低氧预处理人脐带间充质干细胞治疗急性心肌梗死的实验研究
|
摘要
目的：
本课题在体外收集脐带,分离、培养、扩增、鉴定人脐带间充质干细胞(]human umbilical cord mesenchymal stem cells, hUC-MSCs),将hUC-MSCs进行不同浓度低氧预处理,观察抗凋亡能力和分泌细胞因子能力的变化。选取中华小型猪建立急性心肌梗死模型,将低氧预处理hUC-MSCs和未处理hUC-MSCs经心外膜移植到心肌梗死组织周围,比较两者在心肌组织修复中作用有无差别,并进一步探讨可能存在的机制。
方法：
无菌条件下采集足月剖腹产胎儿脐带,经体外分离、培养、扩增hUC-MSCs至第六代,进行鉴定。按照预处理氧浓度不同分为1%02组,3%O2组,5%02组,10%02组和对照组(21%02组),各组hUC-MSCs在设定氧浓度条件下预处理24小时。通过实时定量PCR、ELISA、Annexin V-FITC/PI等方法比较各组细胞抗凋亡能力和细胞因子分泌能力不同,选取结果最佳的组进行动物实验。选取中华小型猪,全麻下经正中切口入胸,结扎冠状动脉左前降支远端1/3处,制作急性心梗模型。将实验动物随机分3组(6只／组)：对照组(Control)在心梗局部注射生理盐水,正常培养hUC-MSCs组(Nor)注射未处理hUC-MSCs,低氧预处理组(Hyp)注射低氧预处理hUC-MSCs。细胞注射量为2.5x107/只,分10到15个点注射。术后即刻、术后6周行超声心动图,静息核素心肌灌注显像检查。6周后人道处死动物,采集心脏标本,用Masson三染色、免疫荧光染色和TUNEL染色观察移植干细胞在体内定植、生存、血管新生及细胞凋亡情况。
结果：
(1)hUC-MSCs表面分子表型CD73、D90、CD105阳性表达,CD11b、CD34、 CD45、CD19、HLA-DR阴性表达。实时定量PCR示促凋亡基因Bax在1%02组、3%02组表达量均显著低于对照组(21%02组)和10%02组(p<0.01),其余各组间比较无统计学差异。抗凋亡基因Bcl-2在所有低氧预处理组表达量均显著高于对照组(p<0.01)；在1%02组表达量显著低于3%02组(p<0.01),在1%02组表达量低于5%02组,有统计学意义(p<0.05),其余各组间比较无统计学差异。凋亡诱导实验后,AnnexinV/PI检测示所有低氧预处理组hUC-MSCs与阳性对照组(21%02组)相比,早期、晚期及总凋亡数量均显著减少(p<0.01)。1%02组和3%02组hUC-MSCs早期凋亡低于10%02组,有统计学意义(p<0.05),其余各组之间无统计学差异。
(2)实时定量PCR示HGF基因在1%02组、3%02组和5%02组表达量均显著高于对照组(21%02组)(p<0.01)；在1%02组和3%02组表达量显著高于10%02组(p<0.01)；VEGF在3%02组表达量较高,但与对照组比较无统计学差异；KGF在3%O2组和5%02组表达量均显著高于对照组、10%02组以及1%02组(p<0.01)；NGF在3%02组和5%02组表达量均显著高于对照组(p<0.01),在3%02组表达量高于10%02组和1%02组,有统计学差异(P<0.05),在5%02组表达量著高于10%02组(p<0.01)。ELISA检测示：HGF分泌量在1%02、3%02组均显著高于对照组和10%02组(p<0.01)。VEGF分泌量在3%02组高于对照组和10%02组,有统计学意义(p<0.05)。KGF分泌量在3%02组和5%02组均显著高于1%02组和对照组(p<0.01)。NGF分泌量在3%02组和5%02组均高于对照组,有统计学意义(p<0.05)。
(3)干细胞移植6周后,超声心动图示低氧预处理组LVEDV低于对照组P<0.05,各组术后6周与术后即刻LVEF的差值比较,低氧预处理组高于对照组,P<0.05。术后6周,低氧预处理组和正常氧干细胞移植组△WT%均显著高于对照组(P<0.01),低氧预处理组高于正常氧干细胞移植组,有统计学意义(P<0.05)。静息放射核素显像示灌注质量缺损百分率(]mass defect percent, MDP)的差值即△MDP比较,两干细胞治疗组显著低于对照组(P<0.01)。各组术后6周与术后即刻LVEF的差值比较,低氧预处理组高于对照组,有统计学意义(P<0.05)。Masson三染色示低氧预处理组纤维组织面积小于正常氧细胞组,后者小于对照组,有统计学意义(Hyp：37.14±1.78%, Nor:41.41±0.58%, Control:47.20±3.07%, P<0.05)。低氧预处理组与对照组相比纤维组织面积显著减少(P<0.01)。
(4)免疫荧光测定显示：在低氧预处理组存活的hUC-MSCs即人p2微球蛋白阳性细胞(Hyp:39.0±7.6cells/hpf, Nor:18.7±5.7cells/hpf,)明显多于正常氧培养组,有统计学意义(P<0.05)。TUNEL染色法示两干细胞治疗组凋亡细胞均显著少于对照组(Hyp:10.0±2.6cells/hpf, Nor:49.0±6.6cells/hpf, Control:87.0±9.0cells/hpf, P<0.01),低氧预处理组凋亡细胞显著少于正常氧培养组(P<0.01)。低氧预处理组Isolactin B4阳性累计光密度值(integrated optical density,IOD)显著多于正常氧培养组和对照组(Hyp:517856.7±43670.5pixels/hpf, Nor:238294.7±66840.0pixels/hpf, Control:137114.0±15168.7pixels/hpf, P<0.01),正常氧培养组Isolactin B4阳性IOD多于对照组,有统计学意义(P<0.05)。
结论：
(1)3%低氧预处理能提高hUC-MSCs抗凋亡能力和分泌细胞因子的能力。
(2)移植低氧预处理hUC-MSCs能在一定程度上改善心肌梗死后心脏功能的恢复。
(3)低氧预处理hUC-MSCs在移植局部有更强的生存能力,能减少心梗局部瘢痕面积,减少纤维化。能通过旁分泌作用促进血管新生,减少心肌细胞凋亡。
Objective:Human umbilical cord mesenchymal stem cells (hUC-MSCs) were often used in cell therapy for myocardial infarction. We assumed that hypoxic preconditioning of hUC-MSCs (HP-MSCs) could enhance their ability of anti-apoptosis and paracrine. In this study, hUC-MSCs was isolated and expanded, and preconditioned with hypoxia in different oxygen concentration. We observed the changes of capacity for anti-apoptosis and paracrine of HP-MSCs. The HP-MSCs were then transplanted into a mini swine myocardial infarction mode to investigate the effect of cell treatment.
Methods:The hUC-MSCs were cultured and expanded to passage6, and were treated in hypoxic incubator with different oxygen concentration for24h before the test. hUC-MSCs was divided into5groups according to the oxygen concentration of hypoxic preconditioning:1%O2,3%O2,5%O2,10%O2,21%O2(control), In vitro, FACS, RT-qPCR, ELISA and Annexin V/PI were performed to investigate the gene expression and cytokine secretion, and the ability of anti-apoptosis of HP-MSCs. Transplantation of HP-MSCs into infarct area was applied surgically on the Zhonghua mini swine. The swine were randomly divided into three groups (n=6in each): Control (normal saline injection), Nor (normal hUC-MSCs injection) and Hyp (HP-MSCs injection). About2.5x107cells in3ml were injected into peri-myocardial infarction area in15spots. Echocardiogram and Single-Photon Emission Computed Tomography (SPECT) were performed at immediately and six weeks postoperatively respectively.6weeks after operation, the animals were euthanized and myocardium tissue in peri-MI area of the heart was harvested to analyze the engraftment of stem cells, myocardium apoptosis and angiogenesis by Masson trichrome staining, immunofluorescence and TUNEL staining.
Results:
(1) The phenotype of hUC-MSCs were positive in CD73、CD90、CD105and negative in CD11b/CD34/CD45/CD19and HLA-DR. RT-qPCR indicated that the gene expression of Bax in1%O2and3%O2groups were down-regulated significantly compared with control and10%O2groups (p<0.01); The gene expression of Bcl-2in1%O2,3%O2,5%O2and10%O2groups were up-regulated significantly compared with control group (p<0.01); After apoptosis induction, Annexin V/PI test demonstrated that the percentage of apoptotic cells in all the hypoxic preconditioning groups decreased significantly as compared to positive control group (p<0.01).RT-qPCR showed that the gene expression of HGF in1%O2,3%O2and5%O2groups were up-regulated significantly as compared to control group (p<0.01). VEGF gene expression in3%O2and5%O2groups increased significantly compared with every other groups (p<0.01). NGF gene expression in3%O2and5%O2groups increased as compared to the control group (p<0.01). The results of ELISA revealed that the protein secretion of HGF in1%O2and3%O2groups raised significantly compared with control and10%O2groups (p<0.01). The protein of VEGF in3%O2group increased significantly as compared to the control and10%O2groups (p<0.01). The protein of KGF in3%O2and5%O2groups increased significantly as compared to the control and1%O2groups (p<0.01). The protein of NGF in3%O2and5%O2groups increased significantly as compared to the control group (p<0.05)
(2)6weeks after transplantation, echocardiogram show that LVEDV in Hyp group reduced significantly as compared to the control group (p<0.05). The change of LVEF in Hyp group improved compared with control group (p<0.05). AWT%in cells treatment groups reduced as compared to the control group (p<0.01) SPECT revealed that AMDP in the cells treatment groups decreased compared with the control group (p<0.01).The change of LVEF in Hyp group increased as compared to the control group(p<0.05). Masson trichrome staining analysis show an improvement in fibrosis area in Hyp group as compared to the control group (p<0.05).(3) β-microglobin was positive only in human cells, which means it reflect the engraftment of human MSCs transplanted into the heart of swine. More positive cells were catched in Hyp group compared with the Nor group (p<0.05). TUNEL staining show that more apoptotic cells were observed in control group as compared to cell treatment group (p<0.01). Isolactin B4is a marker of vascular endothelial cells. More Isolactin B4postive staining were found in Hyp group as compared to the control group(p<0.01). Conclusions:(1) Hypoxic preconditioning hUC-MSCs in3%oxygen concentration enhanced their ability of anti-apoptosis and secretion of cytokines.(2) Transplantation of HP-MSCs improved the restoration of heart function in some extent.
(3) HP-MSCs could survive better in vivo, reduce the apoptosis of cells in the heart, enhance the angiogenesis and reduce the scar by paracrine effect.
