干细胞移植因其可能促进心肌梗死(myocardial infarction, MI)后损伤心肌的修复和再生已经成为当前的研究热点。骨髓间充质干细胞(bone marrow mesenchymal stem cells, MSCs)具备许多其它干细胞没有的优点而被认为是细胞移植治疗心肌梗死的理想种子细胞。MSCs主要通过分化成心肌细胞、促进血管新生或者旁分泌作用等实现心肌损伤后的修复。然而,心肌梗死导致心肌缺血缺氧和大量氧自由基的产生使移植的干细胞存活率急剧下降,严重影响了干细胞效应功能的发挥。因此,深入了解心脏微环境中干细胞凋亡和抗凋亡机制能够为提高干细胞的治疗效果提供有效的理论依据。我们之前的研究已经对缺氧无血清和过氧化氢刺激诱导的MSCs凋亡及其机制进行了深入研究,并且进一步证明了溶血磷脂酸(Lysophophatidic acid, LPA)作为一种内源性的生物活性磷脂信号小分子可以通过G蛋白偶联的LPA受体有效抑制缺氧无血清(hypoxia/serum deprivation, H/SD)诱导的MSCs的凋亡,但是LPA对过氧化氢诱导的MSCs凋亡是否起抑制作用尚不清楚。自噬是哺乳动物细胞降解和回收利用生物大分子和细胞器的主要代谢通路,在调节H/SD和氧化应激条件下细胞的存活和凋亡过程中起到了重要作用,但是自噬是否参与H/SD和过氧化氢条件下对MSCs的保护作用尚不明确。并且,LPA对自噬的作用是否有利于MSCs的存活也是一个未知数。
因此,我们以大鼠骨髓间充质干细胞为研究对象,体外利用过氧化氢和缺氧无血清模拟心肌梗死后的氧化应激和缺血环境,研究LPA是否能够抑制过氧化氢诱导的大鼠MSCs凋亡,探讨自噬对过氧化氢和缺氧无血清环境诱导的MSCs凋亡所起的作用,并进一步验证LPA对自噬的调节是否参与LPA对MSCs凋亡过程的调节,并对其调节机制进行深入分析,最终达到对LPA调节的MSCs凋亡和自噬及其关系进行确认的目的。
研究内容主要包括以下两部分：
1.LPA对过氧化诱导的骨髓间充质干细胞凋亡的调节及其机理研究(1)H202诱导大鼠MSCs凋亡呈浓度和时间依赖性。不同浓度过氧化氢(50,100,150,200,250μM)处理MSCs不同时间(0,2,4,6,8h),Hoechst33342染色显示,随着H202浓度升高皱缩的细胞核和断裂的DNA的比率不断升高,Western blot结果实验显示随着处理时间延长活性caspase3的表达水平逐渐升高,其中250μM H2O2处理MSCs4h时,H202诱导的MSCs凋亡水平开始呈现出显著变化,因此这个处理条件作为制备氧化应激模型的基础条件。
(2)LPA显著抑制H202诱导的MSCs凋亡。表现为：利用不同浓度LPA(1,5,10,25,50μM)分别预处理1h后用H202处理4h,Hoechst33342染色显示受损细胞形态百分比明显降低,Western blot分析显示cleaved-caspase3的表达也明显降低,流式细胞学分析表明Annexin v+/pI和AnnexinV+/PI+细胞的比例明显降低,这些数据表明LPA能够显著抑制过氧化氢诱导的MSCs凋亡作用。
(3)LPA抑制H202诱导的凋亡主要通过Gi蛋白偶联的Lpar3受体激活PI3K/AKT和ERK1/2途径实现。表现在：①Lpar1/3受体抑制剂Ki16425和Gi蛋白特异抑制剂PTX显著逆转了LPA的抗凋亡作用,表现为cleaved-caspase3的表达升高和Annexin V+/PI-田胞百分比增加；②siRNA分别敲低Lparl和Lpar3, Western blot和流式细胞术结果证明Lpar3介导了抗过氧化氢诱导的凋亡作用；③siRNA分别敲低Gi2和Gi3的实验证明Gi2和Gi3蛋白同时参与了LPA介导的抗凋亡途径；④用LPA分别处理MSCs不同时间(0,5,10,15,30,60min),发现LPA分别在5min和10min可以激活AKT和ERK1/2的磷酸化,Ki16425和PTX可以有效抑制LPA激活AKT和ERK1/2通路；⑤ERK1/2通路抑制剂U0126和P13K通路抑制剂LY294002显著抑制了LPA的抗凋亡作用。这些数据表明,LPA可以通过Gi蛋白偶联的Lpar3受体激活P13K/AKT和ERK1/2信号通路抑制过氧化氢诱导的MSCs的凋亡
(4)过氧化氢诱导MSCs自噬对细胞存活起保护作用。表现为：①H202可诱导自噬标志物LC3B Ⅱ/Ⅰ比例的升高和P62表达下降,BECN的表达在各组间没有显著变化；②自噬激动剂GF109203x和抑制齐Bafilomycin A1处理MSCs显示GF109203x可以显著减弱过氧化氢诱导的cleaved-caspase3的升高,而Bafilomycin A1对过氧化氢诱导的MSCs凋亡没有任何显著作用；
(5)LPA介导的抗过氧化氢诱导的凋亡作用不依赖于其促自噬作用。表现为：①与过氧化氢组相比,LPA可诱导自噬标志物LC3B Ⅱ/Ⅰ比例升高,P62保持不变；②自噬抑制剂Bafilomycin A1对LPA的抗凋亡作用没有显著影响。这些结果初步证明LPA介导的抑制过氧化氢诱导的凋亡作用与其诱导的自噬作用没有关系。
第一部分小结：过氧化氢可以显著诱导MSCs的凋亡,LPA预处理可以显著抑制过氧化氢诱导的MSCs凋亡作用,LPA的这种抗凋亡作用通过Gi蛋白偶联的Lpar3受体激活PI3K/AKT和ERK1/2信号通路实现,过氧化氢诱导的自噬对MSCs存活起保护作用,LPA虽然可以促进MSCs自噬但是其促自噬作用并没有参与LPA抵抗过氧化氢诱导的损伤过程,表明在氧化应激条件下LPA的抗凋亡作用与LPA的促自噬作用没有关系。
2.自噬途径在LPA抗缺氧无血清诱导的MSCs凋亡过程的作用及机制研究
(1)H/SD诱导的自噬作用对MSCs存活起保护作用。表现为：①H/SD处理MSCs不同时间点(6,12,24h),结果显示H/SD处理6h已经可以显著诱导凋亡相关蛋白cleaved-caspase3升高和Bcl2/Bax比值下降,自噬相关蛋白LC3B Ⅱ/Ⅰ显著升高和P62降低,而BECN的表达没有显著变化；②利用自噬促进剂GF109203x和雷帕霉索(Rapamycin)以及自噬抑制剂巴弗洛霉素(Bafilomycin A1)和3-MA分别预处理MSCs90min后,进行H/SD处理6h,发现GF109203x和Rapamycin可以显著减弱cleaved-caspase3升高和Bcl2/Bax下降,而Bafilomycin A1和3-MA进一步加强了cleaved-caspase3升高和Bcl2/Bax降低。初步研究表明H/SD处理MSCs6h诱导的自噬对MSCs的存活起保护作用。
(2)H/SD6h条件下LPA促进MSCs自噬参与了LPA的抗凋亡过程。表现为：①LPA呈浓度依赖的进一步促进LC3B Ⅱ/Ⅰ升高,P62在加入LPA前后没有发生显著变化,表明在H/SD6h条件下LPA可以进一步激活MSCs自噬；②不同浓度LPA(1,5,10,25,50μM)预处理MSCs可以显著抑制cleaved-caspase3升高和Bcl2/Bax降低；③利用自噬抑制剂Bafilomycin A1口3-MA预处理MSCs90min后,LPA处理60min,之后进行H/SD处理6h,发现LPA抑制H/SD诱导的MSCs凋亡作用被部分抑制,表明LPA的抗凋亡能力下降与自噬途径被抑制有关。
③LPA促自噬通过Gi蛋白和其它G蛋白偶联的Lpar1/3受体实现。表现为：①Lparl/3受体抑制剂Ki16425可以显著抑制LPA的促自噬的作用；②Gi蛋白抑制剂PTX可以部分抑制LPA诱导的自噬作用。表明LPA的促自噬作用通过Lpar1/3受体偶联的Gi或其它类型的G蛋白实现。
(4)LPA促进MSCs自噬依赖于ERK1/2和AMPK途径。表现在：①我们课题组之前的结果已经证明LPA可以通过Gi蛋白偶联的Lpar1/3受体激活AKT和ERK1/2的磷酸化信号通路,本研究中我们进一步证明LPA可以激活AMPK的磷酸化,并且Ki16425预处理可以抑制LPA促进AMPK磷酸化作用,而PTX预处理对AMPK的磷酸化没有影响；②PI3K抑制剂LY294002、ERK1/2抑制剂U0126和AMPK抑制剂Compound C处理均可以显著减弱H/SD诱导MSCs凋亡；③LY294002、U0126和Compound C预处理MSCs后,只有U0126和Compound C可以降低LPA的促自噬作用。这些数据表明ERK1/2和AMPK通路参与了LPA的促自噬作用。
第二部分小结：H/SD处理MSCs6h可以显著诱导细胞的凋亡和自噬,H/SD诱导的自噬有利于MCSs的存活,并且在H/SD6h条件下LPA能够促进MSCs自噬作用参与了LPA的抗凋亡过程,LPA的促自噬过程主要通过Lpar1/3偶联的Gi蛋白介导的ERK1/2通路和Lpar1/3偶联其它G蛋白介导的AMPK通路实现。
本研究首次证明了过氧化氢诱导的MSCs凋亡可以被LPA所抑制,并且发现LPA的这种抗凋亡作用主要通过Lpar3受体偶联Gi蛋白激活PI3K/AKT和ERK1/2实现,这与之前研究发现的LPA抑制缺血无血清诱导的MSCs相结合,揭示了LPA在将来干细胞移植治疗心肌梗死的临床应用中的重要价值。此外,本研究首次分析了,过氧化氢和缺氧无血清条件下LPA可以促进MSCs的自噬,虽然LPA的促自噬作用在其介导的抗过氧化氢诱导的MSCs凋亡中没有发挥作用,但被证明参与抵抑制缺氧无血清诱导的MSCs凋亡,并进一步分析得到H/SD条件下ERK1/2和AMPK参与了LPA的促自噬作用,为进一步改善MSCs移植治疗心肌梗死的临床应用提供了新思路。鉴于自噬作用参与多种细胞生物学过程(细胞的增殖、分化和迁移等),深入研究干细胞中LPA对自噬的调节与多种细胞学行为之间的关系将会对未来LPA应用于干细胞移植治疗心肌梗死提供更有利的证据。
It has been demonstrated that stem cell transplantation can promote myocardial repair and regeneration in injury myocardium after myocardial infarction (MI), which has currently become a hot area of research. Because bone marrow mesenchymal stem cell (MSC) has many advantages that are not exist in other stem cells, they are considered to be an appealing sourse for cardiac engraftment in the treatment of myocardial infarction. MSCs play their therapeutic roles in myocardium repair mainly through differentiating into myocardial cells, promoting angiogenesis and paracrine role. However, MSCs transplanted into infarcted heart have a low survival rate for the cause of hypoxia/serum deprivation (H/SD) and increasing of reactive oxide species (ROS). Therefore, understanding the mechanisms of apoptosis and anti-apopotosis will provide an effective theoretical basis to improve the therapeutic effect of stem cell. Early investigation indicated that H/SD and hydrogen peroxide (H2O2) can induce MSCs apoptosis and further proved that lysophophatidic acid (LPA), as a kind of endogenous bioactive phospholipid signal molecules, could inhibit MSCs apoptosis induced by H/SD. However, whether LPA can play its anti-apoptosis role in the presence of hydrogen peroxide is not clear. Autophagy, a process for the degradation of protein aggregates and dysfunctional organelles, is required for cellular homeostasis and cell survival in response to stress and is implicated in endogenous protection. Emerging evidence shows that autophagy is associated with the protective effect of ischemic preconditioning and dual role in the situation of H2O2. Meanwhile, the role of LPA on autophagy and apoptosis and their relationship are not clear too.
