摘要
目的:骨髓间充质干细胞(bone marrow mesenchymal stem cells, BM-MSCs)是急性心肌梗死(acute myocardial infarction, AMI)干细胞移植治疗的理想供体之一,然而MSCs移植治疗缺血性心脏病的机制尚未完全阐明。我们提出假设,MSCs移植后心功能改善的原因不仅有MSCs的定向分化作用及血管生成作用,可能会有细胞能量底物代谢的增加,提高心肌细胞的能量来源,进而提高心肌收缩力。为此,本研究将细胞生物学与正电子发射计算机断层扫描-计算机断层扫描(PET-CT)单光子发射计算机断层扫描(SPECT)等分子影像检测手段相结合,并通过MRI检测,重点观察在体动物MSCs移植治疗AMI后心肌葡萄糖代谢、心肌血流灌注及心功能的改变,进而评价MSCs治疗缺血性心脏病的疗效及其机制。
方法:24只中华小型猪(25±5kg)根据干预情况随机分为2组,干细胞移植组(MSCs组,n=12)及对照组(Control组,n=12)。通过开胸结扎左冠状动脉前降支30分钟建立AMI模型,体征平稳后于梗死周边心肌内注射自体骨髓MSCs(2×107,2ml),对照组以相同方法注射无血清的IMDM培养基。在1周及4周时行PET-CT及SPECT检测心肌葡萄糖代谢及心肌血流灌注情况,MRI检测心功能。术后4周为实验观察终点,组织取材后行H&E染色和Masson's Trichrome染色观察梗死面积、炎症细胞浸润及心肌纤维化情况。
结果:PET-CT评价心肌葡萄糖代谢,基线(1周)时MSCs组的最低FDG平均信号强度(MSI)低于Control组(22.10±3.18vs.35.70±3.02,P<0.05),总MSI亦低于Control组(1013.50±29.37vs.1084.00±21.15,P<0.05),其余各指标两组均无显著差异(P>0.05)。4周时,MSCs组左室心肌18F-FDG最低MSI较1周时有明显提高(34.00±4.25vs.22.10±3.18,P<0.01),总MSI较1周时亦明显提高(1075.50±28.30vs.1013.50±29.37,P<0.01),而SRS(20.20±2.24vs.23.80±1.58,P<0.05)及SRS%(29.80±3.31vs.35.10±2.34,P<0.05)较1周时均有减低;左心室梗死区(MSI低于70%的范围内)节段的总MSI及各节段平均MSI较1周时有显著增加(384.60±37.13vs.323.60±18.99,P<0.01;56.25±3.54vs.48.14±2.71,P<0.01);MSCs组左心室代谢缺损面积(Defect, cm2)、缺损范围(Extent,%)及总灌注缺损范围(TPD,%)在4周时虽较1周时有所减低,但无显著性差异(27.20±4.06vs.28.90±2.48;37.70±3.79vs.42.40±2.46;31.70±3.52vs.36.00±2.57;P值均>0.05)。在Control组中,以上参数4周时均较1周时有改善,但均无统计学差异(P>0.05)。MSCs组最低MSI及左心室总MSI在4周与1周时的增加量与Control组相比有显著差异(11.90±2.93vs.1.70±2.00,P<0.05;85.80±19.50vs.1.10±17.09,P<0.01)。MSCs组及Control组分别有6例及5例动物接受SPECT心肌血流灌注检查,1周时MSCs组与Control组相比,各项参数无显著差异(P>0.05);分别在1周及4周时对两组进行自身配对检验,各项心肌血流灌注指标及灌注缺损面积均无显著改变(P值均>0.05)。MRI评价心功能,1周时两组心功能参数无显著差异(P>0.05);MSCs组在4周时,左室射血分数(LVEF)较1周时有显著增加(54.41±2.62vs.47.54±2.43,P<0.01),左室收缩末期容积(ESV)有显著减低(22.85±1.91vs.27.07±1.67,P<0.01),左心室每搏输出量(SV)及心输出量(CO)均较1周时均有显著增加(29.35±1.84vs.26.52±1.46,P<0.05;2.23±0.14vs.1.96±0.13,P<0.05):Control组1周及4周时以各项心功能标均无统计学差异(P>0.05)。
结论:经心肌内注射骨髓MSCs治疗AMI,4周后心功能明显改善,心肌葡萄糖代谢显著提高,而心肌血流灌注未见明显改善。推测心功能的改善与心肌糖代谢增加相关。
目的:干细胞移植治疗缺血性心脏病的机制尚未完全阐明,本课题通过检测猪急性心肌梗死(acute myocardial infarction, AMI)后骨髓间充质干细胞(mesenchymal stem cells, MSCs)移植对左心室心肌整体及局部葡萄糖代谢、心功能的影响,并通过分子生物学手段对葡萄糖转运体、葡萄糖代谢相关酶及可能参与MSCs旁分泌作用的信号转导通路进行初步的研究,以探索MSCs移植治疗AMI的疗效及机制。
方法:32只中华小型猪按干预情况及观察终点随机分为3组:MSCs-1周组(n=8)、MSCs-4周组(n=12)及Control-4周组(n=12)。分离并培养猪MSCs,3-4周后开胸结扎左冠状动脉前降支30分钟建立AMI模型,体征平稳后,MSCs组(MSCs-1周组,MSCs-4周组)于梗死周边心肌内注射自体骨髓MSCs (2×107,2ml),对照组以相同方法注射无血清的IMDM培养基。分别在1周及4周时行PET-CT检测心肌葡萄糖代谢情况,并行MRI检测心功能。按不同的观察终点处死动物并取材,通过实时定量聚合酶链反应(real time-PCR)检测MSCs注射区域葡萄糖转运蛋白(GLUT1、GLUT4)、葡萄糖代谢相关酶(PFK、GAPDH)及mTOR信号通路相关基因表达的水平。
结果:PET-CT检测示,基线(1周)时MSCs-1周组与MSCs-4周组各指标无显著差异,而MSCs-4周组的最低MSI低于Control-4周组(22.10±3.18vs.35.70±3.02,P<0.05),总MSI亦低于Control-4周组(1013.50±29.37vs.1084.00±21.15,P<0.05)。MSCs-4周组4周时左室心肌18F-FDG摄取的最低MSI较1周时有明显提高(34.00±4.25vs.22.10±3.18,P<0.01),总MSI较1周时亦明显提高(1075.50±28.30vs.1013.50±29.37,P<0.01),SRS(20.20±2.24vs.23.80±1.58,P<0.05)及SRS%(29.80±3.31vs.35.10±2.34,P<0.05)较1周时均有减低;左心室梗死区内总MSI及平均MSI较1周时有显著增加(384.60±37.13vs.323.60±18.99,P<0.01;56.25±3.54vs.48.14±2.71,P<0.01);在Control-4周组中,以上参数在4周时与1周时比较,其改变无统计学意义(P>0.05)。局部左心室代谢评价:MSCs-4周组在4周时,以下节段MSI较1周时有显著增加:左心室前壁近心尖段(32.00±5.35vs.44.10±5.90,P<0.05)、前壁中段(57.40±4.00vs.65.30±4.66,P<0.05)、间隔近心尖部(52.00±2.55vs.61.60±2.67,P<0.05)、前间隔中段(62.80±2.85vs.69.50±2.17,P<0.05),其余节段MSI均未见显著性增加;而Control-4周组中,各节段MSI在1周及4周时均无明显差异。MRI评价心功能,基线时3组心功能参数无显著差异(P>0.05)。MSCs组在4周时,左室射血分数(LVEF)较1周时有显著增加(54.41±2.62vs.47.54±2.43,P<0.01),左室收缩末期容积(ESV)有显著减低(22.85±1.91vs.27.07±1.67,P<0.01),左心室每搏输出量(SV)及心输出量(CO)均较1周时均有显著增加(29.35±1.84vs.26.52±1.46,P<0.05;2.23±0.14vs.1.96±0.13,P<0.05);Control组1周及4周时以各项心功能标均无统计学差异(P>0.05)。Real-time PCR检测显示,MSCs-4周组葡萄糖转运蛋白(GLUT1、 GLUT4)、葡萄糖代谢相关酶(PFK、GAPDH)及mTOR信号通路下游蛋白p70s6k的基因表达与Control-4周组及MSCs-1周组相比,均显著增加(P值均<0.05)