本课题在体外收集脐带,分离、培养、扩增、鉴定人脐带间充质干细胞(]human umbilical cord mesenchymal stem cells, hUC-MSCs),将hUC-MSCs进行不同浓度低氧预处理,观察抗凋亡能力和分泌细胞因子能力的变化。选取中华小型猪建立急性心肌梗死模型,将低氧预处理hUC-MSCs和未处理hUC-MSCs经心外膜移植到心肌梗死组织周围,比较两者在心肌组织修复中作用有无差别,并进一步探讨可能存在的机制。
方法：
无菌条件下采集足月剖腹产胎儿脐带,经体外分离、培养、扩增hUC-MSCs至第六代,进行鉴定。按照预处理氧浓度不同分为1%02组,3%O2组,5%02组,10%02组和对照组(21%02组),各组hUC-MSCs在设定氧浓度条件下预处理24小时。通过实时定量PCR、ELISA、Annexin V-FITC/PI等方法比较各组细胞抗凋亡能力和细胞因子分泌能力不同,选取结果最佳的组进行动物实验。选取中华小型猪,全麻下经正中切口入胸,结扎冠状动脉左前降支远端1/3处,制作急性心梗模型。将实验动物随机分3组(6只／组)：对照组(Control)在心梗局部注射生理盐水,正常培养hUC-MSCs组(Nor)注射未处理hUC-MSCs,低氧预处理组(Hyp)注射低氧预处理hUC-MSCs。细胞注射量为2.5x107/只,分10到15个点注射。术后即刻、术后6周行超声心动图,静息核素心肌灌注显像检查。6周后人道处死动物,采集心脏标本,用Masson三染色、免疫荧光染色和TUNEL染色观察移植干细胞在体内定植、生存、血管新生及细胞凋亡情况。
结果：
(1)hUC-MSCs表面分子表型CD73、D90、CD105阳性表达,CD11b、CD34、 CD45、CD19、HLA-DR阴性表达。实时定量PCR示促凋亡基因Bax在1%02组、3%02组表达量均显著低于对照组(21%02组)和10%02组(p<0.01),其余各组间比较无统计学差异。抗凋亡基因Bcl-2在所有低氧预处理组表达量均显著高于对照组(p<0.01)；在1%02组表达量显著低于3%02组(p<0.01),在1%02组表达量低于5%02组,有统计学意义(p<0.05),其余各组间比较无统计学差异。凋亡诱导实验后,AnnexinV/PI检测示所有低氧预处理组hUC-MSCs与阳性对照组(21%02组)相比,早期、晚期及总凋亡数量均显著减少(p<0.01)。1%02组和3%02组hUC-MSCs早期凋亡低于10%02组,有统计学意义(p<0.05),其余各组之间无统计学差异。
(2)实时定量PCR示HGF基因在1%02组、3%02组和5%02组表达量均显著高于对照组(21%02组)(p<0.01)；在1%02组和3%02组表达量显著高于10%02组(p<0.01)；VEGF在3%02组表达量较高,但与对照组比较无统计学差异；KGF在3%O2组和5%02组表达量均显著高于对照组、10%02组以及1%02组(p<0.01)；NGF在3%02组和5%02组表达量均显著高于对照组(p<0.01),在3%02组表达量高于10%02组和1%02组,有统计学差异(P<0.05),在5%02组表达量著高于10%02组(p<0.01)。ELISA检测示：HGF分泌量在1%02、3%02组均显著高于对照组和10%02组(p<0.01)。VEGF分泌量在3%02组高于对照组和10%02组,有统计学意义(p<0.05)。KGF分泌量在3%02组和5%02组均显著高于1%02组和对照组(p<0.01)。NGF分泌量在3%02组和5%02组均高于对照组,有统计学意义(p<0.05)。
(3)干细胞移植6周后,超声心动图示低氧预处理组LVEDV低于对照组P<0.05,各组术后6周与术后即刻LVEF的差值比较,低氧预处理组高于对照组,P<0.05。术后6周,低氧预处理组和正常氧干细胞移植组△WT%均显著高于对照组(P<0.01),低氧预处理组高于正常氧干细胞移植组,有统计学意义(P<0.05)。静息放射核素显像示灌注质量缺损百分率(]mass defect percent, MDP)的差值即△MDP比较,两干细胞治疗组显著低于对照组(P<0.01)。各组术后6周与术后即刻LVEF的差值比较,低氧预处理组高于对照组,有统计学意义(P<0.05)。Masson三染色示低氧预处理组纤维组织面积小于正常氧细胞组,后者小于对照组,有统计学意义(Hyp：37.14±1.78%, Nor:41.41±0.58%, Control:47.20±3.07%, P<0.05)。低氧预处理组与对照组相比纤维组织面积显著减少(P<0.01)。
(4)免疫荧光测定显示：在低氧预处理组存活的hUC-MSCs即人p2微球蛋白阳性细胞(Hyp:39.0±7.6cells/hpf, Nor:18.7±5.7cells/hpf,)明显多于正常氧培养组,有统计学意义(P<0.05)。TUNEL染色法示两干细胞治疗组凋亡细胞均显著少于对照组(Hyp:10.0±2.6cells/hpf, Nor:49.0±6.6cells/hpf, Control:87.0±9.0cells/hpf, P<0.01),低氧预处理组凋亡细胞显著少于正常氧培养组(P<0.01)。低氧预处理组Isolactin B4阳性累计光密度值(integrated optical density,IOD)显著多于正常氧培养组和对照组(Hyp:517856.7±43670.5pixels/hpf, Nor:238294.7±66840.0pixels/hpf, Control:137114.0±15168.7pixels/hpf, P<0.01),正常氧培养组Isolactin B4阳性IOD多于对照组,有统计学意义(P<0.05)。
结论：
(1)3%低氧预处理能提高hUC-MSCs抗凋亡能力和分泌细胞因子的能力。
(2)移植低氧预处理hUC-MSCs能在一定程度上改善心肌梗死后心脏功能的恢复。
(3)低氧预处理hUC-MSCs在移植局部有更强的生存能力,能减少心梗局部瘢痕面积,减少纤维化。能通过旁分泌作用促进血管新生,减少心肌细胞凋亡。
Objective:Human umbilical cord mesenchymal stem cells (hUC-MSCs) were often used in cell therapy for myocardial infarction. We assumed that hypoxic preconditioning of hUC-MSCs (HP-MSCs) could enhance their ability of anti-apoptosis and paracrine. In this study, hUC-MSCs was isolated and expanded, and preconditioned with hypoxia in different oxygen concentration. We observed the changes of capacity for anti-apoptosis and paracrine of HP-MSCs. The HP-MSCs were then transplanted into a mini swine myocardial infarction mode to investigate the effect of cell treatment.
Methods:The hUC-MSCs were cultured and expanded to passage6, and were treated in hypoxic incubator with different oxygen concentration for24h before the test. hUC-MSCs was divided into5groups according to the oxygen concentration of hypoxic preconditioning:1%O2,3%O2,5%O2,10%O2,21%O2(control), In vitro, FACS, RT-qPCR, ELISA and Annexin V/PI were performed to investigate the gene expression and cytokine secretion, and the ability of anti-apoptosis of HP-MSCs. Transplantation of HP-MSCs into infarct area was applied surgically on the Zhonghua mini swine. The swine were randomly divided into three groups (n=6in each): Control (normal saline injection), Nor (normal hUC-MSCs injection) and Hyp (HP-MSCs injection). About2.5x107cells in3ml were injected into peri-myocardial infarction area in15spots. Echocardiogram and Single-Photon Emission Computed Tomography (SPECT) were performed at immediately and six weeks postoperatively respectively.6weeks after operation, the animals were euthanized and myocardium tissue in peri-MI area of the heart was harvested to analyze the engraftment of stem cells, myocardium apoptosis and angiogenesis by Masson trichrome staining, immunofluorescence and TUNEL staining.
Results:
(1) The phenotype of hUC-MSCs were positive in CD73、CD90、CD105and negative in CD11b/CD34/CD45/CD19and HLA-DR. RT-qPCR indicated that the gene expression of Bax in1%O2and3%O2groups were down-regulated significantly compared with control and10%O2groups (p<0.01); The gene expression of Bcl-2in1%O2,3%O2,5%O2and10%O2groups were up-regulated significantly compared with control group (p<0.01); After apoptosis induction, Annexin V/PI test demonstrated that the percentage of apoptotic cells in all the hypoxic preconditioning groups decreased significantly as compared to positive control group (p<0.01).RT-qPCR showed that the gene expression of HGF in1%O2,3%O2and5%O2groups were up-regulated significantly as compared to control group (p<0.01). VEGF gene expression in3%O2and5%O2groups increased significantly compared with every other groups (p<0.01). NGF gene expression in3%O2and5%O2groups increased as compared to the control group (p<0.01). The results of ELISA revealed that the protein secretion of HGF in1%O2and3%O2groups raised significantly compared with control and10%O2groups (p<0.01). The protein of VEGF in3%O2group increased significantly as compared to the control and10%O2groups (p<0.01). The protein of KGF in3%O2and5%O2groups increased significantly as compared to the control and1%O2groups (p<0.01). The protein of NGF in3%O2and5%O2groups increased significantly as compared to the control group (p<0.05)
(2)6weeks after transplantation, echocardiogram show that LVEDV in Hyp group reduced significantly as compared to the control group (p<0.05). The change of LVEF in Hyp group improved compared with control group (p<0.05). AWT%in cells treatment groups reduced as compared to the control group (p<0.01) SPECT revealed that AMDP in the cells treatment groups decreased compared with the control group (p<0.01).The change of LVEF in Hyp group increased as compared to the control group(p<0.05). Masson trichrome staining analysis show an improvement in fibrosis area in Hyp group as compared to the control group (p<0.05).(3) β-microglobin was positive only in human cells, which means it reflect the engraftment of human MSCs transplanted into the heart of swine. More positive cells were catched in Hyp group compared with the Nor group (p<0.05). TUNEL staining show that more apoptotic cells were observed in control group as compared to cell treatment group (p<0.01). Isolactin B4is a marker of vascular endothelial cells. More Isolactin B4postive staining were found in Hyp group as compared to the control group(p<0.01). Conclusions:(1) Hypoxic preconditioning hUC-MSCs in3%oxygen concentration enhanced their ability of anti-apoptosis and secretion of cytokines.(2) Transplantation of HP-MSCs improved the restoration of heart function in some extent.
(3) HP-MSCs could survive better in vivo, reduce the apoptosis of cells in the heart, enhance the angiogenesis and reduce the scar by paracrine effect.
引文
1. S. Mendis, P. Puska, and B. Norrving, Global Atlas on Cardiovascular Disease Prevention and Control,World Health Organization, Geneva, Switzerland,2011.
2. Kajstura, J., Cheng, W., Reiss, K., et al. (1996). Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Laboratory Investigation,74(1),86-107.
3. Sun, Y., Zhang, J. Q., Zhang, J., & Lamparter, S. (2000). Cardiac remodeling by fibrous tissue after infarction in rats. The Journal of Laboratory and Clinical Medicine,135(4),316-323.
4. Sutton, M. G., & Sharpe, N. (2000). Left ventricular remodeling after myocardial infarction:pathophysiology and therapy. Circulation,101(25),2981-2988.