Therefore, hydrogen peroxide and hypoxia/serum deprivation are used to establish oxide stress and ischemic microenvironments models to study the apoptosis and autophagy effects induced by LPA in rat bone marrow mesenchymal stem cells. We further confirm whether the regulation of autophagy by LPA can influence its regulation of apoptosis. Our main work includes two aspects as follows:
Part Ⅰ:The regulation of LPA on hydrogen oxygen induced bone marrow mesenchymal stem cell apoptosis and its mechanism study
(1) H2O2-induced BMSCs apoptosis presents dose and time dependent. Cells treated with different concentrations of H2O2(50,100,150,200,250μM) for4hours revealed that apoptosis characteristics became significant difference from150μM H2O2and reached top at250μM H2O2. Comparing to the control group, cells in H2O2-treated group presented an abnormal morphology with shrinkage in cell size, chromatin condensation and typical fragmented nuclei. Different period experiment (0,2,4,6,8h) was carried on and from the fourth hour cleaved-caspase3protein level begun to increase obviously. Conclusion together, this data suggests that H2O2induced apoptosis dependently on dose and time and the apoptosis and autophagy are began to be markedly induced in250μM H2O2for4h.
(2) LPA can effectively inhibit BMSCs apoptosis induced by H2O2BMSCs were exposed to increasing concentrations of LPA (1,5,10,25,50μM) and followed by exposure to250μM H2O2for4hours. After staining of hoechst.33342, control cells showed normal elongated stem cell morphology with large regular nuclei, but cells treated by H2O2appeared shrunken cell size and fragmented nuclei. When LPA mixed, apoptosis cells decreased pronouncedly closing to normal group. Flow cytometry analysis indicated that exposure of BMSCs to250μM H2O2resulted in apoptosis percentage of about35%Annexin V+/PI-cells (early stage of apoptosis) and5%Annexin V+/PI+cells (middle/late stage of apoptosis). Western blotting results showed that cleaved-caspase3, a key marker of apoptosis, was remarkably inhibited by LPA comparing to H2O2treatment group. These data demonstrated that10μM LPA could effectively inhibit apoptosis induced by250μM H2O2in rat BMSCs for4h.
(3) LPA inhibits H2O2-induced BMSCs apoptosis through LPAR-3/Gi-coupled pathway.
①BMSCs were pre-treated with antagonist of LPAR-1/3receptor Ki16425(10μM) for90min and Gi protein inhibitor PTX(200ng/ml) forl6h before the exposure to H2O2and LPA. Western blot analyses showed that Ki16425and PTX could significantly increase cleaved-caspase3protein level compared to LPA treatment group. Flow cytometric analyses revealed that Ki16425and PTX could markedly raise the percentage of Annexin V+/PI" cells in the presence of LPA.②Lparl and Lpar3were separately knocked down by siRNA transfection and we found that cleaved-caspase3protein level increased markedly after LPAR-3-siRNA mixing, but not by the addition of LPAR-1-siRNA.③Gi2and Gi3were also knocked down by Gi2-siRNA and Gi3-siRNA respectively and the result showed that cleaved-caspase3protein level both increased after transfection of Gi2-siRNA and Gi3-siRNA.④Western blotting showed that LPA could elicit the phosphorylation of ERK1/2and AKT with a significance increase in the5min and10 min, respectively after stimulation of LPA in rat BMSCs, which could be canceled in the presence of Ki16425and PTX.⑤The ERK1/2inhibitor U0126and PI3K inhibitor LY294002both increased cleaved-caspase3expression and attended the LPA's anti-apoptosis. Flow cytometric analyses appeared that Uo126and LY294002both took part in anti-apoptosis role in early stage of apoptosis (Annexin V+/PI-). These data indicate that LPA inhibits H2O2-induced apoptosis mainly through Gi coupled Lpar3receptor to activiat ERK1/2and PI3K/AKT pathways to inhibition transmissionis of apoptosis signal.
(4) Autophagy showed a protective effect in H2O2-induced BMSCs apoptosis.①It iwas showed that LC3Ⅱ/I ratio increased significantly comparing to control from the forth hour and the expression of P62showed a decease tendency as time went on. However, the expression of BECN has no significant difference during these groups.②autophagy promoter GF109203x and inhibitor Bafilomycin Al were separately pre-added in cell culture medium for90min and followed by exposure to H2O2for4h. Western blotting result indicated that GF109203x partly decreased the expression of cleaved-caspase3. But Bafilomycin A1had nothing role in BMSCs survival or apoptosis. These data explained that H2O2-induced autophagy showed a protective role in BMSCs'survival.
(5) LPA protects BMSCs from HOO2-induced apoptosis independent of autophagy.①BMSCs were exposed to increasing concentrations of LPA (1,5,10,25,50μM) and10μMLPA could effectively increase the transformation rate of LC3B I to LC3BⅡ but with no further decrease of P62expression. However, the expression of Beclinl had no significant differences among these groups.②Bafilomycin A1, a autophagy flux inhibitor aiming at the fusion of autophagosome and lysosome, was used to interrupted most macroautophagy pathway. Comparing with LPA+H2O2group, LPA+H2O2+Bafilomycin Al group showed obvious anti-apoptosis role with no significant difference between them. Accordingly, we concluded that LPA rescued BMSCs from H2O2-induced apoptosis was independent of autophagy.
Part I investigation demonstrated that:H2O2induced BMSCs apoptosis in time-and dose-dependent ways; LPA could effectively inhibit H2O2induced apoptosis; LPA inhibited H2O2-induced apoptosis via Gi-coupled LPAR-3receptor to activate ERK1/2and PI3K/AKT signaling pathway; LPA could promote H2O2-induced autophagy which has no connection with the anti-apoptosis role of LPA.
Part II:The regulation of autophagy in the process of H/SD-induced bone marrow mesenchymal stem cell apoptosis influenced by lysophophatidic acid.
(1) Autophagy showed a protective effect in H/SD-induced BMSCs apoptosis.①It iwas showed that LC3Ⅱ/Ⅰ ratio increased significantly comparing to control from the sixth hour and the expression of P62showed a decease tendency as time went on. However, the expression of BECN has no significant difference during these groups.②autophagy promoter GF109203x and rapamycin and autophagy inhibitor Bafilomycin A1and3-MA were separately pre-added in cell culture medium. Western blotting result indicated that GF109203x and rapamycin partly weakened the expression of cleaved-caspase3and increased the ratio of Bcl2/Bax. But Bafilomycin Al and3-MA increased the expression of cleaved-caspase3and decreased the ratio of Bcl2/Bax. These data explained that H/SD-induced autophagy had a protective role in BMSCs survival.
(2) The autophagy induced by LPA in H/SD situation taked part in the anti-apoptosis process of LPA.①Different concentrations of LPA (1,5,10,25,50μM) could increase the transformation rate of LC3B I to LC3B II but with no further decrease of P62expression. However, the expression of Beclinl had no significant differences among these groups.②LPA could effectively inhibit cleaved-caspase3level and increase the ratio of Bcl2/Bax.③aotophagy inhibitor Bafilomycin Al and3-MA weakened the anti-apoptosis role of LPA comparing with LPA group. These data suggested that the dcrease of anti-apoptosis role of LPA has a relationship with the inhibition of autophagy.
(3) LPA promoted MSCs autophagy mainly through Gi coupled and other G protein coupled Lpar3receptor pathways.①Lparl/3inhibitor Ki16425could evidently prevent the pro-autophagy role of LPA.②Gi protein inhibitor PTX could partly suppress autophagy induced by LPA in H/SD.
(4) Autophagy induced by LPA in the situation of H/SD dependented on the pathways of ERK1/2and AMPK.①Our group has demonstrated that LPA can stimulate phosphorylation of ERK1/2and AKT through Gi coupled Lparl/3pathway. We further proved that LPA could activate AMPK's phosphorylation which could be inhibited by Lparl/3inhibitor Kil6425but with no influence with the adding of PTX.②PI3K inhibitor LY294002, ERK1/2inhibitor U0126and AMPK inhibitor Compound C could all attenuate the anti-apoptosis of LPA.③Only U0126and Compound C could prevent the pro-autophagy effect of LPA. These results suggested that ERK1/2and AMPK took part in LPA-induced autophagy.
PartⅡinvestigated that H/SD could induce MCSs apoptosis and autophagy in time dependent way and from sixth hour the level of apoptosis and autophagy began to increase markedly. H/SD-induced autophagy in MSCs showed a protective role in the cel survival. LPA could promote MSCs autophagy which was proved to take part in the anti-apoptosis reponse against H/SD. It was finaly testified that LPA-elicited autophagy mainly by binding Lparl/3coupling Gi protein to activate ERK1/2pathway and other G protein to activate AMPK pathway.