结论:AMI后心肌内注射MSCs可提高心肌细胞葡萄糖代谢及心功能,注射MSCs的区域心肌细胞葡萄糖转运体及糖酵解相关酶表达上调,mTOR通路下游分子p70s6k表达显著升高,提示MSCs可能通过旁分泌作用激活该通路,促进心肌葡萄糖代谢及细胞生长,进而增加心肌收缩、促进心功能改善。
目的:门控单光子发射计算机断层(SPECT)心肌灌注显像不仅可以评价心肌血流灌注情况,亦可评价心功能,测定心室腔容积,对心衰患者的预后评价具有重要意义。本研究旨在探讨静息门控SPECT心肌灌注显像和其他临床变量如体重指数对慢性心力衰竭(CHF)患者心脏性死亡的预测价值,筛选心脏性死亡的预测因子。
方法:73例确诊为慢性心力衰竭(CHF)且左室射血分数(LVEF)<40%的住院患者(年龄50.7±16.5岁;男60例,女13例;缺血性心衰患者25例,非缺血性心衰患者48例),行99mTc-MIBI静息门控SPECT心肌灌注显像,以心脏性死亡作为心脏事件随访所有患者。用Cox比例风险回归分析法检测心脏性死亡的预测因子并用Kaplan-Meier方法估计生存概率。
结果:随访时间为18.6±8.5月(1.1~30.0月)。随访期间内共14例患者(19.2%)发生心脏性死亡。单因素Cox回归分析示体重指数(BMI, Wald4.66, P<0.05)、脑钠肽(BNP, Wald4.87, P<0.05)门控LVEF (Wald4.64, P<0.05),静息运动总评分(SMS, Wald4.43, P<0.05),静息灌注总评分(SRS, Wald4.56, P<0.05)以及灌注异常范围(Def Ext, Wald4.48, P<0.05)为心脏性死亡预测因素。将以上因素纳入多因素Cox回归分析,结果显示BMI (23.3±4.1kg/m2, Wald5.02, P<0.05,RR=0.85)及SRS (11.8±11.5, Wald5.33, P<0.05, RR=1.05)为独立心脏性死亡预测因素。BMI的最佳阈值为25Kg/m2, BMI<25Kg/m2的CHF患者(46例)及BMI≥25Kg/m2者(27例)预后有显著差异(P<0.05),BMI<25Kg/m2者死亡率高(28.3%vs.3.7%,P<0.05)且累计生存率明显高于BMI≥25Kg/m2者(Log-rank6.11, P<0.05); ROC曲线测得SRS最佳阈值为11,SRS≤11的CHF患者(43例)与SRS>11者(30例)两组间死亡率无明显差异(P=0.051),而两组累计生存率有显著差异,SRS≤S11者高于SRS>11者(Log-rank6.83, P<0.01)。 BMI<25Kg/m2同时SRS>11的CHF患者累积生存率明显减降低(Log-rank18.50, P<0.001)。
结论:静息门控SPECT心肌灌注显像对CHF患者有预后价值。BMI<25Kg/m2及SRS>11为发生心脏性死亡的独立危险因素,BMI<25Kg/m2且SRS>11的患者发生心脏性死亡的风险更高,应加强治疗及护理。
Obiective:Bone morrow mesenchymal stem cells (BM-MSCs) have been one of the optimal candidate cells for acute myocardial infarction (AMI) in recent years, however, the mechanism of MSCs transplantation in curing ischemic heart disease has not yet been fully. We proposed, MSCs transplantation improves cardiac function not only by differentiation and angiogenesis of MSCs, but also improve the metabolism of cardiocytes energy substrate, and then improve myocardial contraction. In this study, we will in vivo observe the changes of myocardial glucose metabolism, myocardial perfusion and cardiac function after MSCs transplantation in swine with AMI by means of cell biology and molecular imaging methods including positron emission tomography-computer tomography (PET-CT), single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI), in the purpose of evaluating the effect and mechanism of MSCs transplantation treating ischemic heart disease.
Method:Twenty-four Chinese mini-swine were randomized into2groups of MSCs transplantation group (MSCs group; n=12) and Control group (n=12). Myocardial infarction was induced in swine hearts by occlusion of the left anterior descending artery (LAD). Thirty minutes later, the MSCs group received autologous BM-MSCs transplantation through intramyocardial injection into the peri-infarcted areas and Control group were subjected to cell culture medium in the same way. After1week and4weeks, myocardial glucose metabolism, myocardial perfusion and cardiac function were evaluated in the two groups through PET-CT, SPECT and MRI. On the end point (the4th week), H&E stain and Masson's Trichrome stain were performed to observe the extent of infarction area, inflammatory cells infiltration and myocardial fibrosis.