5. Andersen, H. R., Nielsen, T. T., Rasmussen, K., et al. (2003). A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. The New England Journal of Medicine,349(8),733-742.
6. Costanzo, M. R., Augustine, S., Bourge, R., et al. (1995). Selection and treatment of candidates for heart transplantation. A statement for health professionals from the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation,92(12),3593-3612.
7. Segers, V. F., & Lee, R. T. (2008). Stem-cell therapy for cardiac disease. Nature, 451(7181),937-942.
8. Tongers, J., Losordo, D. W., & Landmesser, U. (2011). Stem and progenitor cell-based therapy in ischaemic heart disease:promise, uncertainties, and challenges. European Heart Journal,32(10),1197-1206.
9. Janssens, S. (2010). Stem cells in the treatment of heart disease. Annual Review of Medicine,61,287-300. C
10. Arminan, A., Gandia, C., Garcia-Verdugo, J. M., et al. (2010). Mesenchymal stem cells provide better results than hematopoietic precursors for the treatment of myocardial infarction. Journal of the American College of Cardiology,55(20), 2244-2253.
11. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell and Tissue Kinetics.1970;3(4):393-403.
12. Friedenstein AJ, Chailakhyan RK, Latsinik NV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation.1974; 17(4):331-340.
13. Caplan Al. Molecular and cellular differentiation of muscle, cartilage, and bone in the developing limb. Progress in Clinical and Biological Research.1986;217:307-318.
14. Piersma AH, Brockbank KGM, Ploemacher RE. Characterization of fibroblastic stromal cells from murine bone marrow. Experimental Hematology. 1985;13(4):237-243.
15. Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. Journal of Clinical Investigation.1999;103(5):697-705.
16. Simonsen, J. L., Rosada, C., Serakinci, N., et al. (2002). Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nature Biotechnology,20(6),592-596.
17. Patel SA, Sherman L, Munoz J, Rameshwar P. Immunological properties of mesenchymal stem cells and clinical implications. Archivum Immunologiae et Therapiae Experimentalis.2008;56(1):1-8.
18. Beyth, S., Borovsky, Z., Mevorach, D., et al. (2005). Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood,105(5),2214-2219
19. Fazel S, Chen L, Weisel RD, et al. Cell transplantation preserves cardiac function after infarction by infarct stabilization:augmentation by stem cell factor. Journal of Thoracic and Cardiovascular Surgery.2005; 130(5):p.1310.
20. Tomita S, Li RK, Weisel RD, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation.1999; 100(19, supplement):II247-II256.
21. Grauss RW, Van Tuyn J, Steendijk P, et al. Forced myocardin expression enhances the therapeutic effect of human mesenchymal stem cells after transplantation in ischemic mouse hearts. Stem Cells.2008;26(4):1083-1093.
22. de Macedo Braga LMG, Lacchini S, Schaan BD, et al. In situ delivery of bone marrow cells and mesenchymal stem cells improves cardiovascular function in hypertensive rats submitted to myocardial infarction. Journal of Biomedical Science.2008;15(3):365-374.
23. Imanishi Y, Saito A, Komoda H, et al. Allogenic mesenchymal stem cell transplantation has a therapeutic effect in acute myocardial infarction in rats. Journal of Molecular and Cellular Cardiology.2008;44(4):662-671.
24. Gyongyosi M, Blanco J, Marian T, et al. Serial noninvasive in vivo positron emission tomographic tracking of percutaneously intramyocardially injected autologous porcine mesenchymal stem cells modified for transgene reporter gene expression. Circulation.2008;1(2):94-103.
25. Hashemi SM, Ghods S, Kolodgie FD, et al. A placebo controlled, dose-ranging, safety study of allogenic mesenchymal stem cells injected by endomyocardial delivery after an acute myocardial infarction. European Heart Journal. 2008;29(2):251-259.
26. Hatzistergos KE, Quevedo H, Oskouei BN, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research.2010;107(7):913-922.
27. Silva GV, Litovsky S, Assad JAR, et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation.2005; 111(2):150-156.
28. Miyahara Y, Nagaya N, Kataoka M, et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nature Medicine. 2006;12(4):459-465.
29. Nesselmann C, Ma N, Bieback K, et al. Mesenchymal stem cells and cardiac repair. Journal of Cellular and Molecular Medicine B.2008;12(5):1795-1810.
30. 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. American Journal of Cardiology. 2004;94(l):92-95
31. Hare JM, Traverse JH, Henry TD, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. Journal of the American College of Cardiology.2009;54(24):2277-2286.
32. Puissant B, Barreau C, Bourin P, et al., Immunomodulatory effect of human adipose tissue-derived adult stem cells:comparison with bone marrowmesenchymal stem cells. British Journal of Haematology.2005:vo1.129, no.1, pp.118-129.
33. Weiss M. L, Anderson C, Medicetty S, et al., Immune properties of human umbilical cord Wharton's jelly-derived cells. Stem Cells.2008:vol.26, no.11, pp. 2865-2874.
34. Mylotte LA, Duffy AM, Murphy M, et al. Metabolic flexibility permits mesenchymal stem cell survival in an ischemic environment. Stem Cells. 2008;26(5):1325-1336.
35. Ward JPT:Oxygen sensors in context. Biochimica Et Biophysica Acta-Bioenergetics 2008,1777:1-14.
36. Miller WM, Wilke CR, Blanch HW:Effects of Dissolved-Oxygen Concentration on Hybridoma Growth and Metabolism in Continuous Culture. Journal of Cellular Physiology 1987,132:524-530.
37. Rosova I, Dao M, Capoccia B, Link D, Nolta JA:Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 2008,26:2173-2182.
38. 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;98:1414-21.
39. Hu X, Yu SP, Fraser JL, Lu Z, Ogle ME, Wang JA, Wei L. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J Thorac Cardiovasc Surg 2008; 135:799-808.
40. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8:315-317.
41. Martinez, E. C., & Kofidis, T. (2011). Adult stem cells for cardiac tissue engineering. Journal of Molecular and Cellular Cardiology,50(2),312-319.
42. Herrmann, J. L., Abarbanell, A. M., Weil, B. R., et al. (2011). Optimizing stem cell function for the treatment of ischemic heart disease. Journal of Surgical Research,166(1),138-145.
43. Haider, H.,& Ashraf, M. (2010). Preconditioning and stem cell survival. Journal of Cardiovascular Translational Research,3(2),89-102.
44. Gulati R, Simari RD. Cell Therapy for Acute Myocardial Infarction. Medical Clinics of North America.2007;91(4):769-785.
45. Smith AG. Embryo-derived stem cells:of mice and men. Annual Review of Cell and Developmental Biology.2001;17:435-462
46. Song H, Song BW, Cha MJ, Choi IG, Hwang KC. Modification of mesenchymal stem cells for cardiac regeneration. Expert Opinion on Biological Therapy. 2010;10(3):309-319.
47. Zhu WG, Li S, Lin LQ, Yan H, Fu T, Zhu JH. Vascular oxidative stress increases dendritic cell adhesion and transmigration induced by homocysteine. Cellular Immunology.2009;254(2):110-116.
48. Frangogiannis NG. Targeting the inflammatory response in healing myocardial infarcts. Current Medicinal Chemistry.2006;13(16):1877-1893.
49. Huang, J., Zhang, Z., Guo, J., et al. (2010). Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circulation Research,106(11), 1753-1762.
50. Alfaro, M. P., Pagni, M., Vincent, A., et al. (2008). The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair. Proceedings of the National Academy of Sciences of the United States of America,105(47),18366-18371
51. Tsubokawa, T., Yagi, K., Nakanishi, C., et al. (2010). Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia. American Journal of Physiology-Heart and Circulatory Physiology,298(5), H1320-H1329.
52. Li, W., Ma, N., Ong, L. L., et al. (2007). Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells,25(8),2118-2127.
53. Wang, D., Shen, W., Zhang, F., Chen, M., Chen, H., & Cao, K. (2010). Connexin43 promotes survival of mesenchymal stem cells in ischaemic heart. Cell Biology International,34(4),415-423.
54. Tang, J. M., Wang, J. N., Zhang, L., et al. (2011). VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovascular Research.
55. Duan, H. F., Wu, C. T., Wu, D. L., et al. (2003). Treatment of myocardial ischemia with bone marrow-derived mesenchymal stem cells overexpressing hepatocyte growth factor. Molecular Therapy,8(3),467-474.
56. Haider, H., Jiang, S., Idris, N. M.,& Ashraf, M. (2008). IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-lalpha/CXCR4 signaling to promote myocardial repair. Circulation Research,103(11),1300-1308
57. Guo Y, He J, Wu J, et al. Locally overexpressing hepatocyte growth factor prevents post-ischemic heart failure by inhibition of apoptosis via calcineurin-mediated pathway and angiogenesis. Archives of Medical Research. 2008;39(2):179-188
58. Ray R, Novotny NM, Crisostomo PR, Lahm T, Abarbanell A, Meldrum DR. Sex steroids and stem cell function. Molecular Medicine.2008;14(7-8):493-501.
59. Yang YJ, Qian HY, Huang J, et al. Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts. European Heart Journal.2008;29(12):1578-1590.
60. Chow DC, Wenning LA, Miller WM, Papoutsakis ET:Modeling pO(2) distributions in the bone marrow hematopoietic compartment. I. Krogh's model. Biophysical Journal 2001,81:675-684.
61. Bizzarri A, Koehler H, Cajlakovic M, Pasic A, Schaupp L, Klimant I, Ribitsch V: Continuous oxygen monitoring in subcutaneous adipose tissue using microdialysis. Analytica Chimica Acta 2006,573:48-56.
62. Harrison JS, Rameshwar P, Chang V, Bandari P:Oxygen saturation in the bone marrow of healthy volunteers. Blood 2002,99:394-394.
63. Frangogiannis, N. G., Smith, C. W., & Entman, M. L. The inflammatory response in myocardial infarction. Cardiovascular Research.2002:P53(1),31-47.
64. Nian, M., Lee, P., Khaper, N., & Liu, P. (2004). Inflammatory cytokines and postmyocardial infarction remodeling. Circulation Research,94(12),1543-1553.
65. Nah, D. Y., & Rhee, M. Y. (2009). The inflammatory response and cardiac repair after myocardial infarction. Korean Circulation Journal,39(10),393-398.
66. Kollar, K., Cook, M. M., Atkinson, K.,& Brooke, G. (2009). Molecular mechanisms involved in mesenchymal stem cell migration to the site of acute myocardial infarction. International Journal of Cell Biology, p.904682.
67. Neuss, S., Becher, E., Woltje, M., Tietze, L.,& Jahnen-Dechent, W. (2004). Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem Cells,22(3),405-414.
68. Steingen, C, Brenig, F., Baumgartner, L., Schmidt, J., Schmidt, A.,& Bloch, W. (2008). Characterization of key mechanisms in transmigration and invasion of mesenchymal stem cells. Journal of Molecular and Cellular Cardiology,44(6), 1072-1084.
