Elbarbary A, Zhu M, Ashjian P, Benhaim P, Hedrick MH, Fraser JK. Differential expression of stem cell mobilization-associated molecules on multi-lineage cells from adipose tissue and bone marrow [J]. Immunol Lett 2003;89(2-3):267-270.
[44]Zimmet H, Porapakkham P, Sata Y, Haas SJ, Itescu S, Forbes A, Krum H. Short-and long-term outcomes of intracoronary and endogenously mobilized bone marrow stem cells in the treatment of ST-segment elevation myocardial infarction: a meta-analysis of randomized control trials [J]. Eur J Heart Fail 2012; 14(1): 91-105.
[45]Hou D, Youssef EA, Brinton TJ, Zhang P, Rogers P, Price ET, Yeung AC, Johnstone BH, Yock PG, March KL. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery:implications for current clinical trials [J]. Circulation 2005; 112(9 Suppl): 1150-156.
[46]Wollert KC, Drexler H. Clinical applications of stem cells for the heart [J]. Circ Res 2005;96(2):151-163.
[47]Wang T, Tang W, Sun S, Ristagno G, Huang Z, Weil MH. Intravenous infusion of bone marrow mesenchymal stem cells improves myocardial function in a rat model of myocardial ischemia [J]. Crit Care Med 2007;35(11):2587-2593.
[48]Dai W, Hale SL, Martin BJ, Kuang JQ, Dow JS, Wold LE, Kloner RA. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium:short- and long-term effects [J]. Circulation 2005;112(2):214-223.
[49]Perin EC. The use of stem cell therapy for cardiovascular disease [J]. Tex Heart Inst J 2005;32(3):390-392.
[50]Poh KK, Sperry E, Young RG, Freyman T, Barringhaus KG, Thompson CA. Repeated direct endomyocardial transplantation of allogeneic mesenchymal stem cells:safety of a high dose, "off-the-shelf", cellular cardiomyoplasty strategy [J]. Int J Cardiol 2007; 117(3):360-364.
[51]Kraitchman DL, Tatsumi M, Gilson WD, Ishimori T, Kedziorek D, Walczak P, Segars WP, Chen HH, Fritzges D, Izbudak I, Young RG, Marcelino M, Pittenger MF, Solaiyappan M, Boston RC, Tsui BM, Wahl RL, Bulte JW. Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction [J]. Circulation 2005; 112(10):1451-1461.
[52]Price MJ, Chou CC, Frantzen M, Miyamoto T, Kar S, Lee S, Shah PK, Martin BJ, Lill M, Forrester JS, Chen PS, Makkar RR. Intravenous mesenchymal stem cell therapy early after reperfused acute myocardial infarction improves left ventricular function and alters electrophysiologic properties [J]. Int J Cardiol 2006;111(2):231-239.
[53]Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn MS. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy [J]. Lancet 2003;362(9385):697-703.
[54]Ma J, Ge J, Zhang S, Sun A, Shen J, Chen L, Wang K, Zou Y. Time course of myocardial stromal cell-derived factor 1 expression and beneficial effects of intravenously administered bone marrow stem cells in rats with experimental myocardial infarction [J]. Basic Res Cardiol 2005;100(3):217-223.
[55]Ghadge SK, Muhlstedt S, Ozcelik C, Bader M. SDF-lalpha as a therapeutic stem cell homing factor in myocardial infarction [J]. Pharmacol Ther 2011;129(1): 97-108.
[56]Cheng Z, Ou L, Zhou X, Li F, Jia X, Zhang Y, Liu X, Li Y, Ward CA, Melo LG, Kong D. Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance [J]. Mol Ther 2008;16(3):571-579.
[57]Zhang D, Fan GC, Zhou X, Zhao T, Pasha Z, Xu M, Zhu Y, Ashraf M, Wang Y. Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium [J]. J Mol Cell Cardiol 2008;44(2): 281-292.
[58]Xie J, Wang H, Song T, Wang Z, Li F, Ma J, Chen J, Nan Y, Yi H, Wang W. Tanshinone IIA and astragaloside IV promote the migration of mesenchymal stem cells by up-regulation of CXCR4 [J]. Protoplasma 2013;250(2):521-530.
[59]Li RK, Mickle DA, Weisel RD, Rao V, Jia ZQ. Optimal time for cardiomyocyte transplantation to maximize myocardial function after left ventricular injury [J]. Ann Thorac Surg 2001;72(6):1957-1963.
[60]Geng YJ. Molecular mechanisms for cardiovascular stem cell apoptosis and growth in the hearts with atherosclerotic coronary disease and ischemic heart failure [J]. Ann N Y Acad Sci 2003;1010:687-697.
[61]Gao L, Bledsoe G, Yin H, Shen B, Chao L, Chao J. Tissue kallikrein-modified mesenchymal stem cells provide enhanced protection against ischemic cardiac injury after myocardial infarction [J]. Circ J 2013;77(8):2134-2144.
[62]Wang M, Tsai BM, Crisostomo PR, Meldrum DR. Pretreatment with adult progenitor cells improves recovery and decreases native myocardial proinflammatory signaling after ischemia [J]. Shock 2006;25(5):454-459.
[63]Horton JA, Hudak KE, Chung EJ, White AO, Scroggins BT, Burkeen JF, Citrin DE. Mesenchymal stem cells inhibit cutaneous radiation-induced fibrosis by suppressing chronic inflammation [J]. Stem Cells 2013;31(10):2231-2241.
[64]Qiu R, Cai A, Dong Y, Zhou Y, Yu D, Huang Y, Zheng D, Rao S, Feng Y, Mai W. SDF-lalpha upregulation by atorvastatin in rats with acute myocardial infarction via nitric oxide production confers anti-inflammatory and anti-apoptotic effects [J]. J Biomed Sci 2012; 19:99.
[65]Franzoni F, Quinones-Galvan A, Regoli F, Ferrannini E, Galetta F. A comparative study of the in vitro antioxidant activity of statins [J]. Int J Cardiol 2003;90(2-3):317-321.
[66]Barone E, Cenini G, Di Domenico F, Martin S, Sultana R, Mancuso C, Murphy MP, Head E, Butterfield DA. Long-term high-dose atorvastatin decreases brain oxidative and nitrosative stress in a preclinical model of Alzheimer disease:a novel mechanism of action [J]. Pharmacol Res 2011;63(3):172-180.
[67]Nakagomi A, Seino Y, Kohashi K, Kosugi M, Endoh Y, Kusama Y, Atarashi H, Mizuno K. Effects of statin therapy on the production of monocyte pro-inflammatory cytokines, cardiac function, and long-term prognosis in chronic heart failure patients with dyslipidemia [J]. Circ J 2012;76(9):2130-2138.
[68]Zhang Q, Yang YJ, Wang H, Dong QT, Wang TJ, Qian HY, Xu H. Autophagy activation:a novel mechanism of atorvastatin to.protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway [J]. Stem Cells Dev 2012;21(8): 1321-1332.
[69]Du Z, Wei C, Yan J, Han B, Zhang M, Peng C, Liu Y. Mesenchymal stem cells overexpressing C-X-C chemokine receptor type 4 improve early liver regeneration of small-for-size liver grafts [J]. Liver Transpl 2013;19(2):215-225.
[1]Nesselmann C, Ma N, Bieback K, Wagner W, Ho A, Konttinen YT, Zhang H, Hinescu ME, Steinhoff G Mesenchymal stem cells and cardiac repair [J]. J Cell Mol Med 2008;12(5B):1795-1810.
[2]Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RC. Xenotransplant cardiac chimera:immune tolerance of adult stem cells [J]. Ann Thorac Surg 2002;74(1): 19-24; discussion 24.
[3]Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, Durand DJ, Fitton T, Kuang JQ, Stewart G, Lehrke S, Baumgartner WW, Martin BJ, Heldman AW, Hare JM. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction [J]. Proc Natl Acad Sci U S A 2005;102(32):11474-11479.
[4]Choi SH, Jung SY, Kwon SM, Baek SH. Perspectives on stem cell therapy for cardiac regeneration. Advances and challenges [J]. Circ J 2012;76(6):1307-1312.
[5]Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart [J]. Circulation 2002;105(1):93-98.
[6]Gojo S, Gojo N, Takeda Y, Mori T, Abe H, Kyo S, Hata J, Umezawa A. In vivo cardiovasculogenesis by direct injection of isolated adult mesenchymal stem cells [J]. Exp Cell Res 2003;288(1):51-59.
[7]Wu T, Harrison RA, Chen X, Ni J, Zhou L, Qiao J, Wang Q, Wei J, Xin D, Zheng J. Tongxinluo (Tong xin luo or Tong-xin-luo) capsule for unstable angina pectoris [J]. Cochrane Database Syst Rev 2006(4):CD004474.
[8]Chen WQ, Zhong L, Zhang L, Ji XP, Zhao YX, Zhang C, Jiang H, Wu YL, Zhang Y. Chinese medicine tongxinluo significantly lowers serum lipid levels and stabilizes vulnerable plaques in a rabbit model [J]. J Ethnopharmacol 2009; 124(1): 103-110.
[9]Zhang L, Liu Y, Lu XT, Wu YL, Zhang C, Ji XP, Wang R, Liu CX, Feng JB, Jiang H, Xu XS, Zhao YX, Zhang Y Traditional Chinese medication Tongxinluo dose-dependently enhances stability of vulnerable plaques:a comparison with a high-dose simvastatin therapy [J]. Am J Physiol Heart Circ Physiol 2009;297(6): H2004-2014.
[10]Su W, Sun A, Xu D, Zhang H, Yang L, Yuan L, Jia J, Zou Y, Wu Y, Wang K, Ge J. Tongxinluo inhibits oxidized low-density lipoprotein-induced maturation of human dendritic cells via activating peroxisome proliferator-activated receptor gamma pathway [J]. J Cardiovasc Pharmacol 2010;56(2):177-183.
[11]Qian HY, Yang YJ, Huang J, Gao RL, Dou KF, Yang GS, Li JJ, Shen R, He ZX, Lu MJ, Zhao SH. Effects of Tongxinluo-facilitated cellular cardiomyoplasty with autologous bone marrow-mesenchymal stem cells on postinfarct swine hearts [J]. Chin Med J (Engl) 2007;120(16):1416-1425.
[12]McGee SL, Hargreaves M. AMPK and transcriptional regulation [J]. Front Biosci 2008;13:3022-3033.
[13]Villarreal-Molina MT, Antuna-Puente B. Adiponectin:anti-inflammatory and cardioprotective effects [J]. Biochimie 2012;94(10):2143-2149.
[14]Dong Q, Yang Y, Song L, Qian H, Xu Z. Atorvastatin prevents mesenchymal stem cells from hypoxia and serum-free injury through activating AMP-activated protein kinase [J]. Int J Cardiol 2011;153(3):311-316.