Results:As evaluated by PET, on the baseline, the minimum FDG mean signal intensity (MSI) in MSCs group was below Control group (22.10±3.18vs.35.70±3.02, P<0.05), and the summed MSI was below Control group (1013.50±29.37vs.1084.00±21.15, P <0.05). Compared to the1st week, the minimum MSI in MSCs group was increased obviously (34.00±4.25vs.22.10±3.18, P<0.01) on the4th week, and also the summed MSI (1075.50±28.30vs.1013.50±29.37, P<0.01); summed rest score (SRS) and SRS%were decreased on the4th week compared to the1st week (20.20±2.24vs.23.80±1.58, P<0.05;29.80±3.31vs.35.10±2.34, P<0.05); the summed MSI in left ventricular infarction area (in area MSI below70) and average MSI were also increased (384.60±37.13vs.323.60±18.99, P<0.01;56.25±3.54vs.48.14±2.71, P<0.01); the metabolism defect area, defect extent and TPD the4th week were lower than those was on the1st week, but there were no significant differences (27.20±4.06vs.28.90±2.48;37.70±3.79vs.42.40±2.46;31.70±3.52vs.36.00±2.57; P>0.05). However, in the Control group, the variables mentioned above had no statistics differences in the endpoint than in the baseline (all P<0.05). The differences of minimum MSI between1st week and4th week in the MSCs group significantly high than the Control group (11.90±2.93vs.1.70±2.00, P<0.05), and also the differences of summed MSI between the two groups (85.80±19.50vs.1.10±17.09, P<0.01). Only6swine in the MSCs group and5swine in the Control group evaluated myocardial perfusion by SPECT. On the baseline, the perfusion variables had no significant differences between the two groups (P>0.05), and there were no differences in variables reflecting myocardial perfusion and defect area between baseline and endpoint in the two groups (P>0.05). As evaluated by MRI, the cardiac functional parameters had no significant differences in the two groups on the baseline. In the MSCs groups, left ventricular ejection fraction (LVEF) was increased significantly (54.41±2.62vs.47.54±2.43, P<0.01) and end-systolic volume (ESV) was significantly reduced (22.85±1.91vs.27.07±1.67, P<0.01) on the4th week compared to the1st week; stroke volume (SV) and cardiac output (CO) in the4th week also increased significantly (29.35±1.84vs.26.52±1.46, P<0.05;2.23±0.14vs.1.96±0.13, P<0.05). In the Control group, there were no significant differences in the cardiac functional parameters on the baseline and endpoint(P>0.05).
Conclusion:Four weeks after MSCs transplantation for curing AMI, cardiac function and myocardial glucose metabolism improved significantly; however, obvious myocardial perfusion improvement was not seen. It is speculated that the cardiac improvement is associated with the enhancement of myocardial glucose metabolism.
Objective:The mechanism of stem cells transplantation in curing ischemic heart diseases has not been clarified. The aim of this study is to investigate the effect and mechanism of bone marrow mesenchymal stem cells (BM-MSCs) transplantation in acute myocardial infarction (AMI) by means of detecting glucose metabolism in global left ventricular myocardium and regional myocardium, combined with assessment of cardiac function, and also to study the changes of glucose transporters, glucose metabolism-related enzymes and the signal transduction pathway which may participate in the MSCs paracrine process.
Methods:Thirty-two Chinese mini-swine were randomized into3groups of MSCs transplantation1-week group (MSCs-lw group; n=8), MSCs transplantation4-week group (MSCs-4w group; n=12) and Control group (n=12). BM-MSCs were separated and cultured for3-4weeks and then myocardial infarction was induced in swine hearts by occlusion of the left anterior descending artery (LAD). Thirty minutes later, the MSCs groups (MSCs-lw group and MSCs-4w group) received autologous MSCs (2×107,2ml) transplantation through intramyocardial injection into the peri-infarcted areas and Control group were subjected to cell culture medium in the same way. Positron emission tomography-computer tomography (PET-CT) and magnetic resonance imaging (MRI) were performed on the1st week and4th week. The swine were killed on the endpoints (1st week or4th week), and the gene expression of glucose transporters (GLUT1, GLUT4), glucose metabolism-related enzymes (PFK, GAPDH) and the proteins in mTOR signal transduction pathway in MSCs injection area were measured by real-time polymerase chain reaction (PCR).
Results:As shown by PET-CT, all the variables had no differences in the MSCs-lw group and MSCs-4w group on the baseline. The minimum FDG mean signal intensity (MSI) in MSCs-4w group was below Control-4w group (22.10±3.18vs.35.70±3.02, P <0.05), and the summed MSI was below Control-4w group (1013.50±29.37vs.1084.00±21.15, P<0.05). Compared to the1st week, the minimum MSI in MSCs-4w group was increased obviously (34.00±4.25vs.22.10±3.18, P<0.01) on the4th week, and also the summed MSI (1075.50±28.30vs.1013.50±29.37, P<0.01); summed rest score (SRS) and SRS%were decreased on the4th week compared to the1st week (20.20±2.24vs.23.80±1.58, P<0.05;29.80±3.31vs.35.10±2.34, P<0.05); the summed MSI in left ventricular infarction area (in area MSI below70) and average MSI were also increased (384.60±37.13vs.323.60±18.99, P<0.01;56.25±3.54vs.48.14±2.71, P <0.01). However, in the Control-4w group, the variables mentioned above had no statistics differences in the endpoint than in the baseline (all P<0.05). Metabolic evaluation in regional left ventricular showed that MSI increased in these segments on the4th week compared to the1st week:apical-anterior segment (32.00±5.35vs.44.10±5.90, P<0.05), mid-anterior segment (57.40±4.00vs.65.30±4.66, P<0.05), apical-septal segment (52.00±2.55vs.61.60±2.67, P<0.05) and mid-anteroseptal segment (62.80±2.85vs.69.50±2.17, P<0.05), and MSI in other segments didn't increase significantly (P>0.05). However, there were no differences in MSI between the1st week and4th week in the Control-4w group. As evaluated by MRI, the cardiac functional parameters had no significant differences in the three groups on the baseline (P>0.05). In the MSCs-4w group, left ventricular ejection fraction (LVEF) was increased significantly (54.41±2.62vs.47.54±2.43, P<0.01) and end-systolic volume (ESV) was significantly reduced (22.85±1.91vs.27.07±1.67, P<0.01) on the4th week compared to the1st week; stroke volume (SV) and cardiac output (CO) in the4th week also increased significantly (29.35±1.84vs.26.52±1.46, P<0.05;2.23±0.14vs.1.96±0.13, P<0.05). In the Control-4w group, there were no significant differences in the cardiac functional parameters on the baseline and endpoint (P>0.05). In the MSCs-4w group, real-time PCR analysis showed positive up-regulation of GLUT1, GLUT4, PFK, GAPDH and p70s6k (a downstream protein in mTOR signal transduction pathway) compared to the Control-4w group and the MSCs-lw group (all P<0.05).
Contusion:Intramyocardial injection of MSCs after AMI could improve cardiocytes glucose metabolism and improve cardiac function. The gene expression of glucose transporters (GLUT1, GLUT4), glucose metabolism-related enzymes (PFK, GAPDH) and p70s6k in MSCs injection area are up-regulated on the4th week after MSCs transplantation. It indicates that MSCs may active mTOR signal transduction pathway through paracrine effect to promote myocardial glucose metabolism and cardiocytes growth and then give rise to improved myocardial contraction and enhanced cardiac function.