69. Hatzistergos, K. E., Quevedo, H., Oskouei, B. N., et al. (2010). Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research,107(7),913-922.
70. Noiseux, N., Gnecchi, M., Lopez-Ilasaca, M., et al. (2006). Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Molecular Therapy,14(6),840-850.
71. Arminan, A., Gandia, C., Bartual, M., et al. (2009). Cardiac differentiation is driven by NKX2.5 and GATA4 nuclear translocation in tissue-specific mesenchymal stem cells. Stem Cells and Development,18(6),907-918.
72. Tang, Y. L., Zhao, Q., Qin, X., et al. (2005). Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. The Annals of Thoracic Surgery,80(1),229-236. discussion 236-7.
73. Mirotsou, M., Jayawardena, T. M., Schmeckpeper, J., Gnecchi, M., & Dzau, V. J. (2011). Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. Journal of Molecular and Cellular Cardiology,50(2),280-289.
74. Gnecchi, M., Zhang, Z., Ni, A., & Dzau, V. J. (2008). Paracrine mechanisms in adult stem cell signaling and therapy. Circulation Research,103(11),1204-1219.
75. Gnecchi, M., He, H., Noiseux, N., et al. (2006). Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. The FASEB Journal,20(6),661-669.
76. Nguyen, B. K., Maltais, S., Perrault, L. P., et al. (2010). Improved function and myocardial repair of infarcted heart by intracoronary injection of mesenchymal stem cell-derived growth factors. Journal of Cardiovascular Translational Research,3(5),547-558.
77. Timmers, L., Lim, S. K., Hoefer, I. E., et al. (2011). Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Research,6(3),206-214.
78. Freyman, T., Polin, G., Osman, H., et al. (2006). A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. European Heart Journal,27(9),1114-1122.
1. S. Mendis, P. Puska, and B. Norrving, Global Atlas on Cardiovascular Disease Prevention and Control,World Health Organization, Geneva, Switzerland,2011.
2. Kajstura, J., Cheng, W., Reiss, K., et al. (1996). Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Laboratory Investigation,74(1),86-107.
3. Sun, Y., Zhang, J. Q., Zhang, J.,& Lamparter, S. (2000). Cardiac remodeling by fibrous tissue after infarction in rats. The Journal of Laboratory and Clinical Medicine,135(4),316-323.
4. Sutton, M. G.,& Sharpe, N. (2000). Left ventricular remodeling after myocardial infarction:pathophysiology and therapy. Circulation,101(25),2981-2988.
5. Andersen, H. R., Nielsen, T. T., Rasmussen, K., et al. (2003). A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. The New England Journal of Medicine,349(8),733-742.
6. Costanzo, M. R., Augustine, S., Bourge, R., et al. (1995). Selection and treatment of candidates for heart transplantation. A statement for health professionals from the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation,92(12),3593-3612.
7. Segers, V. F.,& Lee, R. T. (2008). Stem-cell therapy for cardiac disease. Nature, 451(7181),937-942.
8. Tongers, J., Losordo, D. W.,& Landmesser, U. (2011). Stem and progenitor cell-based therapy in ischaemic heart disease:promise, uncertainties, and challenges. European Heart Journal,32(10),1197-1206.
9. Janssens, S. (2010). Stem cells in the treatment of heart disease. Annual Review of Medicine,61,287-300. C
10. Arminan, A., Gandia, C., Garcia-Verdugo, J. M., et al. (2010). Mesenchymal stem cells provide better results than hematopoietic precursors for the treatment of myocardial infarction. Journal of the American College of Cardiology,55(20), 2244-2253.
11. Martinez, E. C.,& Kofidis, T. (2011). Adult stem cells for cardiac tissue engineering. Journal of Molecular and Cellular Cardiology,50(2),312-319.
12. Herrmann, J. L., Abarbanell, A. M., Weil, B. R., et al. (2011). Optimizing stem cell function for the treatment of ischemic heart disease. Journal of Surgical Research,166(1),138-145.
13. Haider, H.,& Ashraf, M. (2010). Preconditioning and stem cell survival. Journal of Cardiovascular Translational Research,3(2),89-102.
14. Gulati R, Simari RD. Cell Therapy for Acute Myocardial Infarction. Medical Clinics of North America.2007;91(4):769-785.
15. Smith AG. Embryo-derived stem cells:of mice and men. Annual Review of Cell and Developmental Biology.2001;17:435-462
16. Min JY, Yang Y, Sullivan MF, et al. Long-term improvement of cardiac function in rats after infarction by transplantation of embryonic stem cells. Journal of Thoracic and Cardiovascular Surgery.2003;125(2):361-369.
17. Solter D. From teratocarcinomas to embryonic stem cells and beyond:a history of embryonic stem cell research. Nature Reviews Genetics.2006;7(4):319-327.
18. Saric T, Frenzel LP, Hescheler J. Immunological barriers to embryonic stem cell-derived therapies. Cells Tissues Organs.2008;188(1-2):78-90.
19. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature.2001;410(6829):701-705.
20. Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissmann IL, Robbins RC. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature.2004;428(6983):668-673.
21. 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. Circulation Research. 2004;94(5):678-685.
22. Kocher AA, Schuster MD, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nature Medicine. 2001;7(4):43-436.
23. Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. Journal of the American College of Cardiology.2003;41(7):1078-1083.
24. Menasche P, Alfieri O, Janssens S, et al. The myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial:first randomized placebo-controlled study of myoblast transplantation. Circulation.2008;117(9):1189-1200.
25. Hochedlinger K, Jaenisch R. Nuclear reprogramming and pluripotency. Nature. 2006;441(7097):1061-1067.
26. Jaenisch R, Young R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell.2008;132(4):567-582.
27. Nakagawa M, Koyanagi M, Tanabe K, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnology. 2008;26(1):101-106.
28. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell.2007; 131(5):861-872.
29. Yamanaka S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell.2007;1(1):39-49.
30. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science.2007;318(5858):1917-1920.
31. Nelson TJ, Martinez-Fernandez A, Yamada S, Perez-Terzic C, Dceda Y, Terzic A. Repair of acute myocardial infarction with induced pluripotent stem cells induced by human sternness factors. Circulation.2009;120(5):408-416.
32. Zhang J, Wilson GF, Soerens AG, et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circulation Research.2009;104(4):e30-
33. Menasche, P. (2011). Cardiac cell therapy:lessons from clinical trials. Journal of Molecular and Cellular Cardiology,50(2),258-265.
34. Rosenzweig, A. (2006). Cardiac cell therapy-mixed results from mixed cells. The New England Journal of Medicine,355(12),1274-1277.
35. Passier, R., van Laake, L. W., & Mummery, C. L. (2008). Stem-cell-based therapy and lessons from the heart. Nature,453(7193),322-329.
36. Wollert, K. C., & Drexler, H. (2010). Cell therapy for the treatment of coronary heart disease:a critical appraisal. Nature Reviews Cardiology,7(4),204-215.
37. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell and Tissue Kinetics.1970;3(4):393-403.
38. Friedenstein AJ, Chailakhyan RK, Latsinik NV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation.1974;17(4):331-340.
39. Caplan AI. Molecular and cellular differentiation of muscle, cartilage, and bone in the developing limb. Progress in Clinical and Biological Research.1986;217:307-318.
40. Piersma AH, Brockbank KGM, Ploemacher RE. Characterization of fibroblastic stromal cells from murine bone marrow. Experimental Hematology. 1985;13(4):237-243.
41. Wakitani S, Saito T, Caplan AI. Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle and Nerve. 1995;18(12):1417-1426.
42. Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proceedings of the National Academy of Sciences of the United States of America.1999;96(19):10711-10716.
43. Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. Journal of Clinical Investigation.1999;103(5):697-705.
44. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation.2002; 105(1):93-98.
45. Pal S, Kofidis T. New cell therapies in cardiology Expert Rev. Cardiovasc. Ther. 2012:10(8),1023-1037.
46. Puissant B, Barreau C, Bourin P, et al., Immunomodulatory effect of human adipose tissue-derived adult stem cells:comparison with bone marrowmesenchymal stem cells. British Journal of Haematology.2005:vol.129, no. 1,pp.118-129.
47. Weiss M. L, Anderson C, Medicetty S, et al., Immune properties of human umbilical cord Wharton's jelly-derived cells. Stem Cells.2008:vol.26, no.11, pp. 2865-2874.
48. Boyle AJ, McNiece IK, Hare JM. Mesenchymal stem cell therapy for cardiac repair. Methods in Molecular Biology.2010;660:65-84.
49. Khan M, Meduru S, Gogna R, et al. Oxygen cycling in conjunction with stem cell transplantation induces NOS3 expression leading to attenuation of fibrosis and improved cardiac function. Cardiovascular Research.2012;93(1):89-99.
50. Ryan JM, Barry FP, Murphy JM, Mahon BP. Mesenchymal stem cells avoid allogeneic rejection. Journal of Inflammation.2005;2:8
51. Kemp KC, Hows J, Donaldson C. Bone marrow-derived mesenchymal stem cells. Leukemia and Lymphoma.2005;46(11):1531-1544.
52. Zimmet JM, Hare JM. Emerging role for bone marrow derived mesenchymal stem cells in myocardial regenerative therapy. Basic Research in Cardiology. 2005; 100(6):471-481.
53. Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics. Circulation Research.2004;95(1):9-20.
54. Simonsen, J. L., Rosada, C., Serakinci, N., et al. (2002). Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nature Biotechnology,20(6),592-596.
55. Patel SA, Sherman L, Munoz J, Rameshwar P. Immunological properties of mesenchymal stem cells and clinical implications. Archivum Immunologiae et Therapiae Experimentalis.2008;56(1):1-8.
56. Beyth, S., Borovsky, Z., Mevorach, D., et al. (2005). Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood,105(5),2214-2219.
57. Frangogiannis, N. G., Smith, C. W., & Entman, M. L. The inflammatory response in myocardial infarction. Cardiovascular Research.2002:P53(1),31-47.
58. Nian, M., Lee, P., Khaper, N., & Liu, P. (2004). Inflammatory cytokines and postmyocardial infarction remodeling. Circulation Research,94(12),1543-1553.
59. Nah, D. Y., & Rhee, M. Y. (2009). The inflammatory response and cardiac repair after myocardial infarction. Korean Circulation Journal,39(10),393-398.
60. Kollar, K., Cook, M. M., Atkinson, K.,& Brooke, G. (2009). Molecular mechanisms involved in mesenchymal stem cell migration to the site of acute myocardial infarction. International Journal of Cell Biology, p.904682.
61. Neuss, S., Becher, E., Woltje, M., Tietze, L., & Jahnen-Dechent, W. (2004). Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem Cells,22(3),405-414.
62. Majumdar, M. K., Keane-Moore, M., Buyaner, D., et al. (2003). Characterization and functionality of cell surface molecules on human mesenchymal stem cells. Journal of Biomedical Science,10(2),228-241.