[15]Zhang C, Liao Y, Li Q, Chen M, Zhao Q, Deng R, Wu C, Yang A, Guo Z, Wang D, He X. Recombinant adiponectin ameliorates liver ischemia reperfusion injury via activating the AMPK/eNOS pathway [J]. PLoS One 2013;8(6):e66382.
[16]Zhu W, Chen J, Cong X, Hu S, Chen X. Hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells [J]. Stem Cells 2006;24(2):416-425.
[17]Fraser A, Evan G. A license to kill [J]. Cell 1996;85(6):781-784.
[18]Vermes I, Haanen C, Reutelingsperger C. Flow cytometry of apoptotic cell death [J]. J Immunol Methods 2000;243(1-2):167-190.
[19]Fimognari C, Nusse M, Cesari R, Cantelli-Forti'G, Hrelia P. Micronuclei induction, cell cycle delay and apoptosis as markers of cellular stress caused by ursodeoxycholic acid in human lymphocytes [J]. Mutat Res 2001;495(1-2):1-9.
[20]Hirsch T, Marzo I, Kroemer G. Role of the mitochondrial permeability transition pore in apoptosis [J]. Biosci Rep 1997;17(1):67-76.
[21]Cory S, Huang DC, Adams JM. The Bcl-2 family:roles in cell survival and oncogenesis [J]. Oncogene 2003;22(53):8590-8607.
[22]Gustafsson AB, Gottlieb RA. Heart mitochondria:gates of life and death [J]. Cardiovasc Res 2008;77(2):334-343.
[23]Russell RR,3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, Young LH. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury [J]. J Clin Invest 2004;114(4):495-503.
[24]Fukuda K, Yuasa S. Stem cells as a source of regenerative cardiomyocytes [J]. Circ Res 2006,98(8):1002-1013.
[25]Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics [J]. Circ Res 2004;95(1):9-20.
[26]Clifford DM, Fisher SA, Brunskill SJ, Doree C, Mathur A, Watt S, Martin-Rendon E. Stem cell treatment for acute myocardial infarction [J]. Cochrane Database Syst Rev 2012;2:CD006536.
[27]Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts [J]. Nat Med 2003;9(9):1195-1201.
[28]Zhang Z, Li S, Cui M, Gao X, Sun D, Qin X, Narsinh K, Li C, Jia H, Han Y, Wang H, Cao F. Rosuvastatin enhances the therapeutic efficacy of adipose-derived mesenchymal stem cells for myocardial infarction via PI3K/Akt and MEK/ERK pathways [J]. Basic Res Cardiol 2013;108(2):333.
[29]Xu R, Chen J, Cong X, Hu S, Chen X. Lovastatin protects mesenchymal stem cells against hypoxia- and serum deprivation-induced apoptosis by activation of PI3K/Akt and ERK1/2 [J]. J Cell Biochem 2008; 103(1):256-269.
[30]Ghavami S, Hashemi M, Ande SR, Yeganeh B, Xiao W, Eshraghi M, Bus CJ, Kadkhoda K, Wiechec E, Halayko AJ, Los M. Apoptosis and cancer:mutations within caspase genes [J]. J Med Genet 2009;46(8):497-510.
[31]Wikstrom JD, Twig G, Shirihai OS. What can mitochondrial heterogeneity tell us about mitochondrial dynamics and autophagy? [J]. Int J Biochem Cell Biol 2009;41(10):1914-1927.
[32]Lv L, Zhou Z, Huang X, Zhao Y, Zhang L, Shi Y, Sun M, Zhang J. Inhibition of peptidyl-prolyl cis/trans isomerase Pinl induces cell cycle arrest and apoptosis in vascular smooth muscle cells [J]. Apoptosis 2010; 15(1):41-54.
[33]Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins [J]. Genes Dev 2005;19(11):1294-1305.
[34]Antonsson B. Bax and other pro-apoptotic Bcl-2 family "killer-proteins" and their victim the mitochondrion [J]. Cell Tissue Res 2001;306(3):347-361.
[35]Tsujimoto Y, Shimizu S. Bcl-2 family:life-or-death switch [J]. FEBS Lett 2000;466(1):6-10.
[36]Li XD, Yang YJ, Geng YJ, Jin C, Hu FH, Zhao JL, Zhang HT, Cheng YT, Qian HY, Wang LL, Zhang BJ, Wu YL. Tongxinluo reduces myocardial no-reflow and ischemia-reperfusion injury by stimulating the phosphorylation of eNOS via the PKA pathway [J]. Am J Physiol Heart Circ Physiol 2010;299(4):H1255-1261.
[37]Liang JQ, Wu K, Jia ZH, Liu C, Ding J, Huang SN, Yin PP, Wu XC, Wei C, Wu YL, Wang HY Chinese medicine Tongxinluo modulates vascular endothelial function by inducing eNOS expression via the PI-3K/Akt/HIF-dependent signaling pathway [J]. J Ethnopharmacol 2011;133(2):517-523.
[38]Mann JD, Faurot KR, Wilkinson L, Curtis P, Coeytaux RR, Suchindran C, Gay lord SA. Craniosacral therapy for migraine:protocol development for an exploratory controlled clinical trial[J]. BMC Complement Altern Med 2008;8: 28.
[39]Stevens JM. Cytochrome c as an experimental model protein [J]. Metallomics 2011;3(4):319-322.
[40]Gustavsson T, Trane M, Moparthi VK, Miklovyte E, Moparthi L, Gorecki K, Leiding T, Arskold SP, Hagerhall C. A cytochrome c fusion protein domain for convenient detection, quantification, and enhanced production of membrane proteins in Escherichia coli-expression and characterization of cytochrome-tagged Complex I subunits [J]. Protein Sci 2010; 19(8):1445-1460.
[41]Huttemann M, Helling S, Sanderson TH, Sinkler C, Samavati L, Mahapatra G, Varughese A, Lu G, Liu J, Ramzan R, Vogt S, Grossman LI, Doan JW, Marcus K, Lee I. Regulation of mitochondrial respiration and apoptosis through cell signaling:cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation [J]. Biochim Biophys Acta 2012;1817(4):598-609.
[42]Huttemann M, Lee I, Grossman LI, Doan JW, Sanderson TH. Phosphorylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny:'respiration, apoptosis, and human disease [J]. Adv Exp Med Biol 2012;748:237-264.
[43]Huttemann M, Pecina P, Rainbolt M, Sanderson TH, Kagan VE, Samavati L, Doan JW, Lee I. The multiple functions of cytochrome c and their regulation in life and death decisions of the mammalian cell:From respiration to apoptosis [J]. Mitochondrion 2011; 11(3):369-381.
[44]Hardie DG, Scott JW, Pan DA, Hudson ER. Management of cellular energy by the AMP-activated protein kinase system [J]. FEBS Lett 2003;546(1):113-120.
[45]Toyoda T, Hayashi T, Miyamoto L, Yonemitsu S, Nakano M, Tanaka S, Ebihara K, Masuzaki H, Hosoda K, Inoue G, Otaka A, Sato K, Fushiki T, Nakao K. Possible involvement of the alphal isoform of 5'AMP-activated protein kinase in oxidative stress-stimulated glucose transport in skeletal muscle [J]. Am J Physiol Endocrinol Metab 2004;287(1):E166-173.
[46]Emerling BM, Weinberg F, Snyder C, Burgess Z, Mutlu GM, Viollet B, Budinger GR, Chandel NS. Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio [J]. Free Radic Biol Med 2009;46(10):1386-1391.
[47]Li C, Keaney JF, Jr. AMP-activated protein kinase:a stress-responsive kinase with implications for cardiovascular disease [J]. Curr Opin Pharmacol 2010; 10(2): 111-115.
[48]Shen L, Xiong Y, Wang DQ, Howles P, Basford JE, Wang J, Xiong YQ, Hui DY, Woods SC, Liu M. Ginsenoside Rb1 reduces fatty liver by activating AMP-activated protein kinase in obese rats [J]. J Lipid Res 2013;54(5): 1430-1438.
[49]Liu DH, Chen YM, Liu Y, Hao BS, Zhou B, Wu L, Wang M, Chen L, Wu WK, Qian XX. Ginsenoside Rb1 reverses H2O2-induced senescence in human umbilical endothelial cells:involvement of eNOS pathway [J]. J Cardiovasc Pharmacol 2012;59(3):222-230.
[50]Lieberthal W, Zhang L, Patel VA, Levine JS. AMPK protects proximal tubular cells from stress-induced apoptosis by an ATP-independent mechanism:potential role of Akt activation [J]. Am J Physiol Renal Physiol 2011;301(6):F1177-1192.
[51]Salt IP, Morrow VA, Brandie FM, Connell JM, Petrie JR. High glucose inhibits insulin-stimulated nitric oxide production without reducing endothelial nitric-oxide synthase Ser1177 phosphorylation in human aortic endothelial cells [J]. J Biol Chem 2003;278(21):18791-18797.
[52]Boyle JG, Logan PJ, Ewart MA, Reihill JA, Ritchie SA, Connell JM, Cleland SJ, Salt IP. Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase [J]. J Biol Chem 2008;283(17): 11210-11217.
[53]Izumi Y, Shiota M, Kusakabe H, Hikita Y, Nakao T, Nakamura Y, Muro T, Miura K, Yoshiyama M, Iwao H. Pravastatin accelerates ischemia-induced angiogenesis through AMP-activated protein kinase [J]. Hypertens Res 2009;32(8):675-679.
[1]Taghavi S, George JC. Homing of stem cells to ischemic myocardium [J]. Am J Transl Res 2013;5(4):404-411.
[2]Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors [J]. Stem Cells 2006;24(4):1030-1041.
[3]Shi M, Li J, Liao L, Chen B, Li B, Chen L, Jia H, Zhao RC. Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment:role in homing efficiency in NOD/SCID mice [J]. Haematologica 2007;92(7): 897-904.
[4]Freyman T, Polin G, Osman H, Crary J, Lu M, Cheng L, Palasis M, Wilensky RL. A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction [J]. Eur Heart J 2006;27(9): 1114-1122.
[5]Qian H, Yang Y, Huang J, Gao R, Dou K, Yang G, Li J, Shen R, He Z, Lu M, Zhao S. Intracoronary delivery of autologous bone marrow mononuclear cells radiolabeled by 18F-fluoro-deoxy-glucose:tissue distribution and impact on post-infarct swine hearts [J]. J Cell Biochem 2007;102(1):64-74.
[6]Nagaya N, Fujii T, Iwase T, Ohgushi H, Itoh T, Uematsu M, Yamagishi M, Mori H, Kangawa K, Kitamura S. Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis [J]. Am J Physiol Heart Circ Physiol 2004;287(6): H2670-2676.
[7]Li Y, Yu X, Lin S, Li X, Zhang S, Song YH. Insulin-like growth factor 1 enhances the migratory capacity of mesenchymal stem cells [J]. Biochem Biophys Res Commun 2007;356(3):780-784.