In this study it was proved first that H2O2-induced apoptosis could be cancled by LPA. We further found that LPA played its anti-apoptois role against H2O2mainly by bingding Lpar3receptor coupling Gi protein to activate PI3K/AKT and ERK1/2pathways, along with the anti-apoptosis role of LPA against H/SD, which revealed the important values of LPA in the stem cell engrafment for the treatment of yocardial infarction. Besides, we first analyzed the pro-autophagy response of LPA under the condtions of hydrogen peroxide and H/SD. Although autophagy induced by LPA under the existence of H2O2had no connection with LPA's anti-apoptosis role, LPA-induced autophagy in H/SD showed a significant role for its anti-apoptosis effect. The pro-autophagy mechanism by LPA was mainly through Lparl/3coupling Gi protein to activate ERK1/2pathway and other G protein to activate AMPK pathway, which provides a new sight for improving the effect of stem cell transplanting in the treatment of myocardial infartion. Given that autophagy involves in a variety of cell biology processes such as cell proliferation, differentiation and migration, further in-depth studies for the relationships between the autophagy regulation of LPA and variety of cytological behaviors will provide a strong evidence for the stem cell engrafment for the treatment of myocardial infarion.
1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS et al: Executive summary:heart disease and stroke statistics-2013 update:a report from the American Heart Association. Circulation 2013,127(1):143-152.
2. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS et al: Heart disease and stroke statistics-2013 update:a report from the American Heart Association. Circulation 2013, 127(1):e6-e245.
3. Pfeffer MA, Pfeffer JM:Ventricular enlargement following a myocardial infarction. Journal of cardiovascular pharmacology 1987,9 SuppI 2:S18-20.
4. Braunwald E, Pfeffer MA:Ventricular enlargement and remodeling following acute myocardial infarction:mechanisms and management. The American journal of cardiology 1991,68(14):1D-6D.
5. Pfeffer MA, Braunwald E:Ventricular enlargement following infarction is a modifiable process. The American journal of cardiology 1991, 68(14):127D-131D.
6. Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H et al: Cardiomyocytes can be generated from marrow stromal cells in vitro. The Journal of clinical investigation 1999, 103(5):697-705.
7. Payne TR, Oshima H, Okada M, Momoi N, Tobita K, Keller BB, Peng H, Huard J:A relationship between vascular endothelial growth factor, angiogenesis, and cardiac repair after muscle stem cell transplantation into ischemic hearts. Journal of the American College of Cardiology 2007,50(17):1677-1684.
8. Kim SK, Pak HN, Park JH, Fang YF, Kim GI, Park YD, Hwang C, Kim YH, Kim BS:Cardiac cell therapy with mesenchymal stem cell induces cardiac nerve sprouting, angiogenesis, and reduced connexin43-positive gap junctions, but concomitant electrical pacing increases connexin43-positive gap junctions in canine heart. Cardiology in the young 2010,20(3):308-317.
9. Rufaihah AJ, Haider HK, Heng BC, Ye L, Tan RS, Toh WS, Tian XF, Sim EK, Cao T:Therapeutic angiogenesis by transplantation of human embryonic stem cell-derived CD133+endothelial progenitor cells for cardiac repair. Regenerative medicine 2010,5(2):231-244.
10. Chun JL, O'Brien R, Song MH, Wondrasch BF, Berry SE:Injection of vessel-derived stem cells prevents dilated cardiomyopathy and promotes angiogenesis and endogenous cardiac stem cell proliferation in mdx/utrn-/-but not aged mdx mouse models for duchenne muscular dystrophy. Stem cells translational medicine 2013,2(1):68-80.
11. Virag JA, Rolle ML, Reece J, Hardouin S, Feigl EO, Murry CE:Fibroblast growth factor-2 regulates myocardial infarct repair:effects on cell proliferation, scar contraction, and ventricular function. The American journal of pathology 2007,171(5):1431-1440.
12. Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE: 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.
13. Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, Dzau VJ, Pratt RE:Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 2006,14(6):840-850.
14. Gnecchi M, Zhang Z, Ni A, Dzau VJ:Paracrine mechanisms in adult stem cell signaling and therapy. Circulation research 2008,103(11):1204-1219.
15. Wei H, Wang F, Wang X, Yang J, Li Z, Cong X, Chen X:Lysophosphatidic acid promotes secretion of VEGF by increasing expression of 150-kD Oxygen-regulated protein (ORP150) in mesenchymal stem cells. Biochim Biophys Acta 2013,1831(8):1426-1434.
16. Alter BR, Marek MS, Sperber SB:Interventional therapy for the treatment of acute myocardial infarction:thrombolysis with and without angioplasty. A brief review of the literature and the experience at a community hospital. Cardiology clinics 1985,3(1):29-36.
17. Alperin C, Zandstra PW, Woodhouse KA:Engineering cardiac healing using embryonic stem cell-derived cardiac cell seeded constructs. Frontiers in bioscience:a journal and virtual library 2007,12:3694-3712.
18. Liau B, Christoforou N, Leong KW, Bursac N:Pluripotent stem cell-derived cardiac tissue patch with advanced structure and function. Biomaterials 2011, 32(35):9180-9187.
19. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM et al: Bone marrow cells regenerate infarcted myocardium. Nature 2001,410(6829):701-705.
20. Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P:Bone marrow stem cells regenerate infarcted myocardium. Pediatric transplantation 2003,7 Suppl 3:86-88.
21. Li M, Ikehara S:Bone-marrow-derived mesenchymal stem cells for organ repair. Stem Cells Int 2013,2013:132642.
22. Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK, Reinecke H, Xu C, Hassanipour M, Police S et al: Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 2007,25(9):1015-1024.
23. Miniati I, Conforti ML, Bernardo P, Tyndall A, Gensini GF, Matucci-Cerinic M: Hematopoietic stem cell transplantation in autoimmune diseases:algorithm for cardiovascular assessment. Herz 2007,32(1):43-50.
24. Mo XD, Xu LP, Liu DH, Zhang XH, Chen H, Chen YH, Han W, Wang Y, Wang FR, Wang JZ et al: Heart failure after allogeneic hematopoietic stem cell transplantation. International journal of cardiology 2013,167(6):2502-2506.
25. Mauritz C, Martens A, Rojas SV, Schnick T, Rathert C, Schecker N, Menke S, Glage S, Zweigerdt R, Haverich A et al: Induced pluripotent stem cell (iPSC)-derived Flk-1 progenitor cells engraft, differentiate, and improve heart function in a mouse model of acute myocardial infarction. European heart journal 2011,32(21):2634-2641.
26. Badorff C, Brandes RP, Popp R, Rupp S, Urbich C, Aicher A, Fleming I, Busse R, Zeiher AM, Dimmeler S:Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes. Circulation 2003,107(7):1024-1032.
27. Berger S, Aronson D, Lavie P, Lavie L:Endothelial progenitor cells in acute myocardial infarction and sleep-disordered breathing. American journal of respiratory and critical care medicine 2013,187(1):90-98.
28. Chen X, Gu M, Zhao X, Zheng X, Qin Y, You X:Deterioration of cardiac function after acute myocardial infarction is prevented by transplantation of modified endothelial progenitor cells overexpressing endothelial NO synthases. Cellular physiology and biochemistry:international journal of experimental cellular physiology, biochemistry, and pharmacology 2013, 31(2-3):355-365.
29. Martinez G, Rigotti A, Acevedo M, Navarrete C, Rosales J, Giugliano RP, Corbalan R:Cholesterol levels and the association of statins with in-hospital mortality of myocardial infarction patients insights from a Chilean registry of myocardial infarction. Clinical cardiology 2013,36(6):305-311.
30. Pelacho B, Nakamura Y, Zhang J, Ross J, Heremans Y, Nelson-Holte M, Lemke B, Hagenbrock J, Jiang Y, Prosper F et al: Multipotent adult progenitor cell transplantation increases vascularity and improves left ventricular function after myocardial infarction. Journal of tissue engineering and regenerative medicine 2007,1(1):51-59.
31. Rasmusson I, Ringden O, Sundberg B, Le Blanc K:Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 2003,76(8):1208-1213.
32. Fazel S, Tang GH, Angoulvant D, Cimini M, Weisel RD, Li RK, Yau TM: Current status of cellular therapy for ischemic heart disease. The Annals of thoracic surgery 2005,79(6):S2238-2247.
33. Potian JA, Aviv H, Ponzio NM, Harrison JS, Rameshwar P:Veto-like activity of mesenchymal stem cells:functional discrimination between cellular responses to alloantigens and recall antigens. J Immunol 2003, 171(7):3426-3434.
34. Aggarwal S, Pittenger MF:Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005,105(4):1815-1822.
35. Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, Galun E, Rachmilewitz J:Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 2005, 105(5):2214-2219.
36. Ryter SW, Choi AM:Regulation of autophagy in oxygen-dependent cellular stress. Curr Pharm Des 2013,19(15):2747-2756.
37. Takagi H, Matsui Y, Sadoshima J:The role of autophagy in mediating cell survival and death during ischemia and reperfusion in the heart. Antioxid Redox Signal 2007,9(9):1373-1381.
38. Baehrecke EH:Autophagy:dual roles in life and death? Nat Rev Mol Cell Biol 2005,6(6):505-510.
39. Codogno P, Meijer AJ:Autophagy and signaling:their role in cell survival and cell death. Cell death and differentiation 2005,12 Suppl 2:1509-1518.
40. Chen X, Yang XY, Wang ND, Ding C, Yang YJ, You ZJ, Su Q, Chen JH:Serum lysophosphatidic acid concentrations measured by dot immunogold filtration assay in patients with acute myocardial infarction. Scand J Clin Lab Invest 2003,63(7-8):497-503.
41. Chen J, Chen Y, Zhu W, Han Y, Han B, Xu R, Deng L, Cai Y, Cong X, Yang Y et al: Specific LPA receptor subtype mediation of LPA-induced hypertrophy of cardiac myocytes and involvement of Akt and NFkappaB signal pathways. Journal of cellular biochemistry 2008,103(6):1718-1731.
42. Chen J, Han Y, Zhu W, Ma R, Han B, Cong X, Hu S, Chen X:Specific receptor subtype mediation of LPA-induced dual effects in cardiac fibroblasts. FEBS letters 2006,580(19):4737-4745.
43. Chen J, Baydoun AR, Xu R, Deng L, Liu X, Zhu W, Shi L, Cong X, Hu S, Chen X:Lysophosphatidic acid protects mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis. Stem cells 2008,26(1):135-145.