Objective:Gated single photon emission computed tomography (SPECT) myocardial perfusion imaging has proven to be invaluable not only in assessing myocardial perfusion, but also in providing functional and volumetric information. The aim was to investigate the value of rest gated-SPECT myocardial perfusion imaging for predicting cardiac death in patients with chronic heart failure (CHF).
Methods:Seventy-three consecutive hospitalized patients (50.7±16.5years,60men) with defined diagnosis of CHF (25ischemic CHF and48non-ischemic CHF) and echocardiography left ventricular ejection fraction (LVEF)<40%, who underwent rest99mTc-MIBI gated SPECT myocardial perfusion imaging, were followed up for18.6±8.5months (range,1.1-30.0months). Only cardiac death during follow-up served as the endpoint. Cox proportional hazard regression analysis was applied to determine independent predictors of cardiac death and Kaplan-Meier method was applied to estimate the probability of survival with CHF.
Results:During the follow-up period,14(19.2%) cardiac deaths occurred in the73patients. Univariate Cox analysis showed that body mass index (BMI,23.3±4.1Kg/m2, P<0.05), brain natriuretic peptide (BNP, P<0.05), gated-LVEF (20.8%±7.9%, P <0.05), summed motion score (P<0.05), summed rest score (SRS, P<0.05) and defect extent (P<0.05) were significant predictors. When the above predictors were applied to multivariate Cox analysis, BMI (P<0.05, Hazard Ratio=0.85) and SRS (P<0.05, Hazard Ratio=1.05) showed predictive values for future cardiac death. The optimal threshold of BMI was25Kg/m2, the difference of cumulative survival between patients with BMI<25Kg/m2and those with BMI≥25Kg/m2was significant (P<0.05) and patients with BMI<25Kg/m2had lower survival. The optimal threshold of SRS was set as11, the difference of cumulative survival between patients with SRS≤1and those with SRS>11was significant (P<0.01), and patients with SRS>11had lower survival. The patients with BMI<25Kg/m and SRS>11simultaneously had the lowest survival in the73patients with CHF (P<0.001).
Conclusions:The present study indicates that the rest gated SPECT myocardial perfusion imaging gives prognostic information in patients with CHF. Both BMI and SRS are predictors for future occurrence of cardiac death, and patients with BMI<25Kg/m2and SRS>11simultaneously should be treated and cared for intensively.
引文
[1]Passier R, van LLW, Mummery CL. Stem-cell-based therapy and lessons from the heart. Nature.2008.453(7193):322-9.
[2]Segers VF, Lee RT. Stem-cell therapy for cardiac disease. Nature.2008.451(7181): 937-42.
[3]Anderson WF. Prospects for human gene therapy. Science.1984.226(4673):401-9.
[4]Olson EN. A decade of discoveries in cardiac biology. Nat Med.2004.10(5): 467-74.
[5]Nabel GJ. Genetic, cellular and immune approaches to disease therapy:past and future. Nat Med.2004.10(2):135-41.
[6]Dousset V, Tourdias T, Brochet B, Boiziau C, Petry KG. How to trace stem cells for MRI evaluation. J Neurol Sci.2008.265(1-2):122-6.
[7]Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science.1999.284(5411):143-7.
[8]Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature.2001.410(6829):701-5.
[9]Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res.2004.95(1):9-20.
[10]Caplan AI. Review:mesenchymal stem cells:cell-based reconstructive therapy in orthopedics. Tissue Eng.2005.11(7-8):1198-211.
[11]Kraitchman DL, Tatsumi M, Gilson WD, et al. Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation.2005. 112(10):1451-61.
[12]Muller-Ehmsen J, Krausgrill B, Burst V, et al. Effective engraftment but poor mid-term persistence of mononuclear and mesenchymal bone marrow cells in acute and chronic rat myocardial infarction. J Mol Cell Cardiol.2006.41(5):876-84.
[13]Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart:a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation.2002.105(4): 539-42.
[14]Segall G. Assessment of myocardial viability by positron emission tomography. Nucl Med Commun.2002.23(4):323-30.
[15]Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction:double-blind, randomised controlled trial. Lancet.2006.367(9505):113-21.
[16]Assmus B, Schachinger V, Teupe C, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation.2002.106(24):3009-17.
[17]Strauer BE, Brehm M, Zeus T, et al. Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease:the IACT Study. J Am Coll Cardiol.2005.46(9):1651-8.
[18]Dobert N, Britten M, Assmus B, et al. Transplantation of progenitor cells after reperfused acute myocardial infarction:evaluation of perfusion and myocardial viability with FDG-PET and thallium SPECT. Eur J Nucl Med Mol Imaging.2004. 31(8):1146-51.
[19]Bartunek J, Vanderheyden M, Vandekerckhove B, et al. Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction:feasibility and safety. Circulation.2005.112(9 Suppl):1178-83.
[20]Maki MT, Koskenvuo JW, Ukkonen H, et al. Cardiac Function, Perfusion, Metabolism, and Innervation following Autologous Stem Cell Therapy for Acute ST-Elevation Myocardial Infarction. A FINCELL-FNSIGHT Sub-Study with PET and MRI. Front Physiol.2012.3:6.
[21]Castellani M, Colombo A, Giordano R, et al. The Role of PET with 13N-Ammonia and 18F-FDG in the Assessment of Myocardial Perfusion and Metabolism in Patients with Recent AMI and Intracoronary Stem Cell Injection. J Nucl Med.2010. 51(12):1908-16.
[22]Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol.2011.50(2):280-9.
[23]Fuchs S, Baffour R, Zhou YF, et al. Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia. J Am Coll Cardiol.2001.37(6):1726-32.
[24]Tomita S, Mickle DA, Weisel RD, et al. Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation. J Thorac Cardiovasc Surg.2002.123(6):1132-40.
[25]Tang YL, Zhao Q, Zhang YC, et al. Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regul Pept.2004.117(1):3-10.
[26]Halkos ME, Zhao ZQ, Kerendi F, et al. Intravenous infusion of mesenchymal stem cells enhances regional perfusion and improves ventricular function in a porcine model of myocardial infarction. Basic Res Cardiol.2008.103(6):525-36.
[27]Kim BO, Tian H, Prasongsukarn K, et al. Cell transplantation improves ventricular function after a myocardial infarction:a preclinical study of human unrestricted somatic stem cells in a porcine model. Circulation.2005.112(9 Suppl):196-104.
[28]Schachinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction:final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol.2004.44(8):1690-9.