[8]Ma J, Ge J, Zhang S, Sun A, Shen J, Chen L, Wang K, Zou Y. Time course of myocardial stromal cell-derived factor 1 expression and beneficial effects of intravenously administered bone marrow stem cells in rats with experimental myocardial infarction [J]. Basic Res Cardiol 2005;100(3):217-223.
[9]Shirozu M, Nakano T, Inazawa J, Tashiro K, Tada H, Shinohara T, Honjo T. Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene [J]. Genomics 1995;28(3):495-500.
[10]Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor:functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor[J]. Science 1996;272(5263):872-877.
[11]Yamaguchi J, Kusano KF, Masuo O, Kawamoto A, Silver M, Murasawa S, Bosch-Marce M, Masuda H, Losordo DW, Isner JM, Asahara T. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization [J]. Circulation 2003; 107(9): 1322-1328.
[12]Cencioni C, Capogrossi MC, Napolitano M. The SDF-1/CXCR4 axis in stem cell preconditioning [J]. Cardiovasc Res 2012;94(3):400-407.
[13]Penn MS, Pastore J, Miller T, Aras R. SDF-1 in myocardial repair [J]. Gene Ther 2012; 19(6):583-587.
[14]Marquez-Curtis LA, Janowska-Wieczorek A. Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis [J]. Biomed Res Int 2013;2013:561098.
[15]Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes [J]. J Biol Chem 2005;280(42):35760-35766.
[16]Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development [J]. J Exp Med 2006;203(9):2201-2213.
[17]Mazzinghi B, Ronconi E, Lazzeri E, Sagrinati C, Ballerini L, Angelotti ML, Parente E, Mancina R, Netti GS, Becherucci F, Gacci M, Carini M, Gesualdo L, Rotondi M, Maggi E, Lasagni L, Serio M, Romagnani S, Romagnani P. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells [J]. J Exp Med 2008;205(2):479-490.
[18]Liu H, Liu S, Li Y, Wang X, Xue W, Ge G, Luo X. The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury [J]. PLoS One 2012;7(4):e34608.
[19]Li Q, Zhang A, Tao C, Li X, Jin P. The role of SDF-1-CXCR4/CXCR7 axis in biological behaviors of adipose tissue-derived mesenchymal stem cells in vitro [J]. Biochem Biophys Res Commun 2013;441(3):675-680.
[20]Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics [J]. Circ Res 2004;95(1):9-20.
[21]Nesselmann C, Ma N, Bieback K, Wagner W, Ho A, Konttinen YT, Zhang H, Hinescu ME, Steinhoff G. Mesenchymal stem cells and cardiac repair [J]. J Cell Mol Med 2008;12(5B):1795-1810.
[22]Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RC. Xenotransplant cardiac chimera:immune tolerance of adult stem cells [J]. Ann Thorac Surg 2002;74(1): 19-24; discussion 24.
[23]Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, Durand DJ, Fitton T, Kuang JQ, Stewart G, Lehrke S, Baumgartner WW, Martin BJ, Heldman AW, Hare JM. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction [J]. Proc Natl Acad Sci U S A 2005;102(32):11474-11479.
[24]Choi SH, Jung SY, Kwon SM, Baek SH. Perspectives on stem cell therapy for cardiac regeneration. Advances and challenges [J]. Circ J 2012;76(6):1307-1312.
[25]Brenner S, Whiting-Theobald N, Kawai T, Linton GF, Rudikoff AG, Choi U, Ryser MF, Murphy PM, Sechler JM, Malech HL. CXCR4-transgene expression significantly improves marrow engraftment of cultured hematopoietic stem cells [J]. Stem Cells 2004;22(7):1128-1133.
[26]Wynn RF, Hart CA, Corradi-Perini C, O'Neill L, Evans CA, Wraith JE, Fairbairn LJ, Bellantuono I. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow [J]. Blood 2004; 104(9):2643-2645.
[27]Son BR, Marquez-Curtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J, Ratajczak MZ, Janowska-Wieczorek A. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases [J]. Stem Cells 2006;24(5):1254-1264.
[28]Karp JM, Leng Teo GS. Mesenchymal stem cell homing:the devil is in the details [J]. Cell Stem Cell 2009;4(3):206-216.
[29]Umemura T, Higashi Y. Endothelial progenitor cells:therapeutic target for cardiovascular diseases [J]. J Pharmacol Sci 2008;108(1):1-6.
[30]Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P. Adult cardiac stem cells are multipotent and support myocardial regeneration [J]. Cell 2003; 114(6):763-776.
[31]Bollini S, Smart N, Riley PR. Resident cardiac progenitor cells:at the heart of regeneration [J]. J Mol Cell Cardiol 2011;50(2):296-303.
[32]Limana F, Capogrossi MC, Germani A. The epicardium in cardiac repair:from the stem cell view [J]. Pharmacol Ther 2011;129(1):82-96.
[33]Itzhaki-Alfia A, Leor J, Raanani E, Sternik L, Spiegelstein D, Netser S, Holbova R, Pevsner-Fischer M, Lavee J, Barbash IM. Patient characteristics and cell source determine the number of isolated human cardiac progenitor cells [J]. Circulation 2009; 120(25):2559-2566.
[34]Zhang H, Wang H, Li N, Duan CE, Yang YJ. Cardiac progenitor/stem cells on myocardial infarction or ischemic heart disease:what we have known from current research [J]. Heart Fail Rev 2014;19(2):247-258.
[35]Kawaguchi N, Smith AJ, Waring CD, Hasan MK, Miyamoto S, Matsuoka R, Ellison GM. c-kitpos GATA-4 high rat cardiac stem cells foster adult cardiomyocyte survival through IGF-1 paracrine signalling [J]. PLoS One 2010;5(12):e14297.
[36]Chugh AR, Beache GM, Loughran JH, Mewton N, Elmore JB, Kajstura J, Pappas P, Tatooles A, Stoddard MF, Lima JA, Slaughter MS, Anversa P, Bolli R. Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial:surgical aspects and interim analysis of myocardial function and viability by magnetic resonance [J]. Circulation 2012;126(11 Suppl 1):S54-64.
[37]Tang JM, Wang JN, Zhang L, Zheng F, Yang JY, Kong X, Guo LY, Chen L, Huang YZ, Wan Y, Chen SY. VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart [J]. Cardiovasc Res 2011;91(3):402-411.
[38]Kucia M, Reca R, Campbell FR, Zuba-Surma E, Majka M, Ratajczak J, Ratajczak MZ. A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+stem cells identified in adult bone marrow [J]. Leukemia 2006;20(5):857-869.
[39]Wojakowski W, Tendera M, Kucia M, Zuba-Surma E, Paczkowska E, Ciosek J, Halasa M, Krol M, Kazmierski M, Buszman P, Ochala A, Ratajczak J, Machalinski B, Ratajczak MZ. Mobilization of bone marrow-derived Oct-4+ SSEA-4+very small embryonic-like stem cells in patients with acute myocardial infarction [J]. J Am Coll Cardiol 2009;53(1):1-9.
[40]Zuba-Surma EK, Kucia M, Dawn B, Guo Y, Ratajczak MZ, Bolli R. Bone marrow-derived pluripotent very small embryonic-like stem cells (VSELs) are mobilized after acute myocardial infarction [J]. J Mol Cell Cardiol 2008;44(5): 865-873.
[41]Wojakowski W, Tendera M, Kucia M, Zuba-Surma E, Milewski K, Wallace-Bradley D, Kazmierski M, Buszman P, Hrycek E, Cybulski W, Kaluza G, Wieczorek P, Ratajczak J, Ratajczak MZ. Cardiomyocyte differentiation of bone marrow-derived Oct-4+CXCR4+SSEA-1+very small embryonic-like stem cells [J]. Int J Oncol 2010;37(2):237-247.
[42]Zhang Q, Yang YJ, Qian HY, Wang H, Xu H. Very small embryonic-like stem cells (VSELs)-a new promising candidate for use in cardiac regeneration [J]. Ageing Res Rev 2011;10(1):173-177.
[43]Kucia M, Wojakowski W, Reca R, Machalinski B, Gozdzik J, Majka M, Baran J, Ratajczak J, Ratajczak MZ. The migration of bone marrow-derived non-hematopoietic tissue-committed stem cells is regulated in an SDF-1-, HGF-, and LIF-dependent manner [J]. Arch Immunol Ther Exp (Warsz) 2006;54(2): 121-135.
[44]Wollert KC, Drexler H. Clinical applications of stem cells for the heart [J]. Circ Res 2005;96(2):151-163.
[45]Wang T, Tang W, Sun S, Ristagno G, Huang Z, Weil MH. Intravenous infusion of bone marrow mesenchymal stem cells improves myocardial function in a rat model of myocardial ischemia [J]. Crit Care Med 2007;35(11):2587-2593.
[46]Dai W, Hale SL, Martin BJ, Kuang JQ, Dow JS, Wold LE, Kloner RA. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium:short- and long-term effects [J]. Circulation 2005; 112(2):214-223.
[47]Perin EC. The use of stem cell therapy for cardiovascular disease [J]. Tex Heart Inst J 2005;32(3):390-392.
[48]Kraitchman DL, Tatsumi M, Gilson WD, Ishimori T, Kedziorek D, Walczak P, Segars WP, Chen HH, Fritzges D, Izbudak I, Young RG, Marcelino M, Pittenger MF, Solaiyappan M, Boston RC, Tsui BM, Wahl RL, Bulte JW. Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction [J]. Circulation 2005;112(10):1451-1461.
[49]Ghadge SK, Muhlstedt S, Ozcelik C, Bader M. SDF-lalpha as a therapeutic stem cell homing factor in myocardial infarction [J]. Pharmacol Ther 2011;129(1): 97-108.
[50]Kollet O, Petit I, Kahn J, Samira S, Dar A, Peled A, Deutsch V, Gunetti M, Piacibello W, Nagler A, Lapidot T. Human CD34(+)CXCR4(-) sorted cells harbor intracellular CXCR4, which can be functionally expressed and provide NOD/SCID repopulation [J]. Blood 2002;100(8):2778-2786.
[51]Chen Y, Teng X, Chen W, Yang J, Yang Z, Yu Y, Shen Z. Timing of transplantation of autologous bone marrow derived mesenchymal stem cells for treating myocardial infarction [J]. Sci China Life Sci 2014;57(2):195-200.
[52]Kucia M, Dawn B, Hunt G, Guo Y, Wysoczynski M, Majka M, Ratajczak J, Rezzoug F, Ildstad ST, Bolli R, Ratajczak MZ. Cells expressing early cardiac markers reside in the bone marrow and are mobilized into the peripheral blood after myocardial infarction [J]. Circ Res 2004;95(12):1191-1199.