44. Liu X, Hou J, Shi L, Chen J, Sang J, Hu S, Cong X, Chen X:Lysophosphatidic acid protects mesenchymal stem cells against ischemia-induced apoptosis in vivo. Stem cells and development 2009,18(7):947-954.
45. Karliner JS, Honbo N, Summers K, Gray MO, Goetzl EJ:The lysophospholipids sphingosine-1-phosphate and lysophosphatidic acid enhance survival during hypoxia in neonatal rat cardiac myocytes. Journal of molecular and cellular cardiology 2001,33(9):1713-1717.
46. Savitz SI, Dhallu MS, Malhotra S, Mammis A, Ocava LC, Rosenbaum PS, Rosenbaum DM:EDG receptors as a potential therapeutic target in retinal ischemia-reperfusion injury. Brain research 2006,1118(1):168-175.
1 Tiyyagura SR, Pinney SP:Left ventricular remodeling after myocardial infarction:past, present, and future. The Mount Sinai journal of medicine, New york 2006,73(6):840-851.
2. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS et al: Heart disease and stroke statistics-2013 update:a report from the American Heart Association. Circulation 2013, 127(1):e6-e245.
3. Braunwald E, Pfeffer MA:Ventricular enlargement and remodeling following acute myocardial infarction:mechanisms and management. The American journal of cardiology 1991,68(14):1D-6D.
4. Pfeffer MA, Braunwald E:Ventricular enlargement following infarction is a modifiable process. The American journal of cardiology 1991, 68(14):127D-131D.
5. Pfeffer MA, Pfeffer JM:Ventricular enlargement following a myocardial infarction. Journal of cardiovascular pharmacology 1987,9 Suppl 2:S18-20.
6. Chiu RC:Adult stem cell therapy for heart failure. Expert opinion on biological therapy 2003,3(2):215-225.
7. Fraser JK, Schreiber RE, Zuk PA, Hedrick MH:Adult stem cell therapy for the heart. The international journal of biochemistry & cell biology 2004, 36(4):658-666.
8. Fujita J:[The regenerative therapy of heart failure with adult stem cells and cell transplantation]. Nihon Ronen Igakkai zasshi Japanese journal of geriatrics 2004,41(2):166-167.
9. Sharpe N:Cardiac remodeling in coronary artery disease. The American journal of cardiology 2004,93(9A):17B-20B.
10. Caplan AI:Review:mesenchymal stem cells:cell-based reconstructive therapy in orthopedics. Tissue engineering 2005,11(7-8):1198-1211.
11. Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P:Bone marrow stem cells regenerate infarcted myocardium. Pediatric transplantation 2003,7 Suppl 3:86-88.
12. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM et al: Bone marrow cells regenerate infarcted myocardium. Nature 2001,410(6829):701-705.
13. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR:Multilineage potential of adult human mesenchymal stem cells. Science 1999,284(5411):143-147.
14. Pittenger MF, Martin BJ:Mesenchymal stem cells and their potential as cardiac therapeutics. Circulation research 2004,95(1):9-20.
15. Hanabusa K, Nagaya N, Iwase T, Itoh T, Murakami S, Shimizu Y, Taki W, Miyatake K, Kangawa K:Adrenomedullin enhances therapeutic potency of mesenchymal stem cells after experimental stroke in rats. Stroke; a journal of cerebral circulation 2005,36(4):853-858.
16. Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ: Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nature medicine 2003,9(9):1195-1201.
17. Tang N, Zhao Y, Feng R, Liu Y, Wang S, Wei W, Ding Q, An MS, Wen J, Li L: Lysophosphatidic acid accelerates lung fibrosis by inducing differentiation of mesenchymal stem cells into myofibroblasts. J Cell Mol Med 2013.
18. Jiang Y, Gram H, Zhao M, New L, Gu J, Feng L, Di Padova F, Ulevitch RJ, Han J:Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. The Journal of biological chemistry 1997,272(48):30122-30128.
19. Nakamura Y, Wang X, Xu C, Asakura A, Yoshiyama M, From AH, Zhang J: Xenotransplantation of long-term-cultured swine bone marrow-derived mesenchymal stem cells. Stem cells 2007,25(3):612-620.
20. Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, Dzau VJ, Pratt RE:Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 2006,14(6):840-850.
21. Saito T, Kuang JQ, Lin CC, Chiu RC:Transcoronary implantation of bone marrow stromal cells ameliorates cardiac function after myocardial infarction. The Journal of thoracic and cardiovascular surgery 2003, 126(1):114-123.
22. Ambrosio G, Zweier JL, Duilio C, Kuppusamy P, Santoro G, Elia PP, Tritto I, Cirillo P, Condorelli M, Chiariello M et al: Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow. The Journal of biological chemistry 1993,268(25):18532-18541.
23. Becker LB, vanden Hoek TL, Shao ZH, Li CQ, Schumacker PT:Generation of superoxide in cardiomyocytes during ischemia before reperfusion. Am J Physiol 1999,277(6 Pt 2):H2240-2246.
24. Lu L, Quinn MT, Sun Y:Oxidative stress in the infarcted heart:role of de novo angiotensin Ⅱ production. Biochemical and biophysical research communications 2004,325(3):943-951.
25. Vanden Hoek T, Becker LB, Shao ZH, Li CQ, Schumacker PT:Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion. Circulation research 2000,86(5):541-548.
26. Wei H, Li Z, Hu S, Chen X, Cong X:Apoptosis of mesenchymal stem cells induced by hydrogen peroxide concerns both endoplasmic reticulum stress and mitochondrial death pathway through regulation of caspases, p38 and JNK. Journal of cellular biochemistry 2010, 111(4):967-978.
27. Cuervo AM:Autophagy:many paths to the same end. Molecular and cellular biochemistry 2004,263(1-2):55-72.
28. Gottlieb RA, Carreira RS:Autophagy in health and disease.5. Mitophagy as a way of life. Am J Physiol Cell Physiol 2010,299(2):C203-210.
29. Gottlieb RA, Mentzer RM, Jr.:Autophagy:an affair of the heart. Heart failure reviews 2013,18(5):575-584.
30. Terman A, Gustafsson B, Brunk UT:Mitochondrial damage and intralysosomal degradation in cellular aging. Molecular aspects of medicine 2006,27(5-6):471-482.
31. Cardiac Regeneration and Angiogenesis beyond Stem Cell Research: Symposium organised by the Society of Coronary Sinus Interventions. Wiener klinische Wochenschrift 2007',119 Suppl 1:1-32.
32. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ et al: Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature genetics 2004,36(6):585-595.
33. Ryter SW, Choi AM:Regulation of autophagy in oxygen-dependent cellular stress. Curr Pharm Des 2013,19(15):2747-2756.
34. Takagi H, Matsui Y, Sadoshima J:The role of autophagy in mediating cell survival and death during ischemia and reperfusion in the heart. Antioxid Redox Signal 2007,9(9):1373-1381.
35. Baehrecke EH:Autophagy:dual roles in life and death? Nat Rev Mol Cell Biol 2005,6(6):505-510.
36. Codogno P, Meijer AJ:Autophagy and signaling:their role in cell survival and cell death. Cell death and differentiation 2005,12 Suppl 2:1509-1518.
37. Dubin AE, Herr DR, Chun J:Diversity of lysophosphatidic acid receptor-mediated intracellular calcium signaling in early cortical neurogenesis. The Journal of neuroscience:the official journal of the Society for Neuroscience 2010,30(21):7300-7309.
38. Means CK, Brown JH:Sphingosine-1-phosphate receptor signalling in the heart. Cardiovascular research 2009,82(2):193-200.
39. Moolenaar WH, van Meeteren LA, Giepmans BN:The ins and outs of lysophosphatidic acid signaling. BioEssays:news and reviews in molecular, cellular and developmental biology 2004,26(8):870-881.
40. Ye X, Hama K, Contos JJ, Anliker B, Inoue A, Skinner MK, Suzuki H, Amano T, Kennedy G, Arai H et al: LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature 2005,435(7038):104-108.
41. Rivera R, Chun J:Biological effects of lysophospholipids. Reviews of physiology, biochemistry and pharmacology 2008,160:25-46.
42. Chen J, Baydoun AR, Xu R, Deng L, Liu X, Zhu W, Shi L, Cong X, Hu S, Chen X:Lysophosphatidic acid protects mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis. Stem cells 2008,26(1):135-145.
43. Deng W, Balazs L, Wang DA, Van Middlesworth L, Tigyi G, Johnson LR: Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis. Gastroenterology 2002, 123(1):206-216.
44. Fang X, Yu S, LaPushin R, Lu Y, Furui T, Penn LZ, Stokoe D, Erickson JR, Bast RC, Jr., Mills GB:Lysophosphatidic acid prevents apoptosis in fibroblasts via G(i)-protein-mediated activation of mitogen-activated protein kinase. Biochem J2000,352 Pt 1:135-143.
45. Weiner JA, Chun J:Schwann cell survival mediated by the signaling phospholipid lysophosphatidic acid. Proc Natl Acad Sci U S A 1999, 96(9):5233-5238.
46. Levine JS, Koh JS, Triaca V, Lieberthal W:Lysophosphatidic acid:a novel growth and survival factor for renal proximal tubular cells. Am J Physiol 1997,273(4 Pt 2):F575-585.
47. Orosa B, Gonzalez A, Mera A, Gomez-Reino JJ, Conde C:Lysophosphatidic acid receptor 1 suppression sensitizes rheumatoid fibroblast-like synoviocytes to tumor necrosis factor-induced apoptosis. Arthritis Rheum 2012,64(8):2460-2470.
48. Koh JS, Lieberthal W, Heydrick S, Levine JS:Lysophosphatidic acid is a major serum noncytokine survival factor for murine macrophages which acts via the phosphatidylinositol 3-kinase signaling pathway. The Journal of clinical investigation 1998,102(4):716-727.
49. Sun Y, Kim NH, Ji L, Kim SH, Lee J, Rhee HJ:Lysophosphatidic acid activates betacatenin/T cell factor signaling, which contributes to the suppression of apoptosis in H197 cells. Mol Med Rep 2013,8(6):1729-1733.
50. Goldshmit Y, Matteo R, Sztal T, Ellett F, Frisca F, Moreno K, Crombie D, Lieschke GJ, Currie PD, Sabbadini RA et al: Blockage of lysophosphatidic acid signaling improves spinal cord injury outcomes. The American journal of pathology 2012,181(3):978-992.