63. Thankamony, S. P.,& Sackstein, R. (2011). Enforced hematopoietic cell E-and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells. Proceedings of the National Academy of Sciences of the United States of America,108(6),2258-2263.
64. Steingen, C, Brenig, F., Baumgartner, L., Schmidt, J., Schmidt, A.,& Bloch, W. (2008). Characterization of key mechanisms in transmigration and invasion of mesenchymal stem cells. Journal of Molecular and Cellular Cardiology,44(6), 1072-1084.
65. Quevedo, H. C., Hatzistergos, K. E., Oskouei, B. N., et al. (2009). Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proceedings of the National Academy of Sciences of the United States of America,106(33),14022-14027.
66. Hatzistergos, K. E., Quevedo, H., Oskouei, B. N., et al. (2010). Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research,107(7),913-922.
67. Freyman, T., Polin, G., Osman, H., et al. (2006). A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. European Heart Journal,27(9),1114-1122.
68. Shake, J. G., Gruber, P. J., Baumgartner, W. A., et al. (2002). Mesenchymal stem cell implantation in a swine myocardial infarct model:engraftment and functional effects. The Annals of Thoracic Surgery,73(6),1919-1925. discussion 1926.
69. Jiang, W., Ma, A., Wang, T., et al. (2006). Homing and differentiation of mesenchymal stem cells delivered intravenously to ischemic myocardium in vivo: a time-series study. Pfliigers Archiv,453(1),43-52.
70. Noiseux, N., Gnecchi, M., Lopez-Ilasaca, M., et al. (2006). Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Molecular Therapy,14(6),840-850.
71. Arminan, A., Gandia, C., Bartual, M., et al. (2009). Cardiac differentiation is driven by NKX2.5 and GATA4 nuclear translocation in tissue-specific mesenchymal stem cells. Stem Cells and Development,18(6),907-918.
72. Tang, Y. L., Zhao, Q., Qin, X., et al. (2005). Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. The Annals of Thoracic Surgery,80(1),229-236. discussion 236-7.
73. Gnecchi, M., He, H., Noiseux, N., et al. (2006). Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. The FASEB Journal,20(6),661-669.
74. Mirotsou, M., Jayawardena, T. M., Schmeckpeper, J., Gnecchi, M., & Dzau, V. J. (2011). Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. Journal of Molecular and Cellular Cardiology,50(2),280-289.
75. Gnecchi, M., Zhang, Z., Ni, A., & Dzau, V. J. (2008). Paracrine mechanisms in adult stem cell signaling and therapy. Circulation Research,103(11),1204-1219.
76. Uemura, R., Xu, M., Ahmad, N., & Ashraf, M. (2006). Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circulation Research,98(11),1414-1421.
77. Haynesworth, S. E., Baber, M. A., & Caplan, A. I. (1996). Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro:effects of dexamethasone and IL-1 alpha. Journal of Cellular Physiology,166(3),585-592.
78. Nguyen, B. K., Maltais, S., Perrault, L. P., et al. (2010). Improved function and myocardial repair of infarcted heart by intracoronary injection of mesenchymal stem cell-derived growth factors. Journal of Cardiovascular Translational Research,3(5),547-558.
79. Timmers, L., Lim, S. K., Hoefer, I. E., et al. (2011). Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Research,6(3),206-214.
80. Fazel S, Chen L, Weisel RD, et al. Cell transplantation preserves cardiac function after infarction by infarct stabilization:augmentation by stem cell factor. Journal of Thoracic and Cardiovascular Surgery.2005;130(5):p.1310.
81. Tomita S, Li RK, Weisel RD, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation.1999;100(19, supplement):II247-II256.
82. Grauss RW, Van Tuyn J, Steendijk P, et al. Forced myocardin expression enhances the therapeutic effect of human mesenchymal stem cells after transplantation in ischemic mouse hearts. Stem Cells.2008;26(4):1083-1093.
83. de Macedo Braga LMG, Lacchini S, Schaan BD, et al. In situ delivery of bone marrow cells and mesenchymal stem cells improves cardiovascular function in hypertensive rats submitted to myocardial infarction. Journal of Biomedical Science.2008;15(3):365-374.
84. Imanishi Y, Saito A, Komoda H, et al. Allogenic mesenchymal stem cell transplantation has a therapeutic effect in acute myocardial infarction in rats. Journal of Molecular and Cellular Cardiology.2008;44(4):662-671.
85. Gyongyosi M, Blanco J, Marian T, et al. Serial noninvasive in vivo positron emission tomographic tracking of percutaneously intramyocardially injected autologous porcine mesenchymal stem cells modified for transgene reporter gene expression. Circulation.2008; 1(2):94-103.
86. Hashemi SM, Ghods S, Kolodgie FD, et al. A placebo controlled, dose-ranging, safety study of allogenic mesenchymal stem cells injected by endomyocardial delivery after an acute myocardial infarction. European Heart Journal. 2008;29(2):251-259.
87. Hatzistergos KE, Quevedo H, Oskouei BN, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research.2010; 107(7):913-922.
88. Silva GV, Litovsky S, Assad JAR, et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation.2005; 111(2):150-156.
89. Miyahara Y, Nagaya N, Kataoka M, et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nature Medicine. 2006;12(4):459-465.
90. Minguell JJ, Erices A. Mesenchymal stem cells and the treatment of cardiac disease. Experimental Biology and Medicine.2006;231(1):39-49.
91. Nesselmann C, Ma N, Bieback K, et al. Mesenchymal stem cells and cardiac repair. Journal of Cellular and Molecular Medicine B.2008; 12(5):1795-1810.
92. 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. American Journal of Cardiology. 2004;94(1):92-95
93. Katritsis DG, Sotiropoulou PA, Karvouni E, et al. Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium. Catheterization and Cardiovascular Interventions. 2005;65(3):321-329.
94. Katritsis DG, Sotiropoulou P, Giazitzoglou E, Karvouni E, Papamichail M. Electrophysiological effects of intracoronary transplantation of autologous mesenchymal and endothelial progenitor cells. Europace.2007;9(3):167-171.
95. Hare JM, Traverse JH, Henry TD, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. Journal of the American College of Cardiology.2009;54(24):2277-2286.
96. Bartunek J, Wijns D, Dolatabadi M, et al. C-cure multicenter trial:lineage specified bone marrow derived cardiopoietic mesenchymal stem cells for treatment of ischemic cardiomyopathy. Journal of the American College of Cardiology.2011;57, article 200
97. Freyman T, Polin G, Osman H, et al. A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. European Heart Journal.2006;27(9):1114-1122.
98. Song H, Song BW, Cha MJ, Choi IG, Hwang KC. Modification of mesenchymal stem cells for cardiac regeneration. Expert Opinion on Biological Therapy. 2010;10(3):309-319.
99. Mylotte LA, Duffy AM, Murphy M, et al. Metabolic flexibility permits mesenchymal stem cell survival in an ischemic environment. Stem Cells. 2008;26(5):1325-1336.
100. Zhu WG, Li S, Lin LQ, Yan H, Fu T, Zhu JH. Vascular oxidative stress increases dendritic cell adhesion and transmigration induced by homocysteine. Cellular Immunology.2009;254(2):110-116.
101. Frangogiannis NG. Targeting the inflammatory response in healing myocardial infarcts. Current Medicinal Chemistry.2006;13(16):1877-1893.
102. Huang, J., Zhang, Z., Guo, J., et al. (2010). Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circulation Research,106(11),1753-1762.
103. Kobayashi, K., Luo, M., Zhang, Y., et al. (2009). Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction. Nature Cell Biology,11(1),46-55.
104. Alfaro, M. P., Pagni, M., Vincent, A., et al. (2008). The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair. Proceedings of the National Academy of Sciences of the United States of America,105(47),18366-18371.
105. Tsubokawa, T., Yagi, K., Nakanishi, C., et al. (2010). Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia. American Journal of Physiology-Heart and Circulatory Physiology,298(5), H1320-H1329.
106. Li, W., Ma, N., Ong, L. L., et al. (2007). Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells,25(8),2118-2127.
107. Wang, D., Shen, W., Zhang, F., Chen, M., Chen, H., & Cao, K. (2010). Connexin43 promotes survival of mesenchymal stem cells in ischaemic heart. Cell Biology International,34(4),415-423.
108. Tang, J. M., Wang, J. N., Zhang, L., et al. (2011). VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovascular Research.
109. Duan, H. F., Wu, C. T., Wu, D. L., et al. (2003). Treatment of myocardial ischemia with bone marrow-derived mesenchymal stem cells overexpressing hepatocyte growth factor. Molecular Therapy,8(3),467-474.
110. Haider, H., Jiang, S., Idris, N. M.,& Ashraf, M. (2008). IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-lalpha/CXCR4 signaling to promote myocardial repair. Circulation Research,103(11),1300-1308.
111. Guo Y, He J, Wu J, et al. Locally overexpressing hepatocyte growth factor prevents post-ischemic heart failure by inhibition of apoptosis via calcineurin-mediated pathway and angiogenesis. Archives of Medical Research. 2008;39(2):179-188.
112. Ray R, Novotny NM, Crisostomo PR, Lahm T, Abarbanell A, Meldrum DR. Sex steroids and stem cell function. Molecular Medicine.2008;14(7-8):493-501.
113. Yang YJ, Qian HY, Huang J, et al. Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts. European Heart Journal.2008;29(12):1578-1590.
114. Chow DC, Wenning LA, Miller WM, Papoutsakis ET:Modeling pO(2) distributions in the bone marrow hematopoietic compartment. I. Krogh's model. Biophysical Journal 2001,81:675-684.
115. Bizzarri A, Koehler H, Cajlakovic M, Pasic A, Schaupp L, Klimant I, Ribitsch V:Continuous oxygen monitoring in subcutaneous adipose tissue using microdialysis. Analytica Chimica Acta 2006,573:48-56.
116. Harrison JS, Rameshwar P, Chang V, Bandari P:Oxygen saturation in the bone marrow of healthy volunteers. Blood 2002,99:394-394. 。
117. Ward JPT:Oxygen sensors in context. Biochimica Et Biophysica Acta-Bioenergetics 2008,1777:1-14.
118. Miller WM, Wilke CR, Blanch HW:Effects of Dissolved-Oxygen Concentration on Hybridoma Growth and Metabolism in Continuous Culture. Journal of Cellular Physiology 1987,132:524-530.
119. Rosova I, Dao M, Capoccia B, Link D, Nolta JA:Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 2008,26:2173-2182.
120. 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;98:1414-21.
121. Hu X, Yu SP, Fraser JL, Lu Z, Ogle ME, Wang JA, Wei L. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J Thorac Cardiovasc Surg 2008;135:799-808.
2. Kajstura, J., Cheng, W., Reiss, K., et al. (1996). Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Laboratory Investigation,74(1),86-107.