[53]Abbott JD, Huang Y, Liu D, Hickey R, Krause DS, Giordano FJ. Stromal cell-derived factor-lalpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury [J]. Circulation 2004; 110(21):3300-3305.
[54]Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn MS. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy [J]. Lancet 2003;362(9385):697-703.
[55]Zhang S, Sun A, Xu D, Yao K, Huang Z, Jin H, Wang K, Zou Y, Ge J. Impact of timing on efficacy and safetyof intracoronary autologous bone marrow stem cells transplantation in acute myocardial infarction:a pooled subgroup analysis of randomized controlled trials [J]. Clin Cardiol 2009;32(8):458-466.
[56]Elmadbouh I, Haider H, Jiang S, Idris NM, Lu G, Ashraf M. Ex vivo delivered stromal cell-derived factor-lalpha promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium [J]. J Mol Cell Cardiol 2007;42(4): 792-803.
[57]Fujii H, Li SH, Wu J, Miyagi Y, Yau TM, Rakowski H, Egashira K, Guo J, Weisel RD, Li RK. Repeated and targeted transfer of angiogenic plasmids into the infarcted rat heart via ultrasound targeted microbubble destruction enhances cardiac repair [J]. Eur Heart J 2011;32(16):2075-2084.
[58]Segers VF, Tokunou T, Higgins LJ, MacGillivray C, Gannon J, Lee RT. Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction [J]. Circulation 2007; 116(15):1683-1692.
[59]MacArthur JW, Jr., Purcell BP, Shudo Y, Cohen JE, Fairman A, Trubelja A, Patel J, Hsiao P, Yang E, Lloyd K, Hiesinger W, Atluri P, Burdick JA, Woo YJ. Sustained release of engineered stromal cell-derived factor 1-alpha from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction [J]. Circulation 2013;128(11 Suppl 1):S79-86.
[60]Qiu R, Cai A, Dong Y, Zhou Y, Yu D, Huang Y, Zheng D, Rao S, Feng Y, Mai W. SDF-lalpha upregulation by atorvastatin in rats with acute myocardial infarction via nitric oxide production confers anti-inflammatory and anti-apoptotic effects [J]. J Biomed Sci 2012;19:99.
[61]Wang H, Yang YJ, Qian HY, Zhang Q, Gao LJ, Li P, Wang TJ, Wang SD. Statin administration does not improve the mobilization of very small embryonic-like stem cells (VSELs) in contrast to resveratrol treatment in a murine model of acute myocardial infarction [J]. Physiol Res 2012;61(5):543-549.
[62]Bongers J, Lambros T, Ahmad M, Heimer EP. Kinetics of dipeptidyl peptidase IV proteolysis of growth hormone-releasing factor and analogs [J]. Biochim Biophys Acta 1992;1122(2):147-153.
[63]Huber BC, Brunner S, Segeth A, Nathan P, Fischer R, Zaruba MM, Vallaster M, Theiss HD, David R, Gerbitz A, Franz WM. Parathyroid hormone is a DPP-IV inhibitor and increases SDF-1-driven homing of CXCR4(+) stem cells into the ischaemic heart [J]. Cardiovasc Res 2011;90(3):529-537.
[64]Zaruba MM, Theiss HD, Vallaster M, Mehl U, Brunner S, David R, Fischer R, Krieg L, Hirsch E, Huber B, Nathan P, Israel L, Imhof A, Herbach N, Assmann G, Wanke R, Mueller-Hoecker J, Steinbeck G, Franz WM. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction [J]. Cell Stem Cell 2009;4(4):313-323.
[65]Fadini GP, Boscaro E, Albiero M, Menegazzo L, Prison V, de Kreutzenberg S, Agostini C, Tiengo A, Avogaro A. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes:possible role of stromal-derived factor-lalpha [J]. Diabetes Care 2010;33(7):1607-1609.
[66]Cheng Z, Ou L, Zhou X, Li F, Jia X, Zhang Y, Liu X, Li Y, Ward CA, Melo LG, Kong D. Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance [J]. Mol Ther 2008;16(3):571-579.
[67]Zhang D, Fan GC, Zhou X, Zhao T, Pasha Z, Xu M, Zhu Y, Ashraf M, Wang Y. Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium [J]. J Mol Cell Cardiol 2008;44(2): 281-292.
[68]Bhakta S, Hong P, Koc O. The surface adhesion molecule CXCR4 stimulates mesenchymal stem cell migration to stromal cell-derived factor-1 in vitro but does not decrease apoptosis under serum deprivation [J]. Cardiovasc Revasc Med 2006;7(1):19-24.
[69]Tang YL, Zhu W, Cheng M, Chen L, Zhang J, Sun T, Kishore R, Phillips MI, Losordo DW, Qin G. Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression [J]. Circ Res 2009;104(10):1209-1216.
[70]Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T, Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipo'ri D, Lapidot T. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4 [J]. Nat Immunol 2002;3(7):687-694.
[71]Xie J, Wang H, Song T, Wang Z, Li F, Ma J, Chen J, Nan Y, Yi H, Wang W. Tanshinone IIA and astragaloside IV promote the migration of mesenchymal stem cells by up-regulation of CXCR4 [J]. Protoplasma 2013;250(2):521-530.
[72]Rolland-Turner M, Goretti E, Bousquenaud M, Leonard F, Nicolas C, Zhang L,
Maskali F, Marie PY, Devaux Y, Wagner D. Adenosine stimulates the migration of human endothelial progenitor cells. Role of CXCR4 and microRNA-150 [J]. PLoS One 2013;8(1):e54135.
[2]Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics [J]. Circ Res 2004;95(1):9-20.
[3]Nesselmann C, Ma N, Bieback K, Wagner W, Ho A, Konttinen YT, Zhang H, Hinescu ME, Steinhoff G. Mesenchymal stem cells and cardiac repair [J]. J Cell Mol Med 2008;12(5B):1795-1810.
[4]Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RC. Xenotransplant cardiac chimera:immune tolerance of adult stem cells [J]. Ann Thorac Surg 2002;74(1): 19-24; discussion 24.
[5]Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, Durand DJ, Fitton T, Kuang JQ, Stewart G, Lehrke S, Baumgartner WW, Martin BJ, Heldman AW, Hare JM. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction [J]. Proc Natl Acad Sci U S A 2005;102(32):11474-11479.
[6]Choi SH, Jung SY, Kwon SM, Baek SH. Perspectives on stem cell therapy for cardiac regeneration. Advances and challenges [J]. Circ J 2012;76(6):1307-1312.
[7]Leistner DM, Fischer-Rasokat U, Honold J, Seeger FH, Schachinger V, Lehmann R, Martin H, Burck I, Urbich C, Dimmeler S, Zeiher AM, Assmus B. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI):final 5-year results suggest long-term safety and efficacy [J]. Clin Res Cardiol 2011;100(10):925-934.
[8]Schachinger V, Assmus B, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Yu J, Corti R, Mathey DG, Hamm CW, Tonn T, Dimmeler S, Zeiher AM. Intracoronary infusion of bone marrow-derived mononuclear cells abrogates adverse left ventricular remodelling post-acute myocardial infarction:insights from the reinfusion of enriched progenitor cells and infarct remodelling in acute myocardial infarction (REPAIR-AMI) trial [J]. Eur J Heart Fail 2009;11(10): 973-979.
[9]Meyer GP, Wollert KC, Lotz J, Pirr J, Rager U, Lippolt P, Hahn A, Fichtner S, Schaefer A, Arseniev L, Ganser A, Drexler H. Intracoronary bone marrow cell transfer after myocardial infarction:5-year follow-up from the randomized-controlled BOOST trial [J]. Eur Heart J 2009;30(24):2978-2984.
[10]Beitnes JO, Hopp E, Lunde K, Solheim S, Arnesen H, Brinchmann JE, Forfang K, Aakhus S. Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction:the ASTAMI randomised, controlled study [J]. Heart 2009;95(24):1983-1989.
[11]Clifford DM, Fisher SA, Brunskill SJ, Doree C, Mathur A, Watt S, Martin-Rendon E. Stem cell treatment for acute myocardial infarction [J]. Cochrane Database Syst Rev 2012;2:CD006536.
[12]Delewi R, Andriessen A, Tijssen JG, Zijlstra F, Piek JJ, Hirsch A. Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction:a meta-analysis of randomised controlled clinical trials [J]. Heart 2013;99(4):225-232.
[13]Brunskill SJ, Hyde CJ, Doree CJ, Watt SM, Martin-Rendon E. Route of delivery and baseline left ventricular ejection fraction, key factors of bone-marrow-derived cell therapy for ischaemic heart disease [J]. Eur J Heart Fail 2009; 11(9):887-896.
[14]Qian H, Yang Y, Huang J, Gao R, Dou K, Yang G, Li J, Shen R, He Z, Lu M, Zhao S. Intracoronary delivery of autologous bone marrow mononuclear cells radiolabeled by 18F-fluoro-deoxy-glucose:tissue distribution and impact on post-infarct swine hearts [J]. J Cell Biochem 2007;102(1):64-74.
[15]Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, Ganser A, Knapp WH, Drexler H. Monitoring of bone marrow cell homing into the infarcted human myocardium [J]. Circulation 2005;111(17):2198-2202.
[16]Freyman T, Polin G, Osman H, Crary J, Lu M, Cheng L, Palasis M, Wilensky RL. A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction [J]. Eur Heart J 2006;27(9): 1114-1122.
[17]Wu J, Li J, Zhang N, Zhang C. Stem cell-based therapies in ischemic heart diseases:a focus on aspects of microcirculation and inflammation [J]. Basic Res Cardiol 2011;106(3):317-324.
[18]Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts [J]. Nat Med 2003;9(9):1195-1201.
[19]Zhang Z, Li S, Cui M, Gao X, Sun D, Qin X, Narsinh K, Li C, Jia H, Han Y, Wang H, Cao F. Rosuvastatin enhances the therapeutic efficacy of adipose-derived mesenchymal stem cells for myocardial infarction via PI3K/Akt and MEK/ERK pathways [J]. Basic Res Cardiol 2013;108(2):333.
[20]Wassmann S, Laufs U, Muller K, Konkol C, Ahlbory K, Baumer AT, Linz W, Bohm M, Nickenig G. Cellular antioxidant effects of atorvastatin in vitro and in vivo [J]. Arterioscler Thromb Vasc Biol 2002;22(2):300-305.
[21]Liao JK, Laufs U. Pleiotropic effects of statins [J]. Annu Rev Pharmacol Toxicol 2005;45:89-118.
[22]Yang YJ, Qian HY, Huang J, Geng YJ, Gao RL, Dou KF, Yang GS, Li JJ, Shen R, He ZX, Lu MJ, Zhao SH. Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts [J]. Eur Heart J 2008;29(12):1578-1590.