[29]Ge J, Li Y, Qian J, et al. Efficacy of emergent transcatheter transplantation of stem cells for treatment of acute myocardial infarction (TCT-STAMI). Heart.2006. 92(12):1764-7.
[30]Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002.106(15):1913-8.
[31]Urbanek K, Torella D, Sheikh F, et al. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc Natl Acad Sci U S A. 2005.102(24):8692-7.
[32]Pons J, Huang Y, Arakawa-Hoyt J, et al. VEGF improves survival of mesenchymal stem cells in infarcted hearts. Biochem Biophys Res Commun.2008.376(2): 419-22.
[33]Markel TA, Wang Y, Herrmann JL, et al. VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function. Am J Physiol Heart Circ Physiol.2008.295(6): H2308-14.
[34]Perin EC, Dohmann HF, Borojevic R, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003.107(18):2294-302.
[35]Perin EC, Dohmann HF, Borojevic R, et al. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation.2004.110(11 Suppl 1):11213-8.
[36]Stamm C, Westphal B, Kleine HD, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet.2003.361(9351):45-6.
[37]Martin-Rendon E, Brunskill SJ, Hyde CJ, Stanworth SJ, Mathur A, Watt SM. Autologous bone marrow stem cells to treat acute myocardial infarction:a systematic review. Eur Heart J.2008.29(15):1807-18.
[38]Schuleri KH, Amado LC, Boyle AJ, et al. Early improvement in cardiac tissue perfusion due to mesenchymal stem cells. Am J Physiol Heart Circ Physiol.2008. 294(5):H2002-11.
[39]Schuleri KH, Feigenbaum GS, Centola M, et al. Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy. Eur Heart J. 2009.30(22):2722-32.
[40]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. Eur J Heart Fail.2009.11(9):887-96.
[41]Zhou Y, Wang S, Yu Z, et al. Direct injection of autologous mesenchymal stromal cells improves myocardial function. Biochem Biophys Res Commun.2009.390(3): 902-7.
[42]Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction:the BOOST randomised controlled clinical trial. Lancet.2004.364(9429):141-8.
[43]Schachinger V, Erbs S, Elsasser A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med.2006.355(12): 1210-21.
[44]Tendera M, Wojakowski W, Ruzyllo W, et al. Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction:results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial. Eur Heart J.2009.30(11):1313-21.
[45]Assmus B, Honold J, Schachinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med.2006.355(12):1222-32.
[46]Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med.2006.355(12): 1199-209.
[47]Meyer GP, Wollert KC, Lotz J, et al. Intracoronary bone marrow cell transfer after myocardial infarction:eighteen months'follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation.2006.113(10):1287-94.
[48]Sun L, Zhang T, Lan X, Du G. Effects of stem cell therapy on left ventricular remodeling after acute myocardial infarction:a meta-analysis. Clin Cardiol.2010. 33(5):296-302.
[49]Donndorf P, Kundt G, Kaminski A, et al. Intramyocardial bone marrow stem cell transplantation during coronary artery bypass surgery:a meta-analysis. J Thorac Cardiovasc Surg.2011.142(4):911-20.
[50]Wen Y, Meng L, Xie J, Ouyang J. Direct autologous bone marrow-derived stem cell transplantation for ischemic heart disease:a meta-analysis. Expert Opin Biol Ther. 2011.11(5):559-67.
[51]der Spoel TI v, Jansen oLSJ, Agostoni P, et al. Human relevance of pre-clinical studies in stem cell therapy:systematic review and meta-analysis of large animal models of ischaemic heart disease. Cardiovasc Res.2011.91(4):649-58.
[52]Takagi H, Umemoto T. Intracoronary stem cell injection improves left ventricular remodeling after acute myocardial infarction:an updated meta-analysis of randomized trials. Int J Cardiol.2011.151(2):226-8.
[53]Hofmann M, Wollert KC, Meyer GP, et al. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation.2005.111(17):2198-202.
[1]Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol.2003.41(7):1078-83.
[2]Cheng AS, Yau TM. Paracrine effects of cell transplantation:strategies to augment the efficacy of cell therapies. Semin Thorac Cardiovasc Surg.2008. 20(2):94-101.
[3]Fedak PW. Paracrine effects of cell transplantation:modifying ventricular remodeling in the failing heart. Semin Thorac Cardiovasc Surg.2008.20(2): 87-93.
[4]Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res.2008.103(11):1204-19.
[5]Couzin J, Vogel G. Cell therapy. Renovating the heart. Science.2004.304(5668): 192-4.
[6]龚菁,李立环,裴卫东等.犬急性心肌缺血早期心肌葡萄糖、脂肪酸代谢相关酶变化的初步研究.中华心血管病杂志.2006.34(6):546-550.
[7]龚菁,浦介麟,沈锐,杨敏福,何作祥.中华实验猪慢性心肌缺血心肌葡萄糖及脂肪酸代谢相关酶的变化.中华医学杂志.2008.88(31):2209-2213.
[8]Beeres SL, Bengel FM, Bartunek J, et al. Role of imaging in cardiac stem cell therapy. J Am Coll Cardiol.2007.49(11):1137-48.
[9]Halkos ME, Zhao ZQ, Kerendi F, et al. Intravenous infusion of mesenchymal stem cells enhances regional perfusion and improves ventricular function in a porcine model of myocardial infarction. Basic Res Cardiol.2008.103(6): 525-36.
[10]Payne TR, Oshima H, Okada M, et al. A relationship between vascular endothelial growth factor, angiogenesis, and cardiac repair after muscle stem cell transplantation into ischemic hearts. J Am Coll Cardiol.2007.50(17):1677-84.
[11]Stamm C, Kleine HD, Westphal B, et al. CABG and bone marrow stem cell transplantation after myocardial infarction. Thorac Cardiovasc Surg.2004.52(3): 152-8.
[12]Chapon C, Jackson JS, Aboagye EO, Herlihy AH, Jones WA, Bhakoo KK. An in vivo multimodal imaging study using MRI and PET of stem cell transplantation after myocardial infarction in rats. Mol Imaging Biol.2009.11(1):31-8.
[13]Feygin J, Mansoor A, Eckman P, Swingen C, Zhang J. Functional and bioenergetic modulations in the infarct border zone following autologous mesenchymal stem cell transplantation. Am J Physiol Heart Circ Physiol.2007. 293(3):H1772-80.
[14]Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell.2000. 103(2):253-62.
[15]Bodine SC, Stitt TN, Gonzalez M, et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol.2001.3(11):1014-9.
[16]Stokoe D, Stephens LR, Copeland T, et al. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science.1997.277(5325):567-70.
[17]Bodine SC, Stitt TN, Gonzalez M, et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol.2001.3(11):1014-9.
[18]Pende M. mTOR, Akt, S6 kinases and the control of skeletal muscle growth. Bull Cancer.2006.93(5):E39-43.