3. Sun, Y., Zhang, J. Q., Zhang, J., & Lamparter, S. (2000). Cardiac remodeling by fibrous tissue after infarction in rats. The Journal of Laboratory and Clinical Medicine,135(4),316-323.
4. Sutton, M. G., & Sharpe, N. (2000). Left ventricular remodeling after myocardial infarction:pathophysiology and therapy. Circulation,101(25),2981-2988.
5. Andersen, H. R., Nielsen, T. T., Rasmussen, K., et al. (2003). A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. The New England Journal of Medicine,349(8),733-742.
6. Costanzo, M. R., Augustine, S., Bourge, R., et al. (1995). Selection and treatment of candidates for heart transplantation. A statement for health professionals from the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation,92(12),3593-3612.
7. Segers, V. F., & Lee, R. T. (2008). Stem-cell therapy for cardiac disease. Nature, 451(7181),937-942.
8. Tongers, J., Losordo, D. W., & Landmesser, U. (2011). Stem and progenitor cell-based therapy in ischaemic heart disease:promise, uncertainties, and challenges. European Heart Journal,32(10),1197-1206.
9. Janssens, S. (2010). Stem cells in the treatment of heart disease. Annual Review of Medicine,61,287-300. C
10. Arminan, A., Gandia, C., Garcia-Verdugo, J. M., et al. (2010). Mesenchymal stem cells provide better results than hematopoietic precursors for the treatment of myocardial infarction. Journal of the American College of Cardiology,55(20), 2244-2253.
11. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell and Tissue Kinetics.1970;3(4):393-403.
12. Friedenstein AJ, Chailakhyan RK, Latsinik NV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation.1974; 17(4):331-340.
13. Caplan Al. Molecular and cellular differentiation of muscle, cartilage, and bone in the developing limb. Progress in Clinical and Biological Research.1986;217:307-318.
14. Piersma AH, Brockbank KGM, Ploemacher RE. Characterization of fibroblastic stromal cells from murine bone marrow. Experimental Hematology. 1985;13(4):237-243.
15. Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. Journal of Clinical Investigation.1999;103(5):697-705.
16. Simonsen, J. L., Rosada, C., Serakinci, N., et al. (2002). Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nature Biotechnology,20(6),592-596.
17. Patel SA, Sherman L, Munoz J, Rameshwar P. Immunological properties of mesenchymal stem cells and clinical implications. Archivum Immunologiae et Therapiae Experimentalis.2008;56(1):1-8.
18. Beyth, S., Borovsky, Z., Mevorach, D., et al. (2005). Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood,105(5),2214-2219
19. Fazel S, Chen L, Weisel RD, et al. Cell transplantation preserves cardiac function after infarction by infarct stabilization:augmentation by stem cell factor. Journal of Thoracic and Cardiovascular Surgery.2005; 130(5):p.1310.
20. Tomita S, Li RK, Weisel RD, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation.1999; 100(19, supplement):II247-II256.
21. Grauss RW, Van Tuyn J, Steendijk P, et al. Forced myocardin expression enhances the therapeutic effect of human mesenchymal stem cells after transplantation in ischemic mouse hearts. Stem Cells.2008;26(4):1083-1093.
22. de Macedo Braga LMG, Lacchini S, Schaan BD, et al. In situ delivery of bone marrow cells and mesenchymal stem cells improves cardiovascular function in hypertensive rats submitted to myocardial infarction. Journal of Biomedical Science.2008;15(3):365-374.
23. Imanishi Y, Saito A, Komoda H, et al. Allogenic mesenchymal stem cell transplantation has a therapeutic effect in acute myocardial infarction in rats. Journal of Molecular and Cellular Cardiology.2008;44(4):662-671.
24. Gyongyosi M, Blanco J, Marian T, et al. Serial noninvasive in vivo positron emission tomographic tracking of percutaneously intramyocardially injected autologous porcine mesenchymal stem cells modified for transgene reporter gene expression. Circulation.2008;1(2):94-103.
25. Hashemi SM, Ghods S, Kolodgie FD, et al. A placebo controlled, dose-ranging, safety study of allogenic mesenchymal stem cells injected by endomyocardial delivery after an acute myocardial infarction. European Heart Journal. 2008;29(2):251-259.
26. Hatzistergos KE, Quevedo H, Oskouei BN, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research.2010;107(7):913-922.
27. Silva GV, Litovsky S, Assad JAR, et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation.2005; 111(2):150-156.
28. Miyahara Y, Nagaya N, Kataoka M, et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nature Medicine. 2006;12(4):459-465.
29. Nesselmann C, Ma N, Bieback K, et al. Mesenchymal stem cells and cardiac repair. Journal of Cellular and Molecular Medicine B.2008;12(5):1795-1810.
30. 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. American Journal of Cardiology. 2004;94(l):92-95
31. Hare JM, Traverse JH, Henry TD, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. Journal of the American College of Cardiology.2009;54(24):2277-2286.
32. Puissant B, Barreau C, Bourin P, et al., Immunomodulatory effect of human adipose tissue-derived adult stem cells:comparison with bone marrowmesenchymal stem cells. British Journal of Haematology.2005:vo1.129, no.1, pp.118-129.
33. Weiss M. L, Anderson C, Medicetty S, et al., Immune properties of human umbilical cord Wharton's jelly-derived cells. Stem Cells.2008:vol.26, no.11, pp. 2865-2874.
34. Mylotte LA, Duffy AM, Murphy M, et al. Metabolic flexibility permits mesenchymal stem cell survival in an ischemic environment. Stem Cells. 2008;26(5):1325-1336.
35. Ward JPT:Oxygen sensors in context. Biochimica Et Biophysica Acta-Bioenergetics 2008,1777:1-14.
36. Miller WM, Wilke CR, Blanch HW:Effects of Dissolved-Oxygen Concentration on Hybridoma Growth and Metabolism in Continuous Culture. Journal of Cellular Physiology 1987,132:524-530.
37. Rosova I, Dao M, Capoccia B, Link D, Nolta JA:Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 2008,26:2173-2182.
38. 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;98:1414-21.
39. Hu X, Yu SP, Fraser JL, Lu Z, Ogle ME, Wang JA, Wei L. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J Thorac Cardiovasc Surg 2008; 135:799-808.
40. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8:315-317.
41. Martinez, E. C., & Kofidis, T. (2011). Adult stem cells for cardiac tissue engineering. Journal of Molecular and Cellular Cardiology,50(2),312-319.
42. Herrmann, J. L., Abarbanell, A. M., Weil, B. R., et al. (2011). Optimizing stem cell function for the treatment of ischemic heart disease. Journal of Surgical Research,166(1),138-145.
43. Haider, H.,& Ashraf, M. (2010). Preconditioning and stem cell survival. Journal of Cardiovascular Translational Research,3(2),89-102.
44. Gulati R, Simari RD. Cell Therapy for Acute Myocardial Infarction. Medical Clinics of North America.2007;91(4):769-785.
45. Smith AG. Embryo-derived stem cells:of mice and men. Annual Review of Cell and Developmental Biology.2001;17:435-462
46. Song H, Song BW, Cha MJ, Choi IG, Hwang KC. Modification of mesenchymal stem cells for cardiac regeneration. Expert Opinion on Biological Therapy. 2010;10(3):309-319.
47. Zhu WG, Li S, Lin LQ, Yan H, Fu T, Zhu JH. Vascular oxidative stress increases dendritic cell adhesion and transmigration induced by homocysteine. Cellular Immunology.2009;254(2):110-116.
48. Frangogiannis NG. Targeting the inflammatory response in healing myocardial infarcts. Current Medicinal Chemistry.2006;13(16):1877-1893.
49. Huang, J., Zhang, Z., Guo, J., et al. (2010). Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circulation Research,106(11), 1753-1762.
50. Alfaro, M. P., Pagni, M., Vincent, A., et al. (2008). The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair. Proceedings of the National Academy of Sciences of the United States of America,105(47),18366-18371
51. Tsubokawa, T., Yagi, K., Nakanishi, C., et al. (2010). Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia. American Journal of Physiology-Heart and Circulatory Physiology,298(5), H1320-H1329.
52. Li, W., Ma, N., Ong, L. L., et al. (2007). Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells,25(8),2118-2127.
53. Wang, D., Shen, W., Zhang, F., Chen, M., Chen, H., & Cao, K. (2010). Connexin43 promotes survival of mesenchymal stem cells in ischaemic heart. Cell Biology International,34(4),415-423.
54. Tang, J. M., Wang, J. N., Zhang, L., et al. (2011). VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovascular Research.
55. Duan, H. F., Wu, C. T., Wu, D. L., et al. (2003). Treatment of myocardial ischemia with bone marrow-derived mesenchymal stem cells overexpressing hepatocyte growth factor. Molecular Therapy,8(3),467-474.
56. Haider, H., Jiang, S., Idris, N. M.,& Ashraf, M. (2008). IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-lalpha/CXCR4 signaling to promote myocardial repair. Circulation Research,103(11),1300-1308
57. Guo Y, He J, Wu J, et al. Locally overexpressing hepatocyte growth factor prevents post-ischemic heart failure by inhibition of apoptosis via calcineurin-mediated pathway and angiogenesis. Archives of Medical Research. 2008;39(2):179-188
58. Ray R, Novotny NM, Crisostomo PR, Lahm T, Abarbanell A, Meldrum DR. Sex steroids and stem cell function. Molecular Medicine.2008;14(7-8):493-501.
59. Yang YJ, Qian HY, Huang J, et al. Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts. European Heart Journal.2008;29(12):1578-1590.
60. Chow DC, Wenning LA, Miller WM, Papoutsakis ET:Modeling pO(2) distributions in the bone marrow hematopoietic compartment. I. Krogh's model. Biophysical Journal 2001,81:675-684.
61. Bizzarri A, Koehler H, Cajlakovic M, Pasic A, Schaupp L, Klimant I, Ribitsch V: Continuous oxygen monitoring in subcutaneous adipose tissue using microdialysis. Analytica Chimica Acta 2006,573:48-56.
62. Harrison JS, Rameshwar P, Chang V, Bandari P:Oxygen saturation in the bone marrow of healthy volunteers. Blood 2002,99:394-394.
63. Frangogiannis, N. G., Smith, C. W., & Entman, M. L. The inflammatory response in myocardial infarction. Cardiovascular Research.2002:P53(1),31-47.
64. Nian, M., Lee, P., Khaper, N., & Liu, P. (2004). Inflammatory cytokines and postmyocardial infarction remodeling. Circulation Research,94(12),1543-1553.
65. Nah, D. Y., & Rhee, M. Y. (2009). The inflammatory response and cardiac repair after myocardial infarction. Korean Circulation Journal,39(10),393-398.
66. Kollar, K., Cook, M. M., Atkinson, K.,& Brooke, G. (2009). Molecular mechanisms involved in mesenchymal stem cell migration to the site of acute myocardial infarction. International Journal of Cell Biology, p.904682.
67. Neuss, S., Becher, E., Woltje, M., Tietze, L.,& Jahnen-Dechent, W. (2004). Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem Cells,22(3),405-414.