[23]Yang YJ, Qian HY, Huang J, Li JJ, Gao RL, Dou KF, Yang GS, Willerson JT, Geng YJ. Combined therapy with simvastatin and bone marrow-derived mesenchymal stem cells increases benefits in infarcted swine hearts [J]. Arterioscler Thromb Vasc Biol 2009;29(12):2076-2082.
[24]Dong Q, Yang Y, Song L, Qian H, Xu Z. Atorvastatin prevents mesenchymal stem cells from hypoxia and serum-free injury through activating AMP-activated protein kinase [J]. Int J Cardiol 2011;153(3):311-316.
[25]Xu R, Chen J, Cong X, Hu S, Chen X. Lovastatin protects mesenchymal stem cells against hypoxia-and serum deprivation-induced apoptosis by activation of PI3K/Akt and ERK1/2 [J]. J Cell Biochem 2008;103(1):256-269.
[26]Qian HY, Yang YJ, Huang J, Gao RL, Dou KF, Yang GS, Li JJ, Shen R, He ZX, Lu MJ, Zhao SH. Effects of Tongxinluo-facilitated cellular cardiomyoplasty with autologous bone marrow-mesenchymal stem cells on postinfarct swine hearts [J]. Chin Med J (Engl) 2007;120(16):1416-1425.
[27]Wu T, Harrison RA, Chen X, Ni J, Zhou L, Qiao J, Wang Q, Wei J, Xin D, Zheng J. Tongxinluo (Tong xin luo or Tong-xin-luo) capsule for unstable angina pectoris [J]. Cochrane Database Syst Rev 2006(4):CD004474.
[28]Chen WQ, Zhong L, Zhang L, Ji XP, Zhao YX, Zhang C, Jiang H, Wu YL, Zhang Y. Chinese medicine tongxinluo significantly lowers serum lipid levels and stabilizes vulnerable plaques in a rabbit model [J]. J Ethnopharmacol 2009;124(1):103-110.
[29]Zhang L, Liu Y, Lu XT, Wu YL, Zhang C, Ji XP, Wang R, Liu CX, Feng JB, Jiang H, Xu XS, Zhao YX, Zhang Y. Traditional Chinese medication Tongxinluo dose-dependently enhances stability of vulnerable plaques:a comparison with a high-dose simvastatin therapy [J]. Am J Physiol Heart Circ Physiol 2009;297(6): H2004-2014.
[30]Fukuda K, Yuasa S. Stem cells as a source of regenerative cardiomyocytes [J]. Circ Res 2006;98(8):1002-1013.
[31]Xu X, Zhu F, Zhang M, Zeng D, Luo D, Liu G, Cui W, Wang S, Guo W, Xing W, Liang H, Li L, Fu X, Jiang J, Huang H. Stromal cell-derived factor-1 enhances wound healing through recruiting bone marrow-derived mesenchymal stem cells to the wound area and promoting neovascularization [J]. Cells Tissues Organs 2013;197(2):103-113.
[32]Kitaori T, Ito H, Schwarz EM, Tsutsumi R, Yoshitomi H, Oishi S, Nakano M, Fujii N, Nagasawa T, Nakamura T. Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model [J]. Arthritis Rheum 2009;60(3): 813-823.
[33]Son BR, Marquez-Curtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J, Ratajczak MZ, Janowska-Wieczorek A. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases [J]. Stem Cells 2006;24(5):1254-1264.
[34]Abbott JD, Huang Y, Liu D, Hickey R, Krause DS, Giordano FJ. Stromal cell-derived factor-lalpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury [J]. Circulation 2004; 110(21):3300-3305.
[35]Yang D, Sun S, Wang Z, Zhu P, Yang Z, Zhang B. Stromal cell-derived factor-1 receptor CXCR4-overexpressing bone marrow mesenchymal stem cells accelerate wound healing by migrating into skin injury areas [J]. Cell Reprogram 2013;15(3): 206-215.
[36]Bhakta S, Hong P, Koc O. The surface adhesion molecule CXCR4 stimulates mesenchymal stem cell migration to stromal cell-derived factor-1 in vitro but does not decrease apoptosis under serum deprivation [J]. Cardiovasc Revasc Med 2006;7(1):19-24.
[37]Wynn RF, Hart CA, Corradi-Perini C, O'Neill L, Evans CA, Wraith JE, Fairbairn LJ, Bellantuono I. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow [J]. Blood 2004;104(9):2643-2645.
[38]Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors [J]. Stem Cells 2006;24(4):1030-1041
[39]Xu H, Yang YJ, Qian HY, Tang YD, Wang H, Zhang Q. Rosuvastatin treatment activates JAK-STAT pathway and increases efficacy of allogeneic mesenchymal stem cell transplantation in infarcted hearts [J]. Circ J 2011;75(6):1476-1485.
[40]Song L, Yang YJ, Dong QT, Qian HY, Gao RL, Qiao SB, Shen R, He ZX, Lu MJ, Zhao SH, Geng YJ, Gersh BJ. Atorvastatin enhance efficacy of mesenchymal stem cells treatment for swine myocardial infarction via activation of nitric oxide synthase [J]. PLoS One 2013;8(5):e65702.
[41]Foster LJ, Zeemann PA, Li C, Mann M, Jensen ON, Kassem M. Differential expression profiling of membrane proteins by quantitative proteomics in a human mesenchymal stem cell line undergoing osteoblast differentiation [J]. Stem Cells 2005;23(9):1367-1377.
[42]Deans RJ, Moseley AB. Mesenchymal stem cells:biology and potential clinical uses [J]. Exp Hematol 2000;28(8):875-884.
[43]De Ugarte DA, Alfonso Z, Zuk PA, Elbarbary A, Zhu M, Ashjian P, Benhaim P, Hedrick MH, Fraser JK. Differential expression of stem cell mobilization-associated molecules on multi-lineage cells from adipose tissue and bone marrow [J]. Immunol Lett 2003;89(2-3):267-270.
[44]Zimmet H, Porapakkham P, Sata Y, Haas SJ, Itescu S, Forbes A, Krum H. Short-and long-term outcomes of intracoronary and endogenously mobilized bone marrow stem cells in the treatment of ST-segment elevation myocardial infarction: a meta-analysis of randomized control trials [J]. Eur J Heart Fail 2012; 14(1): 91-105.
[45]Hou D, Youssef EA, Brinton TJ, Zhang P, Rogers P, Price ET, Yeung AC, Johnstone BH, Yock PG, March KL. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery:implications for current clinical trials [J]. Circulation 2005; 112(9 Suppl): 1150-156.
[46]Wollert KC, Drexler H. Clinical applications of stem cells for the heart [J]. Circ Res 2005;96(2):151-163.
[47]Wang T, Tang W, Sun S, Ristagno G, Huang Z, Weil MH. Intravenous infusion of bone marrow mesenchymal stem cells improves myocardial function in a rat model of myocardial ischemia [J]. Crit Care Med 2007;35(11):2587-2593.
[48]Dai W, Hale SL, Martin BJ, Kuang JQ, Dow JS, Wold LE, Kloner RA. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium:short- and long-term effects [J]. Circulation 2005;112(2):214-223.
[49]Perin EC. The use of stem cell therapy for cardiovascular disease [J]. Tex Heart Inst J 2005;32(3):390-392.
[50]Poh KK, Sperry E, Young RG, Freyman T, Barringhaus KG, Thompson CA. Repeated direct endomyocardial transplantation of allogeneic mesenchymal stem cells:safety of a high dose, "off-the-shelf", cellular cardiomyoplasty strategy [J]. Int J Cardiol 2007; 117(3):360-364.
[51]Kraitchman DL, Tatsumi M, Gilson WD, Ishimori T, Kedziorek D, Walczak P, Segars WP, Chen HH, Fritzges D, Izbudak I, Young RG, Marcelino M, Pittenger MF, Solaiyappan M, Boston RC, Tsui BM, Wahl RL, Bulte JW. Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction [J]. Circulation 2005; 112(10):1451-1461.
[52]Price MJ, Chou CC, Frantzen M, Miyamoto T, Kar S, Lee S, Shah PK, Martin BJ, Lill M, Forrester JS, Chen PS, Makkar RR. Intravenous mesenchymal stem cell therapy early after reperfused acute myocardial infarction improves left ventricular function and alters electrophysiologic properties [J]. Int J Cardiol 2006;111(2):231-239.
[53]Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn MS. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy [J]. Lancet 2003;362(9385):697-703.
[54]Ma J, Ge J, Zhang S, Sun A, Shen J, Chen L, Wang K, Zou Y. Time course of myocardial stromal cell-derived factor 1 expression and beneficial effects of intravenously administered bone marrow stem cells in rats with experimental myocardial infarction [J]. Basic Res Cardiol 2005;100(3):217-223.
[55]Ghadge SK, Muhlstedt S, Ozcelik C, Bader M. SDF-lalpha as a therapeutic stem cell homing factor in myocardial infarction [J]. Pharmacol Ther 2011;129(1): 97-108.
[56]Cheng Z, Ou L, Zhou X, Li F, Jia X, Zhang Y, Liu X, Li Y, Ward CA, Melo LG, Kong D. Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance [J]. Mol Ther 2008;16(3):571-579.
[57]Zhang D, Fan GC, Zhou X, Zhao T, Pasha Z, Xu M, Zhu Y, Ashraf M, Wang Y. Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium [J]. J Mol Cell Cardiol 2008;44(2): 281-292.
[58]Xie J, Wang H, Song T, Wang Z, Li F, Ma J, Chen J, Nan Y, Yi H, Wang W. Tanshinone IIA and astragaloside IV promote the migration of mesenchymal stem cells by up-regulation of CXCR4 [J]. Protoplasma 2013;250(2):521-530.
[59]Li RK, Mickle DA, Weisel RD, Rao V, Jia ZQ. Optimal time for cardiomyocyte transplantation to maximize myocardial function after left ventricular injury [J]. Ann Thorac Surg 2001;72(6):1957-1963.
[60]Geng YJ. Molecular mechanisms for cardiovascular stem cell apoptosis and growth in the hearts with atherosclerotic coronary disease and ischemic heart failure [J]. Ann N Y Acad Sci 2003;1010:687-697.
[61]Gao L, Bledsoe G, Yin H, Shen B, Chao L, Chao J. Tissue kallikrein-modified mesenchymal stem cells provide enhanced protection against ischemic cardiac injury after myocardial infarction [J]. Circ J 2013;77(8):2134-2144.
[62]Wang M, Tsai BM, Crisostomo PR, Meldrum DR. Pretreatment with adult progenitor cells improves recovery and decreases native myocardial proinflammatory signaling after ischemia [J]. Shock 2006;25(5):454-459.
[63]Horton JA, Hudak KE, Chung EJ, White AO, Scroggins BT, Burkeen JF, Citrin DE. Mesenchymal stem cells inhibit cutaneous radiation-induced fibrosis by suppressing chronic inflammation [J]. Stem Cells 2013;31(10):2231-2241.