51. Holtsberg FW, Steiner MR, Keller JN, Mark RJ, Mattson MP, Steiner SM: Lysophosphatidic acid induces necrosis and apoptosis in hippocampal neurons. JNeurochem 1998,70(1):66-76.
52. Steiner MR, Holtsberg FW, Keller JN, Mattson MP, Steiner SM: Lysophosphatidic acid induction of neuronal apoptosis and necrosis. Ann N Y Acad Sci 2000,905:132-141.
53. Ediger TL, Toews ML:Dual effects of lysophosphatidic acid on human airway smooth muscle cell proliferation and survival. Biochim Biophys Acta 2001, 1531(1-2):59-67.
54. Funke M, Zhao Z, Xu Y, Chun J, Tager AM:The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury. Am J Respir Cell Mol Biol 2012,46(3):355-364.
55. Liu X, Wang J, Sun B, Zhang Y, Zhu J, Li C:Cell growth inhibition, G2M cell cycle arrest, and apoptosis induced by the novel compound Alternol in human gastric carcinoma cell line MGC803. Investigational new drugs 2007, 25(6):505-517.
56. Liu X, Hou J, Shi L, Chen J, Sang J, Hu S, Cong X, Chen X:Lysophosphatidic acid protects mesenchymal stem cells against ischemia-induced apoptosis in vivo. Stem cells and development 2009,18(7):947-954.
57. Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C:A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. Journal of immunological methods 1995,184(1):39-51.
58. Schutte B, Nuydens R, Geerts H, Ramaekers F:Annexin V binding assay as a tool to measure apoptosis in differentiated neuronal cells. Journal of neuroscience methods 1998,86(1):63-69.
59. Glander HJ, Schaller J:Binding of annexin V to plasma membranes of human spermatozoa:a rapid assay for detection of membrane changes after cryostorage. Molecular human reproduction 1999,5(2):109-115.
60. Choi JW, Herr DR, Noguchi K, Yung YC, Lee CW, Mutoh T, Lin ME, Teo ST, Park KE, Mosley AN et al: LPA receptors:subtypes and biological actions. Annu Rev Pharmacol Toxicol 2010,50:157-186.
61. Contos JJ, Ishii I, Chun J:Lysophosphatidic acid receptors. Molecular pharmacology 2000,58(6):1188-1196.
62. Deng W, Wang DA, Gosmanova E, Johnson LR, Tigyi G:LPA protects intestinal epithelial cells from apoptosis by inhibiting the mitochondrial pathway. Am JPhysiol Gastrointest Liver Physiol 2003,284(5):G821-829.
63. Li Z, Wei H, Liu X, Hu S, Cong X, Chen X:LPA rescues ER stress-associated apoptosis in hypoxia and serum deprivation-stimulated mesenchymal stem cells. Journal of cellular biochemistry 2010,111(4):811-820.
64. Pan H, Cheng L, Yang H, Zou W, Cheng R, Hu T:Lysophosphatidic acid rescues human dental pulp cells from ischemia-induced apoptosis. Journal of endodontics 2014,40(2):217-222.
65. Mizushima N:Methods for monitoring autophagy. The international journal of biochemistry & cell biology 2004,36(12):2491-2502.
66. Tanida I, Ueno T, Kominami E:LC3 conjugation system in mammalian autophagy. The international journal of biochemistry & cell biology 2004, 36(12):2503-2518.
67. Hsu CM, Tsai Y, Wan L, Tsai FJ:Bufalin induces G2/M phase arrest and triggers autophagy via the TNF, JNK, BECN-1 and ATG8 pathway in human hepatoma cells. International journal of oncology 2013,43(1):338-348.
68. Zhang W, He C:Regulation of plasma membrane receptors by a new autophagy-related BECN/Beclin family member. Autophagy 2014,10(5).
69. Jiang H, Cheng D, Liu W, Peng J, Feng J:Protein kinase C inhibits autophagy and phosphorylates LC3. Biochemical and biophysical research communications 2010,395(4):471-476.
70. Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, Metivier D, Meley D, Souquere S, Yoshimori T et al: Inhibition of macroautophagy triggers apoptosis. Molecular and cellular biology 2005, 25(3):1025-1040.
71. Klionsky DJ, Elazar Z, Seglen PO, Rubinsztein DC:Does bafilomycin A1 block the fusion of autophagosomes with lysosomes? Autophagy 2008,4(7):849-850.
72. Fukui T, Yoshiyama M, Hanatani A, Omura T, Yoshikawa J, Abe Y:Expression of p22-phox and gp91-phox, essential components of NADPH oxidase, increases after myocardial infarction. Biochemical and biophysical research communications 2001,281(5):1200-1206.
73. Hill MF, Singal PK:Right and left myocardial antioxidant responses during heart failure subsequent to myocardial infarction. Circulation 1997, 96(7):2414-2420.
74. Urao N, McKinney RD, Fukai T, Ushio-Fukai M:NADPH oxidase 2 regulates bone marrow microenvironment following hindlimb ischemia:role in reparative mobilization of progenitor cells. Stem cells 2012,30(5):923-934.
75. Fukai T, Ushio-Fukai M:Superoxide dismutases:role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 2011,15(6):1583-1606.
76. Nathan C, Ding A:SnapShot:Reactive Oxygen Intermediates (ROI). Cell 2010,140(6):951-951 e952.
77. Pervaiz S, Taneja R, Ghaffari S:Oxidative stress regulation of stem and progenitor cells. Antioxid Redox Signal 2009,11(11):2777-2789.
78. Case J, Ingram DA, Haneline LS:Oxidative stress impairs endothelial progenitor cell function. Antioxid Redox Signal 2008,10(11):1895-1907.
79. Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, Nomiyama K, Hosokawa K, Sakurada K, Nakagata N et al:Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 2004, 431(7011):997-1002.
80. Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, Ohmura M, Naka K, Hosokawa K, Ikeda Y et al: Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nature medicine 2006, 12(4):446-451.
81. Kobayashi CI, Suda T:Regulation of reactive oxygen species in stem cells and cancer stem cells. Journal of cellular physiology 2012,227(2):421-430.
82. Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo-Kallanian S, Williams IR, Sears C et al: FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007,128(2):325-339.
83. Naka K, Muraguchi T, Hoshii T, Hirao A:Regulation of reactive oxygen species and genomic stability in hematopoietic stem cells. Antioxid Redox Signal 2008,10(11):1883-1894.
84. Cheng HY, Zhang YN, Wu QL, Sun XM, Sun JR, Huang X:Expression of beclin 1, an autophagy-related protein, in human cervical carcinoma and its clinical significance. Eur J Gynaecol Oncol 2012,33(1):15-20.
85. Fang Y, Moore BJ, Bai Q, Cook KM, Herrick EJ, Nicholl MB:Hydrogen peroxide enhances radiation-induced apoptosis and inhibition of melanoma cell proliferation. Anticancer Res 2013,33(5):1799-1807.
86. Ghosh AS, Dutta S, Raha S:Hydrogen peroxide-induced apoptosis-like cell death in Entamoeba histolytica. Parasitol Int 2010,59(2):166-172.
87. Yao J, Bi HE, Sheng Y, Cheng LB, Wendu RL, Wang CH, Cao GF, Jiang Q: Ultraviolet (UV) and Hydrogen Peroxide Activate Ceramide-ER Stress-AMPK Signaling Axis to Promote Retinal Pigment Epithelium (RPE) Cell Apoptosis. Int J Mol Sci 2013,14(5):10355-10368.
88. Liao Y, Mu G, Zhang L, Zhou W, Zhang J, Yu H:Lysophosphatidic acid stimulates activation of focal adhesion kinase and paxillin and promotes cell motility, via LPA1-3, in human pancreatic cancer. Digestive diseases and sciences 2013,58(12):3524-3533.
89. Yanai N, Matsui N, Furusawa T, Okubo T, Obinata M: Sphingosine-1-phosphate and lysophosphatidic acid trigger invasion of primitive hematopoietic cells into stromal cell layers. Blood 2000, 96(1):139-144.
90. Binder BY, Genetos DC, Leach JK:Lysophosphatidic Acid Protects Human Mesenchymal Stromal Cells from Differentiation-Dependent Vulnerability to Apoptosis. Tissue engineering Part A 2014.
91. Fukushima N, Chun J:The LPA receptors. Prostaglandins & other lipid mediators 2001,64(1-4):21-32.
92. Swarthout JT, Walling HW:Lysophosphatidic acid:receptors, signaling and survival. Cellular and molecular life sciences:CMLS 2000, 57(13-14):1978-1985.
93. Ishii I, Contos JJ, Fukushima N, Chun J:Functional comparisons of the lysophosphatidic acid receptors, LP(A1)/VZG-1/EDG-2, LP(A2)/EDG-4, and LP(A3)/EDG-7 in neuronal cell lines using a retrovirus expression system. Molecular pharmacology 2000,58(5):895-902.
94. Karliner JS, Honbo N, Summers K, Gray MO, Goetzl EJ:The lysophospholipids sphingosine-1-phosphate and lysophosphatidic acid enhance survival during hypoxia in neonatal rat cardiac myocytes. Journal of molecular and cellular cardiology 2001,33(9):1713-1717.
95. Inoue CN, Nagano I, Ichinohasama R, Asato N, Kondo Y, Iinuma K:Bimodal effects of platelet-derived growth factor on rat mesangial cell proliferation and death, and the role of lysophosphatidic acid in cell survival. Clinical science 2001,101(1):11-19.
96. Sautin YY, Crawford JM, Svetlov SI:Enhancement of survival by LPA via Erk1/Erk2 and PI 3-kinase/Akt pathways in a murine hepatocyte cell line. Am JPhysiol Cell Physiol 2001,281(6):C2010-2019.
97. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H et al: Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006,441(7095):885-889.
98. Gustafsson AB, Gottlieb RA:Recycle or die:the role of autophagy in cardioprotection. Journal of molecular and cellular cardiology 2008, 44(4):654-661.
99. Terman A, Brunk UT:Autophagy in cardiac myocyte homeostasis, aging, and pathology. Cardiovascular research 2005,68(3):355-365.
100. Mizushima N, Levine B, Cuervo AM, Klionsky DJ:Autophagy fights disease through cellular self-digestion. Nature 2008,451 (7182):1069-1075.
101. Lee JY, Koga H, Kawaguchi Y, Tang W, Wong E, Gao YS, Pandey UB, Kaushik S, Tresse E, Lu J et al: HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. The EMBO journal 2010, 29(5):969-980.