[19]Roschel H, Ugrinowistch C, Barroso R, et al. Effect of eccentric exercise velocity on akt/mtor/p70(s6k) signaling in human skeletal muscle. Appl Physiol Nutr Metab.2011.36(2):283-90.
[20]Lopez-Caamal F, Garcia MR, Middleton RH, Huber HJ. Positive feedback in the Akt/mTOR pathway and its implications for growth signal progression in skeletal muscle cells:An analytical study. J Theor Biol.2012.301:15-27.
[21]Veilleux A, Houde VP, Bellmann K, Marette A. Chronic inhibition of the mTORCl/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes. Mol Endocrinol. 2010.24(4):766-78.
[22]Pereira MJ, Palming J, Rizell M, et al. mTOR inhibition with rapamycin causes impaired insulin signalling and glucose uptake in human subcutaneous and omental adipocytes. Mol Cell Endocrinol.2012.355(1):96-105.
[23]Tremblay F, Gagnon A, Veilleux A, Sorisky A, Marette A. Activation of the mammalian target of rapamycin pathway acutely inhibits insulin signaling to Akt and glucose transport in 3T3-L1 and human adipocytes. Endocrinology.2005. 146(3):1328-37.
[24]Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart:a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation.2002.105(4):539-42.
[25]Segall G. Assessment of myocardial viability by positron emission tomography. Nucl Med Commun.2002.23(4):323-30.
[26]Strauer BE, Brehm M, Schannwell CM. The therapeutic potential of stem cells in heart disease. Cell Prolif.2008.41 Suppl 1:126-45.
[27]Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol.2011.50(2):280-9.
[28]Dzau VJ, Gnecchi M, Pachori AS, Morello F, Melo LG. Therapeutic potential of endothelial progenitor cells in cardiovascular diseases. Hypertension.2005.46(1): 7-18.
[29]Kinnaird T, Stabile E, Burnett MS, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation.2004.109(12):1543-9.
[30]Kolwicz SC Jr, Tian R. Glucose metabolism and cardiac hypertrophy. Cardiovasc Res.2011.90(2):194-201.
[31]Schwaiger M, Schelbert HR, Ellison D, et al. Sustained regional abnormalities in cardiac metabolism after transient ischemia in the chronic dog model. J Am Coll Cardiol.1985.6(2):336-47.
[32]Qian H, Yang Y, Huang J, et al. Intracoronary delivery of autologous bone marrow mononuclear cells radiolabeled by 18F-fluoro-deoxy-glucose:tissue distribution and impact on post-infarct swine hearts. J Cell Biochem.2007. 102(1):64-74.
[33]Strauer BE, Brehm M, Zeus T, et al. Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease:the IACT Study. J Am Coll Cardiol.2005.46(9): 1651-8.
[34]Dobert N, Britten M, Assmus B, et al. Transplantation of progenitor cells after reperfused acute myocardial infarction:evaluation of perfusion and myocardial viability with FDG-PET and thallium SPECT. Eur J Nucl Med Mol Imaging. 2004.31(8):1146-51.
[35]Bartunek J, Vanderheyden M, Vandekerckhove B, et al. Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction:feasibility and safety. Circulation. 2005.112(9 Suppl):1178-83.
[36]Chen SL, Fang WW, Ye F, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol.2004.94(1):92-5.
[37]沈锐,刘盛,钱海燕等.核素标记自体骨髓单个核细胞监测心脏干细胞移植后存活情况.中华心血管病杂志.2010.38(6):545-548.
[38]Depre C, Rider MH, Hue L. Mechanisms of control of heart glycolysis. Eur J Biochem.1998.258(2):277-90.
[39]Opie LH. Myocardial metabolism and heart disease. Jpn Circ J.1978.42(11): 1223-47.
[40]Salas-Burgos A, Iserovich P, Zuniga F, Vera JC, Fischbarg J. Predicting the three-dimensional structure of the human facilitative glucose transporter glutl by a novel evolutionary homology strategy:insights on the molecular mechanism of substrate migration, and binding sites for glucose and inhibitory molecules. Biophys J.2004.87(5):2990-9.
[41]Gould GW, Holman GD. The glucose transporter family:structure, function and tissue-specific expression. Biochem J.1993.295 (Pt 2):329-41.
[42]Mueckler M. Facilitative glucose transporters. Eur J Biochem.1994.219(3): 713-25.
[43]Yoon YS, Wecker A, Heyd L, et al. Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction. J Clin Invest.2005.115(2):326-38.
[44]Diaz M, Vraskou Y, Gutierrez J, Planas JV. Expression of rainbow trout glucose transporters GLUT1 and GLUT4 during in vitro muscle cell differentiation and regulation by insulin and IGF-I. Am J Physiol Regul Integr Comp Physiol.2009. 296(3):R794-800.
[45]Zoidis E, Ghirlanda-Keller C, Schmid C. Stimulation of glucose transport in osteoblastic cells by parathyroid hormone and insulin-like growth factor I. Mol Cell Biochem.2011.348(1-2):33-42.
[46]Olianas MC, Dedoni S, Onali P. delta-Opioid receptors stimulate GLUT1-mediated glucose uptake through Src- and IGF-1 receptor-dependent activation of PI3-kinase signalling in CHO cells. Br J Pharmacol.2011.163(3): 624-37.
[47]Goldhammer AR, Paradies HH. Phosphofructokinase:structure and function. Curr Top Cell Regul.1979.15:109-41.
[48]Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell.2006.124(3):471-84.
[49]Zhou X, Tan M, Stone HV, et al. Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res.2004.10(20):6779-88.
[50]Shamji AF, Nghiem P, Schreiber SL. Integration of growth factor and nutrient signaling:implications for cancer biology. Mol Cell.2003.12(2):271-80.
[51]Fenton TR, Gout IT. Functions and regulation of the 70kDa ribosomal S6 kinases. Int J Biochem Cell Biol.2011.43(1):47-59.
[52]Rosner M, Hanneder M, Siegel N, Valli A, Fuchs C, Hengstschlager M. The mTOR pathway and its role in human genetic diseases. Mutat Res.2008.659(3): 284-92.
[53]Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ. p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci U S A.2001.98(17):9666-70.
[54]Balasubramanian S, Johnston RK, Moschella PC, Mani SK, Tuxworth WJ Jr, Kuppuswamy D. mTOR in growth and protection of hypertrophying myocardium. Cardiovasc Hematol Agents Med Chem.2009.7(1):52-63.
[55]Sipula IJ, Brown NF, Perdomo G. Rapamycin-mediated inhibition of mammalian target of rapamycin in skeletal muscle cells reduces glucose utilization and increases fatty acid oxidation. Metabolism.2006.55(12):1637-44.