[64]Qiu R, Cai A, Dong Y, Zhou Y, Yu D, Huang Y, Zheng D, Rao S, Feng Y, Mai W. SDF-lalpha upregulation by atorvastatin in rats with acute myocardial infarction via nitric oxide production confers anti-inflammatory and anti-apoptotic effects [J]. J Biomed Sci 2012; 19:99.
[65]Franzoni F, Quinones-Galvan A, Regoli F, Ferrannini E, Galetta F. A comparative study of the in vitro antioxidant activity of statins [J]. Int J Cardiol 2003;90(2-3):317-321.
[66]Barone E, Cenini G, Di Domenico F, Martin S, Sultana R, Mancuso C, Murphy MP, Head E, Butterfield DA. Long-term high-dose atorvastatin decreases brain oxidative and nitrosative stress in a preclinical model of Alzheimer disease:a novel mechanism of action [J]. Pharmacol Res 2011;63(3):172-180.
[67]Nakagomi A, Seino Y, Kohashi K, Kosugi M, Endoh Y, Kusama Y, Atarashi H, Mizuno K. Effects of statin therapy on the production of monocyte pro-inflammatory cytokines, cardiac function, and long-term prognosis in chronic heart failure patients with dyslipidemia [J]. Circ J 2012;76(9):2130-2138.
[68]Zhang Q, Yang YJ, Wang H, Dong QT, Wang TJ, Qian HY, Xu H. Autophagy activation:a novel mechanism of atorvastatin to.protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway [J]. Stem Cells Dev 2012;21(8): 1321-1332.
[69]Du Z, Wei C, Yan J, Han B, Zhang M, Peng C, Liu Y. Mesenchymal stem cells overexpressing C-X-C chemokine receptor type 4 improve early liver regeneration of small-for-size liver grafts [J]. Liver Transpl 2013;19(2):215-225.
[1]Nesselmann C, Ma N, Bieback K, Wagner W, Ho A, Konttinen YT, Zhang H, Hinescu ME, Steinhoff G Mesenchymal stem cells and cardiac repair [J]. J Cell Mol Med 2008;12(5B):1795-1810.
[2]Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RC. Xenotransplant cardiac chimera:immune tolerance of adult stem cells [J]. Ann Thorac Surg 2002;74(1): 19-24; discussion 24.
[3]Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, Durand DJ, Fitton T, Kuang JQ, Stewart G, Lehrke S, Baumgartner WW, Martin BJ, Heldman AW, Hare JM. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction [J]. Proc Natl Acad Sci U S A 2005;102(32):11474-11479.
[4]Choi SH, Jung SY, Kwon SM, Baek SH. Perspectives on stem cell therapy for cardiac regeneration. Advances and challenges [J]. Circ J 2012;76(6):1307-1312.
[5]Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart [J]. Circulation 2002;105(1):93-98.
[6]Gojo S, Gojo N, Takeda Y, Mori T, Abe H, Kyo S, Hata J, Umezawa A. In vivo cardiovasculogenesis by direct injection of isolated adult mesenchymal stem cells [J]. Exp Cell Res 2003;288(1):51-59.
[7]Wu T, Harrison RA, Chen X, Ni J, Zhou L, Qiao J, Wang Q, Wei J, Xin D, Zheng J. Tongxinluo (Tong xin luo or Tong-xin-luo) capsule for unstable angina pectoris [J]. Cochrane Database Syst Rev 2006(4):CD004474.
[8]Chen WQ, Zhong L, Zhang L, Ji XP, Zhao YX, Zhang C, Jiang H, Wu YL, Zhang Y. Chinese medicine tongxinluo significantly lowers serum lipid levels and stabilizes vulnerable plaques in a rabbit model [J]. J Ethnopharmacol 2009; 124(1): 103-110.
[9]Zhang L, Liu Y, Lu XT, Wu YL, Zhang C, Ji XP, Wang R, Liu CX, Feng JB, Jiang H, Xu XS, Zhao YX, Zhang Y Traditional Chinese medication Tongxinluo dose-dependently enhances stability of vulnerable plaques:a comparison with a high-dose simvastatin therapy [J]. Am J Physiol Heart Circ Physiol 2009;297(6): H2004-2014.
[10]Su W, Sun A, Xu D, Zhang H, Yang L, Yuan L, Jia J, Zou Y, Wu Y, Wang K, Ge J. Tongxinluo inhibits oxidized low-density lipoprotein-induced maturation of human dendritic cells via activating peroxisome proliferator-activated receptor gamma pathway [J]. J Cardiovasc Pharmacol 2010;56(2):177-183.
[11]Qian HY, Yang YJ, Huang J, Gao RL, Dou KF, Yang GS, Li JJ, Shen R, He ZX, Lu MJ, Zhao SH. Effects of Tongxinluo-facilitated cellular cardiomyoplasty with autologous bone marrow-mesenchymal stem cells on postinfarct swine hearts [J]. Chin Med J (Engl) 2007;120(16):1416-1425.
[12]McGee SL, Hargreaves M. AMPK and transcriptional regulation [J]. Front Biosci 2008;13:3022-3033.
[13]Villarreal-Molina MT, Antuna-Puente B. Adiponectin:anti-inflammatory and cardioprotective effects [J]. Biochimie 2012;94(10):2143-2149.
[14]Dong Q, Yang Y, Song L, Qian H, Xu Z. Atorvastatin prevents mesenchymal stem cells from hypoxia and serum-free injury through activating AMP-activated protein kinase [J]. Int J Cardiol 2011;153(3):311-316.
[15]Zhang C, Liao Y, Li Q, Chen M, Zhao Q, Deng R, Wu C, Yang A, Guo Z, Wang D, He X. Recombinant adiponectin ameliorates liver ischemia reperfusion injury via activating the AMPK/eNOS pathway [J]. PLoS One 2013;8(6):e66382.
[16]Zhu W, Chen J, Cong X, Hu S, Chen X. Hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells [J]. Stem Cells 2006;24(2):416-425.
[17]Fraser A, Evan G. A license to kill [J]. Cell 1996;85(6):781-784.
[18]Vermes I, Haanen C, Reutelingsperger C. Flow cytometry of apoptotic cell death [J]. J Immunol Methods 2000;243(1-2):167-190.
[19]Fimognari C, Nusse M, Cesari R, Cantelli-Forti'G, Hrelia P. Micronuclei induction, cell cycle delay and apoptosis as markers of cellular stress caused by ursodeoxycholic acid in human lymphocytes [J]. Mutat Res 2001;495(1-2):1-9.
[20]Hirsch T, Marzo I, Kroemer G. Role of the mitochondrial permeability transition pore in apoptosis [J]. Biosci Rep 1997;17(1):67-76.
[21]Cory S, Huang DC, Adams JM. The Bcl-2 family:roles in cell survival and oncogenesis [J]. Oncogene 2003;22(53):8590-8607.
[22]Gustafsson AB, Gottlieb RA. Heart mitochondria:gates of life and death [J]. Cardiovasc Res 2008;77(2):334-343.
[23]Russell RR,3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, Young LH. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury [J]. J Clin Invest 2004;114(4):495-503.
[24]Fukuda K, Yuasa S. Stem cells as a source of regenerative cardiomyocytes [J]. Circ Res 2006,98(8):1002-1013.
[25]Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics [J]. Circ Res 2004;95(1):9-20.
[26]Clifford DM, Fisher SA, Brunskill SJ, Doree C, Mathur A, Watt S, Martin-Rendon E. Stem cell treatment for acute myocardial infarction [J]. Cochrane Database Syst Rev 2012;2:CD006536.
[27]Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts [J]. Nat Med 2003;9(9):1195-1201.
[28]Zhang Z, Li S, Cui M, Gao X, Sun D, Qin X, Narsinh K, Li C, Jia H, Han Y, Wang H, Cao F. Rosuvastatin enhances the therapeutic efficacy of adipose-derived mesenchymal stem cells for myocardial infarction via PI3K/Akt and MEK/ERK pathways [J]. Basic Res Cardiol 2013;108(2):333.
[29]Xu R, Chen J, Cong X, Hu S, Chen X. Lovastatin protects mesenchymal stem cells against hypoxia- and serum deprivation-induced apoptosis by activation of PI3K/Akt and ERK1/2 [J]. J Cell Biochem 2008; 103(1):256-269.
[30]Ghavami S, Hashemi M, Ande SR, Yeganeh B, Xiao W, Eshraghi M, Bus CJ, Kadkhoda K, Wiechec E, Halayko AJ, Los M. Apoptosis and cancer:mutations within caspase genes [J]. J Med Genet 2009;46(8):497-510.
[31]Wikstrom JD, Twig G, Shirihai OS. What can mitochondrial heterogeneity tell us about mitochondrial dynamics and autophagy? [J]. Int J Biochem Cell Biol 2009;41(10):1914-1927.
[32]Lv L, Zhou Z, Huang X, Zhao Y, Zhang L, Shi Y, Sun M, Zhang J. Inhibition of peptidyl-prolyl cis/trans isomerase Pinl induces cell cycle arrest and apoptosis in vascular smooth muscle cells [J]. Apoptosis 2010; 15(1):41-54.
[33]Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins [J]. Genes Dev 2005;19(11):1294-1305.
[34]Antonsson B. Bax and other pro-apoptotic Bcl-2 family "killer-proteins" and their victim the mitochondrion [J]. Cell Tissue Res 2001;306(3):347-361.
[35]Tsujimoto Y, Shimizu S. Bcl-2 family:life-or-death switch [J]. FEBS Lett 2000;466(1):6-10.
[36]Li XD, Yang YJ, Geng YJ, Jin C, Hu FH, Zhao JL, Zhang HT, Cheng YT, Qian HY, Wang LL, Zhang BJ, Wu YL. Tongxinluo reduces myocardial no-reflow and ischemia-reperfusion injury by stimulating the phosphorylation of eNOS via the PKA pathway [J]. Am J Physiol Heart Circ Physiol 2010;299(4):H1255-1261.
[37]Liang JQ, Wu K, Jia ZH, Liu C, Ding J, Huang SN, Yin PP, Wu XC, Wei C, Wu YL, Wang HY Chinese medicine Tongxinluo modulates vascular endothelial function by inducing eNOS expression via the PI-3K/Akt/HIF-dependent signaling pathway [J]. J Ethnopharmacol 2011;133(2):517-523.
[38]Mann JD, Faurot KR, Wilkinson L, Curtis P, Coeytaux RR, Suchindran C, Gay lord SA. Craniosacral therapy for migraine:protocol development for an exploratory controlled clinical trial[J]. BMC Complement Altern Med 2008;8: 28.
[39]Stevens JM. Cytochrome c as an experimental model protein [J]. Metallomics 2011;3(4):319-322.