102. Gustafsson AB, Gottlieb RA:Eat your heart out:Role of autophagy in myocardial ischemia/reperfusion.Autophagy 2008,4(4):416-421.
103. Hariharan N, Zhai P, Sadoshima J:Oxidative stress stimulates autophagic flux during ischemia/reperfusion. Antioxid Redox Signal 2011,14(11):2179-2190.
104. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J:Distinct roles of autophagy in the heart during ischemia and reperfusion:roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circulation research 2007,100(6):914-922.
105. Morales CR, Pedrozo Z, Lavandero S, Hill JA:Oxidative Stress and Autophagy in Cardiovascular Homeostasis. Antioxid Redox Signal 2013.
106. Scherz-Shouval R, Elazar Z:Regulation of autophagy by ROS:physiology and pathology. Trends Biochem Sci 2011,36(1):30-38.
107. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z:Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. The EMBO journal 2007,26(7):1749-1760.
108. Luo Y, Zou P, Zou J, Wang J, Zhou D, Liu L:Autophagy regulates ROS-induced cellular senescence via p21 in a p38 MAPKalpha dependent manner. Exp Gerontol 2011,46(11):860-867.
1. Conget PA, Minguell JJ:Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. Journal of cellular physiology 1999,181(1):67-73.
2. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR:Multilineage potential of adult human mesenchymal stem cells. Science 1999,284(5411):143-147.
3. Deans RJ, Moseley AB:Mesenchymal stem cells:biology and potential clinical uses. Experimental hematology 2000,28(8):875-884.
4. Minguell JJ, Erices A, Conget P:Mesenchymal stem cells. Experimental biology and medicine 2001,226(6):507-520.
5. Imanishi Y, Saito A, Komoda H, Kitagawa-Sakakida S, Miyagawa S, Kondoh H, Ichikawa H, Sawa Y: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.
6. Karpov AA, Uspenskaya YK, Minasian SM, Puzanov MV, Dmitrieva RI, Bilibina AA, Anisimov SV, Galagudza MM:The effect of bone marrow-and adipose tissue-derived mesenchymal stem cell transplantation on myocardial remodelling in the rat model of ischaemic heart failure. International journal of experimental pathology 2013,94(3):169-177.
7. Tang JM, Wang MJ, Yang J, Wang JN:[Incorporation and integration of mesenchymal stem cell-derived myocardial cells into host cardiac myocytes: an experimental study in rats]. Nan fang yi ke da xue xue bao=Journal of Southern Medical University 2007,27(1):38-42.
8. Wang JA, Luo RH, Zhang X, Xie XJ, Hu XY, He AN, Chen J, Li JH:Bone marrow mesenchymal stem cell transplantation combined with perindopril treatment attenuates infarction remodelling in a rat model of acute myocardial infarction. Journal of Zhejiang University Science B 2006, 7(8):641-647.
9. Liu X, Hou J, Shi L, Chen J, Sang J, Hu S, Cong X, Chen X:Lysophosphatidic acid protects mesenchymal stem cells against ischemia-induced apoptosis in vivo. Stem cells and development 2009,18(7):947-954.
10. Mauritz C, Martens A, Rojas SV, Schnick T, Rathert C, Schecker N, Menke S, Glage S, Zweigerdt R, Haverich A et al: Induced pluripotent stem cell (iPSC)-derived FIk-1 progenitor cells engraft, differentiate, and improve heart function in a mouse model of acute myocardial infarction. European heart journal 2011,32(21):2634-2641.
11. Wei H, Wang F, Wang X, Yang J, Li Z, Cong X, Chen X:Lysophosphatidic acid promotes secretion of VEGF by increasing expression of 150-kD Oxygen-regulated protein (ORP150) in mesenchymal stem cells. Biochim Biophys Acta 2013,1831(8):1426-1434.
12. Ishikane S, Hosoda H, Yamahara K, Akitake Y, Kyoungsook J, Mishima K, Iwasaki K, Fujiwara M, Miyazato M, Kangawa K et al: Allogeneic transplantation of fetal membrane-derived mesenchymal stem cell sheets increases neovascularization and improves cardiac function after myocardial infarction in rats. Transplantation 2013,96(8):697-706.
13. Tang YL, Zhao Q, Qin X, Shen L, Cheng L, Ge J, Phillips MI: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 2005,80(1):229-236; discussion 236-227.
14. Heil M, Ziegelhoeffer T, Mees B, Schaper W:A different outlook on the role of bone marrow stem cells in vascular growth:bone marrow delivers software not hardware. Circulation research 2004,94(5):573-574.
15. Bernstein HS, Srivastava D:Stem cell therapy for cardiac disease. Pediatric research 2012,71(4 Pt 2):491-499.
16. Mathur A, Martin JF:Stem cells and repair of the heart. Lancet 2004, 364(9429):183-192.
17. Segers VF, Lee RT:Stem-cell therapy for cardiac disease. Nature 2008, 451(7181):937-942.
18. Pittenger MF, Martin BJ:Mesenchymal stem cells and their potential as cardiac therapeutics. Circulation research 2004,95(1):9-20.
19. Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE: 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.
20. Tang YL, Zhao Q, Zhang YC, Cheng L, Liu M, Shi J, Yang YZ, Pan C, Ge J, Phillips MI:Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regulatory peptides 2004, 117(1):3-10.
21. Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H et al: Cardiomyocytes can be generated from marrow stromal cells in vitro. The Journal of clinical investigation 1999, 103(5):697-705.
22. Jiang Y, Gram H, Zhao M, New L, Gu J, Feng L, Di Padova F, Ulevitch RJ, Han J:Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. The Journal of biological chemistry 1997,272(48):30122-30128.
23. Nakamura Y, Wang X, Xu C, Asakura A, Yoshiyama M. From AH, Zhang J: Xenotransplantation of long-term-cultured swine bone marrow-derived mesenchymal stem cells. Stem cells 2007,25(3):612-620.
24. Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, Dzau VJ, Pratt RE:Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 2006,14(6):840-850.
25. Saito T, Kuang JQ, Lin CC, Chiu RC:Transcoronary implantation of bone marrow stromal cells ameliorates cardiac function after myocardial infarction. The Journal of thoracic and cardiovascular surgery 2003, 126(1):114-123.
26. Chen J, Baydoun AR, Xu R, Deng L, Liu X, Zhu W, Shi L, Cong X, Hu S, Chen X:Lysophosphatidic acid protects mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis. Stem cells 2008,26(1):135-145.
27. Mehrpour M, Esclatine A, Beau I, Codogno P:Overview of macroautophagy regulation in mammalian cells. Cell research 2010,20(7):748-762.
28. Ryter SW, Choi AM:Regulation of autophagy in oxygen-dependent cellular stress. Curr Pharm Des 2013,19(15):2747-2756.
29. Takagi H, Matsui Y, Sadoshima J:The role of autophagy in mediating cell survival and death during ischemia and reperfusion in the heart. Antioxid Redox Signal 2007,9(9):1373-1381.
30. Carloni S, Buonocore G, Balduini W:Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiology of disease 2008, 32(3):329-339.
31. Hamacher-Brady A, Brady NR, Gottlieb RA:Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. The Journal of biological chemistry 2006,281(40):29776-29787.
32. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J:Distinct roles of autophagy in the heart during ischemia and reperfusion:roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circulation research 2007,100(6):914-922.
33. Wang L, Hu X, Zhu W, Jiang Z, Zhou Y, Chen P, Wang J:Increased leptin by hypoxic-preconditioning promotes autophagy of mesenchymal stem cells and protects them from apoptosis. Science China Life sciences 2014,57(2):171-180.
34. Zhang Q, Yang YJ, Wang H, Dong QT. Wang TJ, Qian HY, Xu H:Autophagy activation:a novel mechanism of atorvastatin to protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway. Stem cells and development 2012,21(8):1321-1332.
35. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T. Ohsumi Y, Tokuhisa T, Mizushima N:The role of autophagy during the early neonatal starvation period. Nature 2004,432(7020):1032-1036.
36. Li Z, Wei H, Liu X, Hu S, Cong X, Chen X:LPA rescues ER stress-associated apoptosis in hypoxia and serum deprivation-stimulated mesenchymal stem cells. Journal of cellular biochemistry 2010,111(4):811-820.
37. Roy B, Pattanaik AK, Das J, Bhutia SK, Behera B, Singh P, Maiti TK:Role of PI3K/Akt/mTOR and MEK/ERK pathway in Concanavalin A induced autophagy in HeLa cells. Chemico-biological interactions 2014,210:96-102.
38. Singh BN, Kumar D, Shankar S, Srivastava RK:Rottlerin induces autophagy which leads to apoptotic cell death through inhibition of PI3K/Akt/mTOR pathway in human pancreatic cancer stem cells. Biochem Pharmacol 2012, 84(9):1154-1163.
39. Chang CL, Ho MC, Lee PH, Hsu CY, Huang WP, Lee H:S1P(5) is required for sphingosine 1-phosphate-induced autophagy in human prostate cancer PC-3 cells. Am J Physiol Cell Physiol 2009,297(2):C451-458.
40. Lavieu G. Scarlatti F, Sala G, Carpentier S, Levade T, Ghidoni R, Botti J, Codogno P:Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation. The Journal of biological chemistry 2006,281(13):8518-8527.
41. Yang Z, Klionsky DJ:Mammalian autophagy:core molecular machinery and signaling regulation. Current opinion in cell biology 2010,22(2):124-131.
42. Srinivas V, Bohensky J, Shapiro IM:Autophagy:a new phase in the maturation of growth plate chondrocytes is regulated by HIF, mTOR and AMP kinase. Cells, tissues, organs 2009,189(1-4):88-92.
43. Kim EK, Park JM, Lim S, Choi JW, Kim HS, Seok H, Seo JK, Oh K, Lee DS, Kim KT et al: Activation of AMP-activated protein kinase is essential for lysophosphatidic acid-induced cell migration in ovarian cancer cells. The Journal of biological chemistry 2011,286(27):24036-24045.
44. Milano V, Piao Y, LaFortune T, de Groot J:Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. Molecular cancer therapeutics 2009,8(2):394-406.
45. Paglin S, Hollister T, Delohery T, Hackett N, McMahill M, Sphicas E, Domingo D, Yahalom J:A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer research 2001, 61(2):439-444.
46. Laufs U:Beyond lipid-lowering:effects of statins on endothelial nitric oxide. European journal of clinical pharmacology 2003,58(11):719-731.