[1]Porrello ER, Olson EN. Building a new heart from old parts:stem cell turnover in the aging heart. Circ Res.2010.107(11):1292-4.
[2]Barry FP, Murphy JM. Mesenchymal stem cells:clinical applications and biological characterization. Int J Biochem Cell Biol.2004.36(4):568-84.
[3]Kamihata H, Matsubara H, Nishiue T, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation.2001.104(9):1046-52.
[4]Pons J, Huang Y, Arakawa-Hoyt J, et al. VEGF improves survival of mesenchymal stem cells in infarcted hearts. Biochem Biophys Res Commun.2008.376(2): 419-22.
[5]Tang YL, Zhao Q, Zhang YC, et al. Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regul Pept.2004.117(1):3-10.
[6]徐亚丽,高云华,刘永亮等.旁分泌效应联合超声生物学效应在MSCs归巢与修复缺血心肌的作用.中国超声医学杂志.2009.25(10):920-924.
[7]Beltrami AP, Urbanek K, Kajstura J, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med.2001.344(23):1750-7.
[8]Tang JM, Wang JN, Zhang L, et al. VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovasc Res.2011. 91(3):402-11.
[9]曹青,王飞,林继先,陈书艳.骨髓间充质干细胞对CD117~±心脏干细胞分化过程中转化生长因子βⅢ型受体表达的影响.中国组织工程研究与临床康复.2009.(36):7057-7062.
[10]Dzau VJ, Gnecchi M, Pachori AS, Morello F, Melo LG. Therapeutic potential of endothelial progenitor cells in cardiovascular diseases. Hypertension.2005.46(1): 7-18.
[11]Kinnaird T, Stabile E, Burnett MS, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 2004.109(12):1543-9.
[12]侯炳波,王挹青.骨髓间充质干细胞通过旁分泌作用治疗心肌缺血研究进展.中国分子心脏病学杂志.2007.7(2):117-120.
[13]Heil M, Ziegelhoeffer T, Mees B, Schaper W. A different outlook on the role of bone marrow stem cells in vascular growth:bone marrow delivers software not hardware. Circ Res.2004.94(5):573-4.
[14]Fuchs S, Baffour R, Zhou YF, et al. Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia. J Am Coll Cardiol.2001.37(6):1726-32.
[15]Markel TA, Wang Y, Herrmann JL, et al. VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function. Am J Physiol Heart Circ Physiol.2008.295(6): H2308-14.
[16]Yoon YS, Wecker A, Heyd L, et al. Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction. J Clin Invest.2005.115(2):326-38.
[17]Abarbanell AM, Wang Y, Herrmann JL, et al. Toll-like receptor 2 mediates mesenchymal stem cell-associated myocardial recovery and VEGF production following acute ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol.2010. 298(5):H1529-36.
[18]Varoga D, Paulsen F, Mentlein R, et al. TLR-2-mediated induction of vascular endothelial growth factor (VEGF) in cartilage in septic joint disease. J Pathol.2006. 210(3):315-24.
[19]Nagaya N, Fujii T, Iwase T, et al. Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis. Am J Physiol Heart Circ Physiol.2004.287(6): H2670-6.
[20]Zhou Y, Wang S, Yu Z, et al. Direct injection of autologous mesenchymal stromal cells improves myocardial function. Biochem Biophys Res Commun.2009.390(3): 902-7.
[21]Fazel S, Chen L, Weisel RD, et al. Cell transplantation preserves cardiac function after infarction by infarct stabilization:augmentation by stem cell factor. J Thorac Cardiovasc Surg.2005.130(5):1310.
[22]Tang YL, Zhao Q, Qin X, et al. Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. Ann Thorac Surg.2005.80(1):229-36; discussion 236-7.
[23]Kinnaird T, Stabile E, Burnett MS, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res.2004.94(5): 678-85.
[24]Dai W, Hale SL, Martin BJ, et al. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium:short- and long-term effects. Circulation.2005. 112(2):214-23.
[25]Nagaya N, Kangawa K, Itoh T, et al. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation. 2005.112(8):1128-35.
[26]Xu M, Uemura R, Dai Y, Wang Y, Pasha Z, Ashraf M. In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function. J Mol Cell Cardiol.2007. 42(2):441-8.
[27]Gnecchi M, He H, Liang OD, et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med.2005.11(4): 367-8.
[28]Gnecchi M, He H, Noiseux N, et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J.2006.20(6):661-9.
[29]张润峰,高连如.间充质干细胞修复心肌的旁分泌效应机制.山西医科大学学报.2010.41(9):840-842,封3.
[30]张伟,葛薇,李长虹等.骨髓间充质干细胞通过分泌TGF-β1抑制T细胞的增殖.中国免疫学杂志.2005.21(3):168-171.
[31]Nian M, Lee P, Khaper N, Liu P. Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res.2004.94(12):1543-53.
[32]Lu L, Chen SS, Zhang JQ, Ramires FJ, Sun Y. Activation of nuclear factor-kappaB and its proinflammatory mediator cascade inthe infarcted rat heart. Biochem Biophys Res Commun.2004.321(4):879-85.
[33]Dhingra S, Sharma AK, Singla DK, Singal PK. p38 and ERK1/2 MAPKs mediate the interplay of TNF-alpha and IL-10 in regulatingoxidative stress and cardiac myocyte apoptosis. Am J Physiol Heart Circ Physiol.2007.293(6):H3524-31.
[34]Sugano M, Tsuchida K, Hata T, Makino N. In vivo transfer of soluble TNF-alpha receptor 1 gene improves cardiac functionand reduces infarct size after myocardial infarction in rats. FASEB J.2004.18(7):911-3.
[35]Li B, Liao YH, Cheng X, Ge H, Guo H, Wang M. Effects of carvedilol on cardiac cytokines expression and remodeling in rat with acute myocardial infarction. Int J Cardiol.2006.111(2):247-55.
[36]Capsoni F, Minonzio F, Mariani C, Ongari AM, Bonara P, Fiorelli G. Development of phagocytic function of cultured human monocytes is regulated bycell surface IL-10. Cell Immunol.1998.189(1):51-9.
[37]Kaur K, Sharma AK, Dhingra S, Singal PK. Interplay of TNF-alpha and IL-10 in regulating oxidative stress in isolated adultcardiac myocytes. J Mol Cell Cardiol. 2006.41(6):1023-30.
[38]Carlson DL, Maass DL, White J, Sikes P, Horton JW. Caspase inhibition reduces cardiac myocyte dyshomeostasis and improves cardiaccontractile function after major burn injury. J Appl Physiol.2007.103(1):323-30.
[39]Schottelius AJ, Mayo MW, Sartor RB, Baldwin AS Jr. Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclearfactor kappaB DNA binding. J Biol Chem.1999.274(45):31868-74.