[40]Gustavsson T, Trane M, Moparthi VK, Miklovyte E, Moparthi L, Gorecki K, Leiding T, Arskold SP, Hagerhall C. A cytochrome c fusion protein domain for convenient detection, quantification, and enhanced production of membrane proteins in Escherichia coli-expression and characterization of cytochrome-tagged Complex I subunits [J]. Protein Sci 2010; 19(8):1445-1460.
[41]Huttemann M, Helling S, Sanderson TH, Sinkler C, Samavati L, Mahapatra G, Varughese A, Lu G, Liu J, Ramzan R, Vogt S, Grossman LI, Doan JW, Marcus K, Lee I. Regulation of mitochondrial respiration and apoptosis through cell signaling:cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation [J]. Biochim Biophys Acta 2012;1817(4):598-609.
[42]Huttemann M, Lee I, Grossman LI, Doan JW, Sanderson TH. Phosphorylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny:'respiration, apoptosis, and human disease [J]. Adv Exp Med Biol 2012;748:237-264.
[43]Huttemann M, Pecina P, Rainbolt M, Sanderson TH, Kagan VE, Samavati L, Doan JW, Lee I. The multiple functions of cytochrome c and their regulation in life and death decisions of the mammalian cell:From respiration to apoptosis [J]. Mitochondrion 2011; 11(3):369-381.
[44]Hardie DG, Scott JW, Pan DA, Hudson ER. Management of cellular energy by the AMP-activated protein kinase system [J]. FEBS Lett 2003;546(1):113-120.
[45]Toyoda T, Hayashi T, Miyamoto L, Yonemitsu S, Nakano M, Tanaka S, Ebihara K, Masuzaki H, Hosoda K, Inoue G, Otaka A, Sato K, Fushiki T, Nakao K. Possible involvement of the alphal isoform of 5'AMP-activated protein kinase in oxidative stress-stimulated glucose transport in skeletal muscle [J]. Am J Physiol Endocrinol Metab 2004;287(1):E166-173.
[46]Emerling BM, Weinberg F, Snyder C, Burgess Z, Mutlu GM, Viollet B, Budinger GR, Chandel NS. Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio [J]. Free Radic Biol Med 2009;46(10):1386-1391.
[47]Li C, Keaney JF, Jr. AMP-activated protein kinase:a stress-responsive kinase with implications for cardiovascular disease [J]. Curr Opin Pharmacol 2010; 10(2): 111-115.
[48]Shen L, Xiong Y, Wang DQ, Howles P, Basford JE, Wang J, Xiong YQ, Hui DY, Woods SC, Liu M. Ginsenoside Rb1 reduces fatty liver by activating AMP-activated protein kinase in obese rats [J]. J Lipid Res 2013;54(5): 1430-1438.
[49]Liu DH, Chen YM, Liu Y, Hao BS, Zhou B, Wu L, Wang M, Chen L, Wu WK, Qian XX. Ginsenoside Rb1 reverses H2O2-induced senescence in human umbilical endothelial cells:involvement of eNOS pathway [J]. J Cardiovasc Pharmacol 2012;59(3):222-230.
[50]Lieberthal W, Zhang L, Patel VA, Levine JS. AMPK protects proximal tubular cells from stress-induced apoptosis by an ATP-independent mechanism:potential role of Akt activation [J]. Am J Physiol Renal Physiol 2011;301(6):F1177-1192.
[51]Salt IP, Morrow VA, Brandie FM, Connell JM, Petrie JR. High glucose inhibits insulin-stimulated nitric oxide production without reducing endothelial nitric-oxide synthase Ser1177 phosphorylation in human aortic endothelial cells [J]. J Biol Chem 2003;278(21):18791-18797.
[52]Boyle JG, Logan PJ, Ewart MA, Reihill JA, Ritchie SA, Connell JM, Cleland SJ, Salt IP. Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase [J]. J Biol Chem 2008;283(17): 11210-11217.
[53]Izumi Y, Shiota M, Kusakabe H, Hikita Y, Nakao T, Nakamura Y, Muro T, Miura K, Yoshiyama M, Iwao H. Pravastatin accelerates ischemia-induced angiogenesis through AMP-activated protein kinase [J]. Hypertens Res 2009;32(8):675-679.
[1]Taghavi S, George JC. Homing of stem cells to ischemic myocardium [J]. Am J Transl Res 2013;5(4):404-411.
[2]Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors [J]. Stem Cells 2006;24(4):1030-1041.
[3]Shi M, Li J, Liao L, Chen B, Li B, Chen L, Jia H, Zhao RC. Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment:role in homing efficiency in NOD/SCID mice [J]. Haematologica 2007;92(7): 897-904.
[4]Freyman T, Polin G, Osman H, Crary J, Lu M, Cheng L, Palasis M, Wilensky RL. A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction [J]. Eur Heart J 2006;27(9): 1114-1122.
[5]Qian H, Yang Y, Huang J, Gao R, Dou K, Yang G, Li J, Shen R, He Z, Lu M, Zhao S. Intracoronary delivery of autologous bone marrow mononuclear cells radiolabeled by 18F-fluoro-deoxy-glucose:tissue distribution and impact on post-infarct swine hearts [J]. J Cell Biochem 2007;102(1):64-74.
[6]Nagaya N, Fujii T, Iwase T, Ohgushi H, Itoh T, Uematsu M, Yamagishi M, Mori H, Kangawa K, Kitamura S. Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis [J]. Am J Physiol Heart Circ Physiol 2004;287(6): H2670-2676.
[7]Li Y, Yu X, Lin S, Li X, Zhang S, Song YH. Insulin-like growth factor 1 enhances the migratory capacity of mesenchymal stem cells [J]. Biochem Biophys Res Commun 2007;356(3):780-784.
[8]Ma J, Ge J, Zhang S, Sun A, Shen J, Chen L, Wang K, Zou Y. Time course of myocardial stromal cell-derived factor 1 expression and beneficial effects of intravenously administered bone marrow stem cells in rats with experimental myocardial infarction [J]. Basic Res Cardiol 2005;100(3):217-223.
[9]Shirozu M, Nakano T, Inazawa J, Tashiro K, Tada H, Shinohara T, Honjo T. Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene [J]. Genomics 1995;28(3):495-500.
[10]Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor:functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor[J]. Science 1996;272(5263):872-877.
[11]Yamaguchi J, Kusano KF, Masuo O, Kawamoto A, Silver M, Murasawa S, Bosch-Marce M, Masuda H, Losordo DW, Isner JM, Asahara T. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization [J]. Circulation 2003; 107(9): 1322-1328.
[12]Cencioni C, Capogrossi MC, Napolitano M. The SDF-1/CXCR4 axis in stem cell preconditioning [J]. Cardiovasc Res 2012;94(3):400-407.
[13]Penn MS, Pastore J, Miller T, Aras R. SDF-1 in myocardial repair [J]. Gene Ther 2012; 19(6):583-587.
[14]Marquez-Curtis LA, Janowska-Wieczorek A. Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis [J]. Biomed Res Int 2013;2013:561098.
[15]Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes [J]. J Biol Chem 2005;280(42):35760-35766.
[16]Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development [J]. J Exp Med 2006;203(9):2201-2213.
[17]Mazzinghi B, Ronconi E, Lazzeri E, Sagrinati C, Ballerini L, Angelotti ML, Parente E, Mancina R, Netti GS, Becherucci F, Gacci M, Carini M, Gesualdo L, Rotondi M, Maggi E, Lasagni L, Serio M, Romagnani S, Romagnani P. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells [J]. J Exp Med 2008;205(2):479-490.
[18]Liu H, Liu S, Li Y, Wang X, Xue W, Ge G, Luo X. The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury [J]. PLoS One 2012;7(4):e34608.
[19]Li Q, Zhang A, Tao C, Li X, Jin P. The role of SDF-1-CXCR4/CXCR7 axis in biological behaviors of adipose tissue-derived mesenchymal stem cells in vitro [J]. Biochem Biophys Res Commun 2013;441(3):675-680.
[20]Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics [J]. Circ Res 2004;95(1):9-20.
[21]Nesselmann C, Ma N, Bieback K, Wagner W, Ho A, Konttinen YT, Zhang H, Hinescu ME, Steinhoff G. Mesenchymal stem cells and cardiac repair [J]. J Cell Mol Med 2008;12(5B):1795-1810.
[22]Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RC. Xenotransplant cardiac chimera:immune tolerance of adult stem cells [J]. Ann Thorac Surg 2002;74(1): 19-24; discussion 24.
[23]Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, Durand DJ, Fitton T, Kuang JQ, Stewart G, Lehrke S, Baumgartner WW, Martin BJ, Heldman AW, Hare JM. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction [J]. Proc Natl Acad Sci U S A 2005;102(32):11474-11479.
[24]Choi SH, Jung SY, Kwon SM, Baek SH. Perspectives on stem cell therapy for cardiac regeneration. Advances and challenges [J]. Circ J 2012;76(6):1307-1312.
[25]Brenner S, Whiting-Theobald N, Kawai T, Linton GF, Rudikoff AG, Choi U, Ryser MF, Murphy PM, Sechler JM, Malech HL. CXCR4-transgene expression significantly improves marrow engraftment of cultured hematopoietic stem cells [J]. Stem Cells 2004;22(7):1128-1133.
[26]Wynn RF, Hart CA, Corradi-Perini C, O'Neill L, Evans CA, Wraith JE, Fairbairn LJ, Bellantuono I. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow [J]. Blood 2004; 104(9):2643-2645.
[27]Son BR, Marquez-Curtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J, Ratajczak MZ, Janowska-Wieczorek A. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases [J]. Stem Cells 2006;24(5):1254-1264.
[28]Karp JM, Leng Teo GS. Mesenchymal stem cell homing:the devil is in the details [J]. Cell Stem Cell 2009;4(3):206-216.
[29]Umemura T, Higashi Y. Endothelial progenitor cells:therapeutic target for cardiovascular diseases [J]. J Pharmacol Sci 2008;108(1):1-6.
[30]Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P. Adult cardiac stem cells are multipotent and support myocardial regeneration [J]. Cell 2003; 114(6):763-776.
[31]Bollini S, Smart N, Riley PR. Resident cardiac progenitor cells:at the heart of regeneration [J]. J Mol Cell Cardiol 2011;50(2):296-303.
[32]Limana F, Capogrossi MC, Germani A. The epicardium in cardiac repair:from the stem cell view [J]. Pharmacol Ther 2011;129(1):82-96.
[33]Itzhaki-Alfia A, Leor J, Raanani E, Sternik L, Spiegelstein D, Netser S, Holbova R, Pevsner-Fischer M, Lavee J, Barbash IM. Patient characteristics and cell source determine the number of isolated human cardiac progenitor cells [J]. Circulation 2009; 120(25):2559-2566.
[34]Zhang H, Wang H, Li N, Duan CE, Yang YJ. Cardiac progenitor/stem cells on myocardial infarction or ischemic heart disease:what we have known from current research [J]. Heart Fail Rev 2014;19(2):247-258.