68. Steingen, C, Brenig, F., Baumgartner, L., Schmidt, J., Schmidt, A.,& Bloch, W. (2008). Characterization of key mechanisms in transmigration and invasion of mesenchymal stem cells. Journal of Molecular and Cellular Cardiology,44(6), 1072-1084.
69. Hatzistergos, K. E., Quevedo, H., Oskouei, B. N., et al. (2010). Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research,107(7),913-922.
70. Noiseux, N., Gnecchi, M., Lopez-Ilasaca, M., et al. (2006). Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Molecular Therapy,14(6),840-850.
71. Arminan, A., Gandia, C., Bartual, M., et al. (2009). Cardiac differentiation is driven by NKX2.5 and GATA4 nuclear translocation in tissue-specific mesenchymal stem cells. Stem Cells and Development,18(6),907-918.
72. Tang, Y. L., Zhao, Q., Qin, X., et al. (2005). Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. The Annals of Thoracic Surgery,80(1),229-236. discussion 236-7.
73. Mirotsou, M., Jayawardena, T. M., Schmeckpeper, J., Gnecchi, M., & Dzau, V. J. (2011). Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. Journal of Molecular and Cellular Cardiology,50(2),280-289.
74. Gnecchi, M., Zhang, Z., Ni, A., & Dzau, V. J. (2008). Paracrine mechanisms in adult stem cell signaling and therapy. Circulation Research,103(11),1204-1219.
75. Gnecchi, M., He, H., Noiseux, N., et al. (2006). Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. The FASEB Journal,20(6),661-669.
76. Nguyen, B. K., Maltais, S., Perrault, L. P., et al. (2010). Improved function and myocardial repair of infarcted heart by intracoronary injection of mesenchymal stem cell-derived growth factors. Journal of Cardiovascular Translational Research,3(5),547-558.
77. Timmers, L., Lim, S. K., Hoefer, I. E., et al. (2011). Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Research,6(3),206-214.
78. Freyman, T., Polin, G., Osman, H., et al. (2006). A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. European Heart Journal,27(9),1114-1122.
1. S. Mendis, P. Puska, and B. Norrving, Global Atlas on Cardiovascular Disease Prevention and Control,World Health Organization, Geneva, Switzerland,2011.
2. Kajstura, J., Cheng, W., Reiss, K., et al. (1996). Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Laboratory Investigation,74(1),86-107.
3. Sun, Y., Zhang, J. Q., Zhang, J.,& Lamparter, S. (2000). Cardiac remodeling by fibrous tissue after infarction in rats. The Journal of Laboratory and Clinical Medicine,135(4),316-323.
4. Sutton, M. G.,& Sharpe, N. (2000). Left ventricular remodeling after myocardial infarction:pathophysiology and therapy. Circulation,101(25),2981-2988.
5. Andersen, H. R., Nielsen, T. T., Rasmussen, K., et al. (2003). A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. The New England Journal of Medicine,349(8),733-742.
6. Costanzo, M. R., Augustine, S., Bourge, R., et al. (1995). Selection and treatment of candidates for heart transplantation. A statement for health professionals from the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation,92(12),3593-3612.
7. Segers, V. F.,& Lee, R. T. (2008). Stem-cell therapy for cardiac disease. Nature, 451(7181),937-942.
8. Tongers, J., Losordo, D. W.,& Landmesser, U. (2011). Stem and progenitor cell-based therapy in ischaemic heart disease:promise, uncertainties, and challenges. European Heart Journal,32(10),1197-1206.
9. Janssens, S. (2010). Stem cells in the treatment of heart disease. Annual Review of Medicine,61,287-300. C
10. Arminan, A., Gandia, C., Garcia-Verdugo, J. M., et al. (2010). Mesenchymal stem cells provide better results than hematopoietic precursors for the treatment of myocardial infarction. Journal of the American College of Cardiology,55(20), 2244-2253.
11. Martinez, E. C.,& Kofidis, T. (2011). Adult stem cells for cardiac tissue engineering. Journal of Molecular and Cellular Cardiology,50(2),312-319.
12. Herrmann, J. L., Abarbanell, A. M., Weil, B. R., et al. (2011). Optimizing stem cell function for the treatment of ischemic heart disease. Journal of Surgical Research,166(1),138-145.
13. Haider, H.,& Ashraf, M. (2010). Preconditioning and stem cell survival. Journal of Cardiovascular Translational Research,3(2),89-102.
14. Gulati R, Simari RD. Cell Therapy for Acute Myocardial Infarction. Medical Clinics of North America.2007;91(4):769-785.
15. Smith AG. Embryo-derived stem cells:of mice and men. Annual Review of Cell and Developmental Biology.2001;17:435-462
16. Min JY, Yang Y, Sullivan MF, et al. Long-term improvement of cardiac function in rats after infarction by transplantation of embryonic stem cells. Journal of Thoracic and Cardiovascular Surgery.2003;125(2):361-369.
17. Solter D. From teratocarcinomas to embryonic stem cells and beyond:a history of embryonic stem cell research. Nature Reviews Genetics.2006;7(4):319-327.
18. Saric T, Frenzel LP, Hescheler J. Immunological barriers to embryonic stem cell-derived therapies. Cells Tissues Organs.2008;188(1-2):78-90.
19. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature.2001;410(6829):701-705.
20. Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissmann IL, Robbins RC. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature.2004;428(6983):668-673.
21. 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. Circulation Research. 2004;94(5):678-685.
22. Kocher AA, Schuster MD, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nature Medicine. 2001;7(4):43-436.
23. Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. Journal of the American College of Cardiology.2003;41(7):1078-1083.
24. Menasche P, Alfieri O, Janssens S, et al. The myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial:first randomized placebo-controlled study of myoblast transplantation. Circulation.2008;117(9):1189-1200.
25. Hochedlinger K, Jaenisch R. Nuclear reprogramming and pluripotency. Nature. 2006;441(7097):1061-1067.
26. Jaenisch R, Young R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell.2008;132(4):567-582.
27. Nakagawa M, Koyanagi M, Tanabe K, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnology. 2008;26(1):101-106.
28. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell.2007; 131(5):861-872.
29. Yamanaka S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell.2007;1(1):39-49.
30. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science.2007;318(5858):1917-1920.
31. Nelson TJ, Martinez-Fernandez A, Yamada S, Perez-Terzic C, Dceda Y, Terzic A. Repair of acute myocardial infarction with induced pluripotent stem cells induced by human sternness factors. Circulation.2009;120(5):408-416.
32. Zhang J, Wilson GF, Soerens AG, et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circulation Research.2009;104(4):e30-
33. Menasche, P. (2011). Cardiac cell therapy:lessons from clinical trials. Journal of Molecular and Cellular Cardiology,50(2),258-265.
34. Rosenzweig, A. (2006). Cardiac cell therapy-mixed results from mixed cells. The New England Journal of Medicine,355(12),1274-1277.
35. Passier, R., van Laake, L. W., & Mummery, C. L. (2008). Stem-cell-based therapy and lessons from the heart. Nature,453(7193),322-329.
36. Wollert, K. C., & Drexler, H. (2010). Cell therapy for the treatment of coronary heart disease:a critical appraisal. Nature Reviews Cardiology,7(4),204-215.
37. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell and Tissue Kinetics.1970;3(4):393-403.
38. Friedenstein AJ, Chailakhyan RK, Latsinik NV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation.1974;17(4):331-340.
39. Caplan AI. Molecular and cellular differentiation of muscle, cartilage, and bone in the developing limb. Progress in Clinical and Biological Research.1986;217:307-318.
40. Piersma AH, Brockbank KGM, Ploemacher RE. Characterization of fibroblastic stromal cells from murine bone marrow. Experimental Hematology. 1985;13(4):237-243.
41. Wakitani S, Saito T, Caplan AI. Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle and Nerve. 1995;18(12):1417-1426.
42. Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proceedings of the National Academy of Sciences of the United States of America.1999;96(19):10711-10716.
43. Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. Journal of Clinical Investigation.1999;103(5):697-705.
44. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation.2002; 105(1):93-98.
45. Pal S, Kofidis T. New cell therapies in cardiology Expert Rev. Cardiovasc. Ther. 2012:10(8),1023-1037.
46. Puissant B, Barreau C, Bourin P, et al., Immunomodulatory effect of human adipose tissue-derived adult stem cells:comparison with bone marrowmesenchymal stem cells. British Journal of Haematology.2005:vol.129, no. 1,pp.118-129.
47. Weiss M. L, Anderson C, Medicetty S, et al., Immune properties of human umbilical cord Wharton's jelly-derived cells. Stem Cells.2008:vol.26, no.11, pp. 2865-2874.
48. Boyle AJ, McNiece IK, Hare JM. Mesenchymal stem cell therapy for cardiac repair. Methods in Molecular Biology.2010;660:65-84.
49. Khan M, Meduru S, Gogna R, et al. Oxygen cycling in conjunction with stem cell transplantation induces NOS3 expression leading to attenuation of fibrosis and improved cardiac function. Cardiovascular Research.2012;93(1):89-99.
50. Ryan JM, Barry FP, Murphy JM, Mahon BP. Mesenchymal stem cells avoid allogeneic rejection. Journal of Inflammation.2005;2:8
51. Kemp KC, Hows J, Donaldson C. Bone marrow-derived mesenchymal stem cells. Leukemia and Lymphoma.2005;46(11):1531-1544.
52. Zimmet JM, Hare JM. Emerging role for bone marrow derived mesenchymal stem cells in myocardial regenerative therapy. Basic Research in Cardiology. 2005; 100(6):471-481.
53. Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics. Circulation Research.2004;95(1):9-20.
54. Simonsen, J. L., Rosada, C., Serakinci, N., et al. (2002). Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nature Biotechnology,20(6),592-596.
55. Patel SA, Sherman L, Munoz J, Rameshwar P. Immunological properties of mesenchymal stem cells and clinical implications. Archivum Immunologiae et Therapiae Experimentalis.2008;56(1):1-8.
56. Beyth, S., Borovsky, Z., Mevorach, D., et al. (2005). Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood,105(5),2214-2219.
57. Frangogiannis, N. G., Smith, C. W., & Entman, M. L. The inflammatory response in myocardial infarction. Cardiovascular Research.2002:P53(1),31-47.
58. Nian, M., Lee, P., Khaper, N., & Liu, P. (2004). Inflammatory cytokines and postmyocardial infarction remodeling. Circulation Research,94(12),1543-1553.
59. Nah, D. Y., & Rhee, M. Y. (2009). The inflammatory response and cardiac repair after myocardial infarction. Korean Circulation Journal,39(10),393-398.
60. Kollar, K., Cook, M. M., Atkinson, K.,& Brooke, G. (2009). Molecular mechanisms involved in mesenchymal stem cell migration to the site of acute myocardial infarction. International Journal of Cell Biology, p.904682.
61. Neuss, S., Becher, E., Woltje, M., Tietze, L., & Jahnen-Dechent, W. (2004). Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem Cells,22(3),405-414.