47. Sun Q, Fan W, Zhong Q:Regulation of Beclin 1 in autophagy. Autophagy 2009, 5(5):713-716.
48. Jaakkola PM, Pursiheimo JP:p62 degradation by autophagy:another way for cancer cells to survive under hypoxia. Autophagy 2009,5(3):410-412.
49. Ichimura Y, Kominami E, Tanaka K, Komatsu M:Selective turnover of p62/A170/SQSTM1 by autophagy. Autophagy 2008,4(8):1063-1066.
50. Chang CL, Liao JJ, Huang WP, Lee H:Lysophosphatidic acid inhibits serum deprivation-induced autophagy in human prostate cancer PC-3 cells. Autophagy 2007,3(3):268-270.
51. Chen Y, Azad MB, Gibson SB:Superoxide is the major reactive oxygen species regulating autophagy. Cell death and differentiation 2009, 16(7):1040-1052.
52. Hu P, Lai D, Lu P, Gao J, He H:ERK and Akt signaling pathways are involved in advanced glycation end product-induced autophagy in rat vascular smooth muscle cells. International journal of molecular medicine 2012, 29(4):613-618.
53. Mizushima N:Methods for monitoring autophagy. The international journal of biochemistry & cell biology 2004,36(12):2491-2502.
54. Nie Y, Han BM, Liu XB, Yang JJ, Wang F, Cong XF, Chen X:Identification of MicroRNAs involved in hypoxia-and serum deprivation-induced apoptosis in mesenchymal stem cells. International journal of biological sciences 2011, 7(6):762-768.
55. Mortensen M, Watson AS, Simon AK:Lack of autophagy in the hematopoietic system leads to loss of hematopoietic stem cell function and dysregulated myeloid proliferation. Autophagy 2011,7(9):1069-1070.
56. Vessoni AT, Muotri AR, Okamoto OK:Autophagy in stem cell maintenance and differentiation. Stem cells and development 2012,21(4):513-520.
57. Nishida K, Kyoi S, Yamaguchi O, Sadoshima J, Otsu K:The role of autophagy in the heart. Cell death and differentiation 2009,16(1):31-38.
58. Wang ZV, Rothermel BA, Hill JA:Autophagy in hypertensive heart disease. The Journal of biological chemistry 2010,285(12):8509-8514.
59. Hew KW, Keller KA:Postnatal anatomical and functional development of the heart:a species comparison. Birth defects research Part B, Developmental and reproductive toxicology 2003,68(4):309-320.
60. Sutherland FJ, Shattock MJ, Baker KE, Hearse DJ:Mouse isolated perfused heart:characteristics and cautions. Clinical and experimental pharmacology & physiology 2003,30(11):867-878.
61. Ziman AP, Gomez-Viquez NL, Bloch RJ, Lederer WJ:Excitation-contraction coupling changes during postnatal cardiac development. Journal of molecular and cellular cardiology 2010,48(2):379-386.
62. Sautin YY, Crawford JM, Svetlov SI:Enhancement of survival by LPA via Erkl/Erk2 and PI 3-kinase/Akt pathways in a murine hepatocyte cell line. Am J Physiol Cell Physiol 2001,281(6):C2010-2019.
63. Deng W, Wang DA, Gosmanova E, Johnson LR, Tigyi G:LPA protects intestinal epithelial cells from apoptosis by inhibiting the mitochondrial pathway. Am JPhysiol Gastrointest Liver Physiol 2003,284(5):G821-829.
64. She C, Zhu LQ, Zhen YF, Wang XD, Dong QR:Activation of AMPK protects against hydrogen peroxide-induced osteoblast apoptosis through autophagy induction and NADPH maintenance:new implications for osteonecrosis treatment? Cellular signalling 2014,26(1):1-8.
65. Lu C, Wang W, Jia Y, Liu X, Tong Z, Li B:Inhibition of AMPK/autophagy potentiates parthenolide-induced apoptosis in human breast cancer cells. Journal of cellular biochemistry 2014.
66. Rhim JH, Jang IS, Song KY, Ha MK, Cho SC, Yeo EJ, Park SC: Lysophosphatidic acid and adenylyl cyclase inhibitor increase proliferation of senescent human diploid fibroblasts by inhibiting adenosine monophosphate-activated protein kinase. Rejuvenation research 2008, 11(4):781-792.
1. Tiyyagura SR, Pinney SP:Left ventricular remodeling after myocardial infarction:past, present, and future. The Mount Sinai journal of medicine, New York 2006,73(6):840-851.
2. Kannel WB:Incidence and epidemiology of heart failure. Heart failure reviews 2000,5(2):167-173.
3. Bramucci E, Repetto A, Ferrario M, Canosi U, Boschetti E, Brambilla N, Gnecchi M, Merlini PA, Ardissino D, Angoli L et al: Effectiveness of adjunctive stent implantation following directional coronary atherectomy for treatment of left anterior descending ostial stenosis. The American journal of cardiology 2002,90(10):1074-1078.
4. McMurray JJ, Pfeffer MA:Heart failure. Lancet 2005,365(9474):1877-1889.
5. Urbanek K, Quaini F, Tasca G, Torella D, Castaldo C, Nadal-Ginard B, Leri A, Kajstura J, Quaini E, Anversa P:Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America 2003,100(18):10440-10445.
6. Anversa P, Kajstura J, Leri A, Bolli R:Life and death of cardiac stem cells:a paradigm shift in cardiac biology. Circulation 2006,113(11):1451-1463.
7. Lanza R, Moore MA, Wakayama T, Perry AC, Shieh JH, Hendrikx J, Leri A, Chimenti S, Monsen A, Nurzynska D et al: Regeneration of the infarcted heart with stem cells derived by nuclear transplantation. Circulation research 2004, 94(6):820-827.
8. Anversa P, Rota M, Urbanek K, Hosoda T, Sonnenblick EH, Leri A, Kajstura J, Bolli R:Myocardial aging-a stem cell problem. Basic research in cardiology 2005,100(6):482-493.
9. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR:Multilineage potential of adult human mesenchymal stem cells. Science 1999,284(5411):143-147.
10. Fukuhara S, Tomita S, Yamashiro S, Morisaki T, Yutani C, Kitamura S, Nakatani T:Direct cell-cell interaction of cardiomyocytes is key for bone marrow stromal cells to go into cardiac lineage in vitro. J Thorac Cardiovasc Surg 2003,125(6):1470-1480.
11. Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H et al: Cardiomyocytes can be generated from marrow stromal cells in vitro. JClin Invest 1999,103(5):697-705.
12. 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.
13. Sussman MA, Murry CE:Bones of contention:marrow-derived cells in myocardial regeneration. Journal of molecular and cellular cardiology 2008, 44(6):950-953.
14. Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ: Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 2003,9(9):1195-1201.
15. Conget PA, Minguell JJ:Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. Journal of cellular physiology 1999,181(1):67-73.
16. Fernandez M, Simon V, Herrera G, Cao C, Del Favero H, Minguell JJ:Detection of stromal cells in peripheral blood progenitor cell collections from breast cancer patients. Bone marrow transplantation 1997,20(4):265-271.
17. Erices A, Conget P, Minguell JJ:Mesenchymal progenitor cells in human umbilical cord blood. British journal of haematology 2000,109(1):235-242.
18. Conget PA, Allers C, Minguell JJ:Identification of a discrete population of human bone marrow-derived mesenchymal cells exhibiting properties of uncommitted progenitors. Journal of hematotherapy & stem cell research 2001, 10(6):749-758.
19. Conget PA, Minguell JJ:Adenoviral-mediated gene transfer into ex vivo expanded human bone marrow mesenchymal progenitor cells. Experimental hematology 2000,28(4):382-390.
20. Partridge K, Yang X, Clarke NM, Okubo Y, Bessho K, Sebald W, Howdle SM, Shakesheff KM, Oreffo RO:Adenoviral BMP-2 gene transfer in mesenchymal stem cells:in vitro and in vivo bone formation on biodegradable polymer scaffolds. Biochemical and biophysical research communications 2002, 292(1):144-152.
21. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE et al: Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nature medicine 1999,5(3):309-313.
22. Barry FP, Murphy JM:Mesenchymal stem cells:clinical applications and biological characterization. The international journal of biochemistry & cell biology 2004,36(4):568-584.
23. Deans RJ, Moseley AB:Mesenchymal stem cells:biology and potential clinical uses. Experimental hematology 2000,28(8):875-884.
24. Minguell JJ, Erices A, Conget P:Mesenchymal stem cells. Experimental biology and medicine 2001,226(6):507-520.
25. Ito T, Suzuki A, Okabe M, Imai E, Hori M:Application of bone marrow-derived stem cells in experimental nephrology. Experimental nephrology 2001,9(6):444-450.
26. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M et al: Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002, 418(6893):41-49.
27. Neuhuber B, Gallo G, Howard L, Kostura L, Mackay A, Fischer I:Reevaluation of in vitro differentiation protocols for bone marrow stromal cells: disruption of actin cytoskeleton induces rapid morphological changes and mimics neuronal phenotype. Journal of neuroscience research 2004, 77(2):192-204.
28. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E:Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006,8(4):315-317.
29. Graf T:Differentiation plasticity of hematopoietic cells. Blood 2002, 99(9):3089-3101.
30. Lodie TA, Blickarz CE, Devarakonda TJ, He C, Dash AB, Clarke J, Gleneck K, Shihabuddin L, Tubo R:Systematic analysis of reportedly distinct populations of multipotent bone marrow-derived stem cells reveals a lack of distinction. Tissue engineering 2002,8(5):739-751.
31. Gronthos S, Zannettino AC, Hay SJ, Shi S, Graves SE, Kortesidis A, Simmons PJ: Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow. Journal of cell science 2003,116(Pt 9):1827-1835.
32. Piersma AH, Ploemacher RE, Brockbank KG:Transplantation of bone marrow fibroblastoid stromal cells in mice via the intravenous route. British journal of haematology 1983,54(2):285-290.
33. Pereira RF, Halford KW, O'Hara MD, Leeper DB, Sokolov BP, Pollard MD, Bagasra O, Prockop DJ:Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proceedings of the National Academy of Sciences of the United States of America 1995,92(11):4857-4861.
34. Devine SM, Cobbs C, Jennings M, Bartholomew A, Hoffman R:Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood 2003,101(8):2999-3001.
35. Allers C, Sierralta WD, Neubauer S, Rivera F, Minguell JJ, Conget PA:Dynamic of distribution of human bone marrow-derived mesenchymal stem cells after transplantation into adult unconditioned mice. Transplantation 2004, 78(4):503-508.