[35]Kawaguchi N, Smith AJ, Waring CD, Hasan MK, Miyamoto S, Matsuoka R, Ellison GM. c-kitpos GATA-4 high rat cardiac stem cells foster adult cardiomyocyte survival through IGF-1 paracrine signalling [J]. PLoS One 2010;5(12):e14297.
[36]Chugh AR, Beache GM, Loughran JH, Mewton N, Elmore JB, Kajstura J, Pappas P, Tatooles A, Stoddard MF, Lima JA, Slaughter MS, Anversa P, Bolli R. Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial:surgical aspects and interim analysis of myocardial function and viability by magnetic resonance [J]. Circulation 2012;126(11 Suppl 1):S54-64.
[37]Tang JM, Wang JN, Zhang L, Zheng F, Yang JY, Kong X, Guo LY, Chen L, Huang YZ, Wan Y, Chen SY. VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart [J]. Cardiovasc Res 2011;91(3):402-411.
[38]Kucia M, Reca R, Campbell FR, Zuba-Surma E, Majka M, Ratajczak J, Ratajczak MZ. A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+stem cells identified in adult bone marrow [J]. Leukemia 2006;20(5):857-869.
[39]Wojakowski W, Tendera M, Kucia M, Zuba-Surma E, Paczkowska E, Ciosek J, Halasa M, Krol M, Kazmierski M, Buszman P, Ochala A, Ratajczak J, Machalinski B, Ratajczak MZ. Mobilization of bone marrow-derived Oct-4+ SSEA-4+very small embryonic-like stem cells in patients with acute myocardial infarction [J]. J Am Coll Cardiol 2009;53(1):1-9.
[40]Zuba-Surma EK, Kucia M, Dawn B, Guo Y, Ratajczak MZ, Bolli R. Bone marrow-derived pluripotent very small embryonic-like stem cells (VSELs) are mobilized after acute myocardial infarction [J]. J Mol Cell Cardiol 2008;44(5): 865-873.
[41]Wojakowski W, Tendera M, Kucia M, Zuba-Surma E, Milewski K, Wallace-Bradley D, Kazmierski M, Buszman P, Hrycek E, Cybulski W, Kaluza G, Wieczorek P, Ratajczak J, Ratajczak MZ. Cardiomyocyte differentiation of bone marrow-derived Oct-4+CXCR4+SSEA-1+very small embryonic-like stem cells [J]. Int J Oncol 2010;37(2):237-247.
[42]Zhang Q, Yang YJ, Qian HY, Wang H, Xu H. Very small embryonic-like stem cells (VSELs)-a new promising candidate for use in cardiac regeneration [J]. Ageing Res Rev 2011;10(1):173-177.
[43]Kucia M, Wojakowski W, Reca R, Machalinski B, Gozdzik J, Majka M, Baran J, Ratajczak J, Ratajczak MZ. The migration of bone marrow-derived non-hematopoietic tissue-committed stem cells is regulated in an SDF-1-, HGF-, and LIF-dependent manner [J]. Arch Immunol Ther Exp (Warsz) 2006;54(2): 121-135.
[44]Wollert KC, Drexler H. Clinical applications of stem cells for the heart [J]. Circ Res 2005;96(2):151-163.
[45]Wang T, Tang W, Sun S, Ristagno G, Huang Z, Weil MH. Intravenous infusion of bone marrow mesenchymal stem cells improves myocardial function in a rat model of myocardial ischemia [J]. Crit Care Med 2007;35(11):2587-2593.
[46]Dai W, Hale SL, Martin BJ, Kuang JQ, Dow JS, Wold LE, Kloner RA. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium:short- and long-term effects [J]. Circulation 2005; 112(2):214-223.
[47]Perin EC. The use of stem cell therapy for cardiovascular disease [J]. Tex Heart Inst J 2005;32(3):390-392.
[48]Kraitchman DL, Tatsumi M, Gilson WD, Ishimori T, Kedziorek D, Walczak P, Segars WP, Chen HH, Fritzges D, Izbudak I, Young RG, Marcelino M, Pittenger MF, Solaiyappan M, Boston RC, Tsui BM, Wahl RL, Bulte JW. Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction [J]. Circulation 2005;112(10):1451-1461.
[49]Ghadge SK, Muhlstedt S, Ozcelik C, Bader M. SDF-lalpha as a therapeutic stem cell homing factor in myocardial infarction [J]. Pharmacol Ther 2011;129(1): 97-108.
[50]Kollet O, Petit I, Kahn J, Samira S, Dar A, Peled A, Deutsch V, Gunetti M, Piacibello W, Nagler A, Lapidot T. Human CD34(+)CXCR4(-) sorted cells harbor intracellular CXCR4, which can be functionally expressed and provide NOD/SCID repopulation [J]. Blood 2002;100(8):2778-2786.
[51]Chen Y, Teng X, Chen W, Yang J, Yang Z, Yu Y, Shen Z. Timing of transplantation of autologous bone marrow derived mesenchymal stem cells for treating myocardial infarction [J]. Sci China Life Sci 2014;57(2):195-200.
[52]Kucia M, Dawn B, Hunt G, Guo Y, Wysoczynski M, Majka M, Ratajczak J, Rezzoug F, Ildstad ST, Bolli R, Ratajczak MZ. Cells expressing early cardiac markers reside in the bone marrow and are mobilized into the peripheral blood after myocardial infarction [J]. Circ Res 2004;95(12):1191-1199.
[53]Abbott JD, Huang Y, Liu D, Hickey R, Krause DS, Giordano FJ. Stromal cell-derived factor-lalpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury [J]. Circulation 2004; 110(21):3300-3305.
[54]Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn MS. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy [J]. Lancet 2003;362(9385):697-703.
[55]Zhang S, Sun A, Xu D, Yao K, Huang Z, Jin H, Wang K, Zou Y, Ge J. Impact of timing on efficacy and safetyof intracoronary autologous bone marrow stem cells transplantation in acute myocardial infarction:a pooled subgroup analysis of randomized controlled trials [J]. Clin Cardiol 2009;32(8):458-466.
[56]Elmadbouh I, Haider H, Jiang S, Idris NM, Lu G, Ashraf M. Ex vivo delivered stromal cell-derived factor-lalpha promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium [J]. J Mol Cell Cardiol 2007;42(4): 792-803.
[57]Fujii H, Li SH, Wu J, Miyagi Y, Yau TM, Rakowski H, Egashira K, Guo J, Weisel RD, Li RK. Repeated and targeted transfer of angiogenic plasmids into the infarcted rat heart via ultrasound targeted microbubble destruction enhances cardiac repair [J]. Eur Heart J 2011;32(16):2075-2084.
[58]Segers VF, Tokunou T, Higgins LJ, MacGillivray C, Gannon J, Lee RT. Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction [J]. Circulation 2007; 116(15):1683-1692.
[59]MacArthur JW, Jr., Purcell BP, Shudo Y, Cohen JE, Fairman A, Trubelja A, Patel J, Hsiao P, Yang E, Lloyd K, Hiesinger W, Atluri P, Burdick JA, Woo YJ. Sustained release of engineered stromal cell-derived factor 1-alpha from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction [J]. Circulation 2013;128(11 Suppl 1):S79-86.
[60]Qiu R, Cai A, Dong Y, Zhou Y, Yu D, Huang Y, Zheng D, Rao S, Feng Y, Mai W. SDF-lalpha upregulation by atorvastatin in rats with acute myocardial infarction via nitric oxide production confers anti-inflammatory and anti-apoptotic effects [J]. J Biomed Sci 2012;19:99.
[61]Wang H, Yang YJ, Qian HY, Zhang Q, Gao LJ, Li P, Wang TJ, Wang SD. Statin administration does not improve the mobilization of very small embryonic-like stem cells (VSELs) in contrast to resveratrol treatment in a murine model of acute myocardial infarction [J]. Physiol Res 2012;61(5):543-549.
[62]Bongers J, Lambros T, Ahmad M, Heimer EP. Kinetics of dipeptidyl peptidase IV proteolysis of growth hormone-releasing factor and analogs [J]. Biochim Biophys Acta 1992;1122(2):147-153.
[63]Huber BC, Brunner S, Segeth A, Nathan P, Fischer R, Zaruba MM, Vallaster M, Theiss HD, David R, Gerbitz A, Franz WM. Parathyroid hormone is a DPP-IV inhibitor and increases SDF-1-driven homing of CXCR4(+) stem cells into the ischaemic heart [J]. Cardiovasc Res 2011;90(3):529-537.
[64]Zaruba MM, Theiss HD, Vallaster M, Mehl U, Brunner S, David R, Fischer R, Krieg L, Hirsch E, Huber B, Nathan P, Israel L, Imhof A, Herbach N, Assmann G, Wanke R, Mueller-Hoecker J, Steinbeck G, Franz WM. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction [J]. Cell Stem Cell 2009;4(4):313-323.
[65]Fadini GP, Boscaro E, Albiero M, Menegazzo L, Prison V, de Kreutzenberg S, Agostini C, Tiengo A, Avogaro A. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes:possible role of stromal-derived factor-lalpha [J]. Diabetes Care 2010;33(7):1607-1609.
[66]Cheng Z, Ou L, Zhou X, Li F, Jia X, Zhang Y, Liu X, Li Y, Ward CA, Melo LG, Kong D. Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance [J]. Mol Ther 2008;16(3):571-579.
[67]Zhang D, Fan GC, Zhou X, Zhao T, Pasha Z, Xu M, Zhu Y, Ashraf M, Wang Y. Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium [J]. J Mol Cell Cardiol 2008;44(2): 281-292.
[68]Bhakta S, Hong P, Koc O. The surface adhesion molecule CXCR4 stimulates mesenchymal stem cell migration to stromal cell-derived factor-1 in vitro but does not decrease apoptosis under serum deprivation [J]. Cardiovasc Revasc Med 2006;7(1):19-24.
[69]Tang YL, Zhu W, Cheng M, Chen L, Zhang J, Sun T, Kishore R, Phillips MI, Losordo DW, Qin G. Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression [J]. Circ Res 2009;104(10):1209-1216.
[70]Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T, Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipo'ri D, Lapidot T. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4 [J]. Nat Immunol 2002;3(7):687-694.
[71]Xie J, Wang H, Song T, Wang Z, Li F, Ma J, Chen J, Nan Y, Yi H, Wang W. Tanshinone IIA and astragaloside IV promote the migration of mesenchymal stem cells by up-regulation of CXCR4 [J]. Protoplasma 2013;250(2):521-530.
[72]Rolland-Turner M, Goretti E, Bousquenaud M, Leonard F, Nicolas C, Zhang L,
Maskali F, Marie PY, Devaux Y, Wagner D. Adenosine stimulates the migration of human endothelial progenitor cells. Role of CXCR4 and microRNA-150 [J]. PLoS One 2013;8(1):e54135.