62. Majumdar, M. K., Keane-Moore, M., Buyaner, D., et al. (2003). Characterization and functionality of cell surface molecules on human mesenchymal stem cells. Journal of Biomedical Science,10(2),228-241.
63. Thankamony, S. P.,& Sackstein, R. (2011). Enforced hematopoietic cell E-and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells. Proceedings of the National Academy of Sciences of the United States of America,108(6),2258-2263.
64. Steingen, C, Brenig, F., Baumgartner, L., Schmidt, J., Schmidt, A.,& Bloch, W. (2008). Characterization of key mechanisms in transmigration and invasion of mesenchymal stem cells. Journal of Molecular and Cellular Cardiology,44(6), 1072-1084.
65. Quevedo, H. C., Hatzistergos, K. E., Oskouei, B. N., et al. (2009). Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proceedings of the National Academy of Sciences of the United States of America,106(33),14022-14027.
66. Hatzistergos, K. E., Quevedo, H., Oskouei, B. N., et al. (2010). Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research,107(7),913-922.
67. Freyman, T., Polin, G., Osman, H., et al. (2006). A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. European Heart Journal,27(9),1114-1122.
68. Shake, J. G., Gruber, P. J., Baumgartner, W. A., et al. (2002). Mesenchymal stem cell implantation in a swine myocardial infarct model:engraftment and functional effects. The Annals of Thoracic Surgery,73(6),1919-1925. discussion 1926.
69. Jiang, W., Ma, A., Wang, T., et al. (2006). Homing and differentiation of mesenchymal stem cells delivered intravenously to ischemic myocardium in vivo: a time-series study. Pfliigers Archiv,453(1),43-52.
70. Noiseux, N., Gnecchi, M., Lopez-Ilasaca, M., et al. (2006). Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Molecular Therapy,14(6),840-850.
71. Arminan, A., Gandia, C., Bartual, M., et al. (2009). Cardiac differentiation is driven by NKX2.5 and GATA4 nuclear translocation in tissue-specific mesenchymal stem cells. Stem Cells and Development,18(6),907-918.
72. Tang, Y. L., Zhao, Q., Qin, X., et al. (2005). Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. The Annals of Thoracic Surgery,80(1),229-236. discussion 236-7.
73. Gnecchi, M., He, H., Noiseux, N., et al. (2006). Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. The FASEB Journal,20(6),661-669.
74. Mirotsou, M., Jayawardena, T. M., Schmeckpeper, J., Gnecchi, M., & Dzau, V. J. (2011). Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. Journal of Molecular and Cellular Cardiology,50(2),280-289.
75. Gnecchi, M., Zhang, Z., Ni, A., & Dzau, V. J. (2008). Paracrine mechanisms in adult stem cell signaling and therapy. Circulation Research,103(11),1204-1219.
76. Uemura, R., Xu, M., Ahmad, N., & Ashraf, M. (2006). Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circulation Research,98(11),1414-1421.
77. Haynesworth, S. E., Baber, M. A., & Caplan, A. I. (1996). Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro:effects of dexamethasone and IL-1 alpha. Journal of Cellular Physiology,166(3),585-592.
78. Nguyen, B. K., Maltais, S., Perrault, L. P., et al. (2010). Improved function and myocardial repair of infarcted heart by intracoronary injection of mesenchymal stem cell-derived growth factors. Journal of Cardiovascular Translational Research,3(5),547-558.
79. Timmers, L., Lim, S. K., Hoefer, I. E., et al. (2011). Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Research,6(3),206-214.
80. Fazel S, Chen L, Weisel RD, et al. Cell transplantation preserves cardiac function after infarction by infarct stabilization:augmentation by stem cell factor. Journal of Thoracic and Cardiovascular Surgery.2005;130(5):p.1310.
81. Tomita S, Li RK, Weisel RD, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation.1999;100(19, supplement):II247-II256.
82. Grauss RW, Van Tuyn J, Steendijk P, et al. Forced myocardin expression enhances the therapeutic effect of human mesenchymal stem cells after transplantation in ischemic mouse hearts. Stem Cells.2008;26(4):1083-1093.
83. de Macedo Braga LMG, Lacchini S, Schaan BD, et al. In situ delivery of bone marrow cells and mesenchymal stem cells improves cardiovascular function in hypertensive rats submitted to myocardial infarction. Journal of Biomedical Science.2008;15(3):365-374.
84. Imanishi Y, Saito A, Komoda H, et al. Allogenic mesenchymal stem cell transplantation has a therapeutic effect in acute myocardial infarction in rats. Journal of Molecular and Cellular Cardiology.2008;44(4):662-671.
85. Gyongyosi M, Blanco J, Marian T, et al. Serial noninvasive in vivo positron emission tomographic tracking of percutaneously intramyocardially injected autologous porcine mesenchymal stem cells modified for transgene reporter gene expression. Circulation.2008; 1(2):94-103.
86. Hashemi SM, Ghods S, Kolodgie FD, et al. A placebo controlled, dose-ranging, safety study of allogenic mesenchymal stem cells injected by endomyocardial delivery after an acute myocardial infarction. European Heart Journal. 2008;29(2):251-259.
87. Hatzistergos KE, Quevedo H, Oskouei BN, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research.2010; 107(7):913-922.
88. Silva GV, Litovsky S, Assad JAR, et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation.2005; 111(2):150-156.
89. Miyahara Y, Nagaya N, Kataoka M, et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nature Medicine. 2006;12(4):459-465.
90. Minguell JJ, Erices A. Mesenchymal stem cells and the treatment of cardiac disease. Experimental Biology and Medicine.2006;231(1):39-49.
91. Nesselmann C, Ma N, Bieback K, et al. Mesenchymal stem cells and cardiac repair. Journal of Cellular and Molecular Medicine B.2008; 12(5):1795-1810.
92. 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. American Journal of Cardiology. 2004;94(1):92-95
93. Katritsis DG, Sotiropoulou PA, Karvouni E, et al. Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium. Catheterization and Cardiovascular Interventions. 2005;65(3):321-329.
94. Katritsis DG, Sotiropoulou P, Giazitzoglou E, Karvouni E, Papamichail M. Electrophysiological effects of intracoronary transplantation of autologous mesenchymal and endothelial progenitor cells. Europace.2007;9(3):167-171.
95. Hare JM, Traverse JH, Henry TD, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. Journal of the American College of Cardiology.2009;54(24):2277-2286.
96. Bartunek J, Wijns D, Dolatabadi M, et al. C-cure multicenter trial:lineage specified bone marrow derived cardiopoietic mesenchymal stem cells for treatment of ischemic cardiomyopathy. Journal of the American College of Cardiology.2011;57, article 200
97. Freyman T, Polin G, Osman H, et al. A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. European Heart Journal.2006;27(9):1114-1122.
98. Song H, Song BW, Cha MJ, Choi IG, Hwang KC. Modification of mesenchymal stem cells for cardiac regeneration. Expert Opinion on Biological Therapy. 2010;10(3):309-319.
99. Mylotte LA, Duffy AM, Murphy M, et al. Metabolic flexibility permits mesenchymal stem cell survival in an ischemic environment. Stem Cells. 2008;26(5):1325-1336.
100. Zhu WG, Li S, Lin LQ, Yan H, Fu T, Zhu JH. Vascular oxidative stress increases dendritic cell adhesion and transmigration induced by homocysteine. Cellular Immunology.2009;254(2):110-116.
101. Frangogiannis NG. Targeting the inflammatory response in healing myocardial infarcts. Current Medicinal Chemistry.2006;13(16):1877-1893.
102. Huang, J., Zhang, Z., Guo, J., et al. (2010). Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circulation Research,106(11),1753-1762.
103. Kobayashi, K., Luo, M., Zhang, Y., et al. (2009). Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction. Nature Cell Biology,11(1),46-55.
104. Alfaro, M. P., Pagni, M., Vincent, A., et al. (2008). The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair. Proceedings of the National Academy of Sciences of the United States of America,105(47),18366-18371.
105. Tsubokawa, T., Yagi, K., Nakanishi, C., et al. (2010). Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia. American Journal of Physiology-Heart and Circulatory Physiology,298(5), H1320-H1329.
106. Li, W., Ma, N., Ong, L. L., et al. (2007). Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells,25(8),2118-2127.
107. Wang, D., Shen, W., Zhang, F., Chen, M., Chen, H., & Cao, K. (2010). Connexin43 promotes survival of mesenchymal stem cells in ischaemic heart. Cell Biology International,34(4),415-423.
108. Tang, J. M., Wang, J. N., Zhang, L., et al. (2011). VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovascular Research.
109. Duan, H. F., Wu, C. T., Wu, D. L., et al. (2003). Treatment of myocardial ischemia with bone marrow-derived mesenchymal stem cells overexpressing hepatocyte growth factor. Molecular Therapy,8(3),467-474.
110. Haider, H., Jiang, S., Idris, N. M.,& Ashraf, M. (2008). IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-lalpha/CXCR4 signaling to promote myocardial repair. Circulation Research,103(11),1300-1308.
111. Guo Y, He J, Wu J, et al. Locally overexpressing hepatocyte growth factor prevents post-ischemic heart failure by inhibition of apoptosis via calcineurin-mediated pathway and angiogenesis. Archives of Medical Research. 2008;39(2):179-188.
112. Ray R, Novotny NM, Crisostomo PR, Lahm T, Abarbanell A, Meldrum DR. Sex steroids and stem cell function. Molecular Medicine.2008;14(7-8):493-501.
113. Yang YJ, Qian HY, Huang J, et al. Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts. European Heart Journal.2008;29(12):1578-1590.
114. Chow DC, Wenning LA, Miller WM, Papoutsakis ET:Modeling pO(2) distributions in the bone marrow hematopoietic compartment. I. Krogh's model. Biophysical Journal 2001,81:675-684.
115. Bizzarri A, Koehler H, Cajlakovic M, Pasic A, Schaupp L, Klimant I, Ribitsch V:Continuous oxygen monitoring in subcutaneous adipose tissue using microdialysis. Analytica Chimica Acta 2006,573:48-56.
116. Harrison JS, Rameshwar P, Chang V, Bandari P:Oxygen saturation in the bone marrow of healthy volunteers. Blood 2002,99:394-394. 。
117. Ward JPT:Oxygen sensors in context. Biochimica Et Biophysica Acta-Bioenergetics 2008,1777:1-14.
118. Miller WM, Wilke CR, Blanch HW:Effects of Dissolved-Oxygen Concentration on Hybridoma Growth and Metabolism in Continuous Culture. Journal of Cellular Physiology 1987,132:524-530.
119. Rosova I, Dao M, Capoccia B, Link D, Nolta JA:Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 2008,26:2173-2182.
120. 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;98:1414-21.
121. Hu X, Yu SP, Fraser JL, Lu Z, Ogle ME, Wang JA, Wei L. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J Thorac Cardiovasc Surg 2008;135:799-808.