[40]杜优优,周胜华,周滔等.骨髓间充质干细胞移植对心肌梗死后炎性细胞因子表达的调节.中国组织工程研究与临床康复.2008.12(8):1440-1444.
[41]Guo J, Lin GS, Bao CY, Hu ZM, Hu MY. Anti-inflammation role for mesenchymal stem cells transplantation in myocardial infarction. Inflammation.2007.30(3-4): 97-104.
[42]Ohnishi S, Sumiyoshi H, Kitamura S, Nagaya N. Mesenchymal stem cells attenuate cardiac fibroblast proliferation and collagen synthesis through paracrine actions. FEBS Lett.2007.581(21):3961-6.
[43]Psaltis PJ, Paton S, See F, et al. Enrichment for STRO-1 expression enhances the cardiovascular paracrine activity of human bone marrow-derived mesenchymal cell populations. J Cell Physiol.2010.223(2):530-40.
[44]Chen FH, Tuan RS. Mesenchymal stem cells in arthritic diseases. Arthritis Res Ther. 2008.10(5):223.
[45]Ling L, Nurcombe V, Cool SM. Wnt signaling controls the fate of mesenchymal stem cells. Gene.2009.433(1-2):1-7.
[46]Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res.2008.103(11):1204-19.
[47]Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci U S A.2001. 98(18):10344-9.
[48]Zhang M, Mal N, Kiedrowski M, et al. SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. FASEB J.2007.21(12):3197-207.
[49]Misao Y, Takemura G, Arai M, et al. Importance of recruitment of bone marrow-derived CXCR4+ cells in post-infarct cardiac repair mediated by G-CSF. Cardiovasc Res.2006.71(3):455-65.
[50]Pasha Z, Wang Y, Sheikh R, Zhang D, Zhao T, Ashraf M. Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. Cardiovasc Res.2008.77(1):134-42.
[51]Wollert KC, Drexler H. Mesenchymal stem cells for myocardial infarction: promises and pitfalls. Circulation.2005.112(2):151-3.
[52]Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol.2011.50(2):280-9.
[53]Block GJ, DiMattia GD, Prockop DJ. Stanniocalcin-1 regulates extracellular ATP-induced calcium waves in human epithelial cancer cells by stimulating ATP release from bystander cells. PLoS One.2010.5(4):e10237.
[54]Kelly ML, Wang M, Crisostomo PR, et al. TNF receptor 2, not TNF receptor 1, enhances mesenchymal stem cell-mediated cardiac protection following acute ischemia. Shock.2010.33(6):602-7.
[55]Sam J, Angoulvant D, Fazel S, Weisel RD, Li RK. Heart cell implantation after myocardial infarction. Coron Artery Dis.2005.16(2):85-91.
[56]Uemura R, Xu M, Ahmad N, Ashraf M. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res. 2006.98(11):1414-21.
[57]Nguyen BK, Maltais S, Perrault LP, et al. Improved function and myocardial repair of infarcted heart by intracoronary injection of mesenchymal stem cell-derived growth factors. J Cardiovasc Transl Res.2010.3(5):547-58.
[58]韩瑜,陈曦,陈静海,韩变梅,柳明洙.大鼠骨髓间充质干细胞条件培养液对心脏成纤维细胞胶原合成的影响.中国分子心脏病学杂志.2006.6(1):43-46.
[59]Mirotsou M, Zhang Z, Deb A, et al. Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc Natl Acad Sci U S A.2007.104(5):1643-8.
[60]Rojas M, Xu J, Woods CR, et al. Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol.2005.33(2):145-52.
[61]Abdel AMT, Atta HM, Mahfouz S, et al. Therapeutic potential of bone marrow-derived mesenchymal stem cells on experimental liver fibrosis. Clin Biochem.2007.40(12):893-9.
[62]Semedo P, Correa-Costa M, Antonio CM, et al. Mesenchymal stem cells attenuate renal fibrosis through immune modulation and remodeling properties in a rat remnant kidney model. Stem Cells.2009.27(12):3063-73.
[63]Berry MF, Engler AJ, Woo YJ, et al. Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance. Am J Physiol Heart Circ Physiol.2006.290(6):H2196-203.
[64]Xu X, Xu Z, Xu Y, Cui G. Effects of mesenchymal stem cell transplantation on extracellular matrix after myocardial infarction in rats. Coron Artery Dis.2005. 16(4):245-55.
[65]Ohnishi S, Yasuda T, Kitamura S, Nagaya N. Effect of hypoxia on gene expression of bone marrow-derived mesenchymal stem cells and mononuclear cells. Stem Cells. 2007.25(5):1166-77.
[66]Ohnishi S, Yanagawa B, Tanaka K, et al. Transplantation of mesenchymal stem cells attenuates myocardial injury and dysfunction in a rat model of acute myocarditis. J Mol Cell Cardiol.2007.42(1):88-97.
[67]Yu Q, Watson RR, Marchalonis JJ, Larson DF. A role for T lymphocytes in mediating cardiac diastolic function. Am J Physiol Heart Circ Physiol.2005.289(2): H643-51.
[68]Tang J, Wang J, Guo L, et al. Mesenchymal stem cells modified with stromal cell-derived factor 1 alpha improve cardiac remodeling via paracrine activation of hepatocyte growth factor in a rat model of myocardial infarction. Mol Cells.2010. 29(1):9-19.
[69]Misao Y, Takemura G, Arai M, et al. Bone marrow-derived myocyte-like cells and regulation of repair-related cytokines after bone marrow cell transplantation. Cardiovasc Res.2006.69(2):476-90.
[70]Dhein S, Garbade J, Rouabah D, et al. Effects of autologous bone marrow stem cell transplantation on beta-adrenoceptor density and electrical activation pattern in a rabbit model of non-ischemic heart failure. J Cardiothorac Surg.2006.1:17.
[71]Garbade J, Dhein S, Lipinski C, et al. Bone marrow-derived stem cells attenuate impaired contractility and enhance capillary density in a rabbit model of Doxorubicin-induced failing hearts. J Card Surg.2009.24(5):591-9.
[72]Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev.2005.85(3):1093-129.
[73]Hu Q, Wang X, Lee J, et al. Profound bioenergetic abnormalities in peri-infarct myocardial regions. Am J Physiol Heart Circ Physiol.2006.291(2):H648-57.
[74]Feygin J, Mansoor A, Eckman P, Swingen C, Zhang J. Functional and bioenergetic modulations in the infarct border zone following autologous mesenchymal stem cell transplantation. Am J Physiol Heart Circ Physiol.2007.293(3):H1772-80.
[75]Gnecchi M, He H, Melo LG, et al. Early beneficial effects of bone marrow-derived mesenchymal stem cells overexpressing Akt on cardiac metabolism after myocardial infarction. Stem Cells.2009.27(4):971-9.