36. Williams AR, Hare JM:Mesenchymal stem cells:biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circulation research 2011,109(8):923-940.
37. Melo LG, Pachori AS, Kong D, Gnecchi M, Wang K, Pratt RE, Dzau VJ: Molecular and cell-based therapies for protection, rescue, and repair of ischemic myocardium:reasons for cautious optimism. Circulation 2004, 109(20):2386-2393.
38. Pittenger MF, Martin BJ:Mesenchymal stem cells and their potential as cardiac therapeutics. Circulation research 2004,95(1):9-20.
39. Tomita S. Li RK, Weisel RD. Mickle DA, Kim EJ, Sakai T, Jia ZQ:Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 1999,100(19 Suppl):II247-256.
40. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS et al: Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nature medicine 2005, 11(4):367-368.
41. Gnecchi M, He H, Noiseux N, Liang OD, Zhang L, Morello F, Mu H, Melo LG, Pratt RE, Ingwall JS et al: Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2006,20(6):661-669.
42. Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, Fuchs S, Epstein SE:Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 2004, 109(12):1543-1549.
43. Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, Dzau VJ, Pratt RE:Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 2006,14(6):840-850.
44. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM et al: Bone marrow cells regenerate infarcted myocardium. Nature 2001,410(6829):701-705.
45. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA:Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 2001, 107(11):1395-1402.
46. Yoon YS, Wecker A, Heyd L, Park JS, Tkebuchava T, Kusano K, Hanley A, Scadova H, Qin G, Cha DH et al: Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction. J Clin Invest 2005,115(2):326-338.
47. Hattan N, Kawaguchi H, Ando K, Kuwabara E, Fujita J, Murata M, Suematsu M, Mori H, Fukuda K:Purified cardiomyocytes from bone marrow mesenchymal stem cells produce stable intracardiac grafts in mice. Cardiovascular research 2005,65(2):334-344.
48. Hakuno D, Fukuda K, Makino S, Konishi F, Tomita Y, Manabe T, Suzuki Y, Umezawa A, Ogawa S:Bone marrow-derived regenerated cardiomyocytes (CMG Cells) express functional adrenergic and muscarinic receptors. Circulation 2002,105(3):380-386.
49. Rangappa S, Entwistle JW, Wechsler AS, Kresh JY:Cardiomyocyte-mediated contact programs human mesenchymal stem cells to express cardiogenic phenotype. The Journal of thoracic and cardiovascular surgery 2003, 126(1):124-132.
50. Xu M, Wani M, Dai YS, Wang J, Yan M, Ayub A, Ashraf M:Differentiation of bone marrow stromal cells into the cardiac phenotype requires intercellular communication with myocytes. Circulation 2004,110(17):2658-2665.
51. Liechty KW, MacKenzie TC, Shaaban AF, Radu A, Moseley AM, Deans R, Marshak DR, Flake AW:Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 2000,6(11):1282-1286.
52. Pochampally RR, Neville BT, Schwarz EJ, Li MM, Prockop DJ:Rat adult stem cells (marrow stromal cells) engraft and differentiate in chick embryos without evidence of cell fusion. Proceedings of the National Academy of Sciences of the United States of America 2004,101(25):9282-9285.
53. Fukuda K:Molecular characterization of regenerated cardiomyocytes derived from adult mesenchymal stem cells. Congenital anomalies 2002, 42(1):1-9.
54. Wollert KC, Drexler H:Mesenchymal stem cells for myocardial infarction: promises and pitfalls. Circulation 2005,112(2):151-153.
55. Shake JG, Gruber PJ, Baumgartner WA, Senechal G, Meyers J, Redmond JM, Pittenger MF, Martin BJ:Mesenchymal stem cell implantation in a swine myocardial infarct model:engraftment and functional effects. The Annals of thoracic surgery 2002,73(6):1919-1925; discussion 1926.
56. Galmiche MC. Koteliansky VE, Briere J, Herve P, Charbord P:Stromal cells from human long-term marrow cultures are mesenchymal cells that differentiate following a vascular smooth muscle differentiation pathway. Blood 1993,82(1):66-76.
57. Nagaya N, Fujii T, Iwase T, Ohgushi H, Itoh T, Uematsu M, Yamagishi M, Mori H, Kangawa K, Kitamura S:Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis. American journal of physiology Heart and circulatory physiology 2004,287(6):H2670-2676.
58. Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, Fujii T, Uematsu M, Ohgushi H, Yamagishi M et al: Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation 2005,112(8):1128-1135.
59. Gojo S, Gojo N, Takeda Y, Mori T, Abe H, Kyo S, Hata J, Umezawa A:In vivo cardiovasculogenesis by direct injection of isolated adult mesenchymal stem cells. Experimental cell research 2003,288(1):51-59.
60. Davani S, Marandin A, Mersin N, Royer B, Kantelip B, Herve P, Etievent JP, Kantelip JP:Mesenchymal progenitor cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a rat cellular cardiomyoplasty model. Circulation 2003,108 Suppl 1:11253-258.
61. Kawada H, Fujita J, Kinjo K, Matsuzaki Y, Tsuma M, Miyatake H, Muguruma Y, Tsuboi K, Itabashi Y. Ikeda Y et al: Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood 2004,104(12):3581-3587.
62. Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, Durand DJ, Fitton T, Kuang JQ, Stewart G et al: Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proceedings of the National Academy of Sciences of the United States of America 2005,102(32):11474-11479.
63. Wang JS, Shum-Tim D, Chedrawy E, Chiu RC:The coronary delivery of marrow stromal cells for myocardial regeneration:pathophysiologic and therapeutic implications. The Journal of thoracic and cardiovascular surgery 2001,122(4):699-705.
64. Carmeliet P:Angiogenesis in health and disease. Nature medicine 2003, 9(6):653-660.
65. Asahara T, Kawamoto A, Masuda H:Concise review:Circulating endothelial progenitor cells for vascular medicine. Stem cells 2011,29(11):1650-1655.
66. Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ: Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. Journal of molecular and cellular cardiology 2011,50(2):280-289.
67. Gnecchi M, Zhang Z, Ni A, Dzau VJ:Paracrine mechanisms in adult stem cell signaling and therapy. Circulation research 2008,103(11):1204-1219.
68. Psaltis PJ, Zannettino AC, Worthley SG, Gronthos S:Concise review: mesenchymal stromal cells:potential for cardiovascular repair. Stem cells 2008,26(9):2201-2210.
69. Silva GV, Litovsky S, Assad JA, Sousa AL, Martin BJ, Vela D, Coulter SC, Lin J, Ober J, Vaughn WK 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.
70. Loffredo F, Lee RT:Therapeutic vasculogenesis:it takes two. Circulation research 2008,103(2):128-130.
71. Melero-Martin JM, De Obaldia ME, Kang SY, Khan ZA, Yuan L, Oettgen P, Bischoff J:Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells. Circulation research 2008,103(2):194-202.
72. Au P, Tam J, Fukumura D, Jain RK:Bone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature. Blood 2008, 111(9):4551-4558.
73. Caplan D, Waters G, Dede G, Michaud J, Reddy A:A study of syntactic processing in aphasia I:behavioral (psycholinguistic) aspects. Brain and language 2007,101(2):103-150.
74. Tang YL, Zhao Q, Zhang YC, Cheng L, Liu M, Shi J, Yang YZ, Pan C, Ge J, Phillips MI:Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regul Pept 2004, 117(1):3-10.
75. Ono I, Yamashita T, Hida T, Jin HY, Ito Y, Hamada H, Akasaka Y, Ishii T, Jimbow K:Local administration of hepatocyte growth factor gene enhances the regeneration of dermis in acute incisional wounds. The Journal of surgical research 2004,120(1):47-55.
76. Nakamura T, Mizuno S, Matsumoto K, Sawa Y, Matsuda H:Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. JClin Invest 2000,106(12):1511-1519.
77. Okumura H, Nagaya N, Itoh T, Okano I, Hino J, Mori K, Tsukamoto Y, Ishibashi-Ueda H, Miwa S. Tambara K et al: Adrenomedullin infusion attenuates myocardial ischemia/reperfusion injury through the phosphatidylinositol 3-kinase/Akt-dependent pathway. Circulation 2004, 109(2):242-248.
78. Tsuruda T, Kato J, Kitamura K, Kawamoto M, Kuwasako K, Imamura T, Koiwaya Y, Tsuji T, Kangawa K, Eto T:An autocrine or a paracrine role of adrenomedullin in modulating cardiac fibroblast growth. Cardiovascular research 1999,43(4):958-967.
79. Nishikimi T, Yoshihara F, Horinaka S, Kobayashi N, Mori Y, Tadokoro K, Akimoto K, Minamino N, Kangawa K, Matsuoka H:Chronic administration of adrenomedullin attenuates transition from left ventricular hypertrophy to heart failure in rats. Hypertension 2003,42(5):1034-1041.
80. Fuller SJ, Mynett JR, Sugden PH:Stimulation of cardiac protein synthesis by insulin-like growth factors. The Biochemical journal 1992,282 (Pt 1):85-90.
81. Florini JR, Ewton DZ, Coolican SA:Growth hormone and the insulin-like growth factor system in myogenesis. Endocrine reviews 1996,17(5):481-517.
82. Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE: 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.
83. Jiang S, Haider H, Idris NM, Salim A, Ashraf M:Supportive interaction between cell survival signaling and angiocompetent factors enhances donor cell survival and promotes angiomyogenesis for cardiac repair. Circulation research 2006,99(7):776-784.
84. Uemura R, Xu M, Ahmad N, Ashraf M:Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circulation research 2006,98(11):1414-1421.
85. Xu M, Uemura R, Dai Y, Wang Y, Pasha Z, Ashraf M:In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function. Journal of molecular and cellular cardiology 2007,42(2):441-448.
86. Feygin J, Mansoor A, Eckman P, Swingen C, Zhang J:Functional and bioenergetic modulations in the infarct border zone following autologous mesenchymal stem cell transplantation. American journal of physiology Heart and circulatory physiology 2007,293(3):H1772-1780.
87. Gnecchi M, He H, Melo LG, Noiseaux N, Morello F, de Boer RA, Zhang L, Pratt RE, Dzau VJ, Ingwall JS:Early beneficial effects of bone marrow-derived mesenchymal stem cells overexpressing Akt on cardiac metabolism after myocardial infarction. Stem cells 2009,27(4):971-979.
88. Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS, Mazhari R, Boyle AJ, Zambrano JP, Rodriguez JE et al: Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation research 2010,107(7):913-922.
89. Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, Pasumarthi KB, Virag JI, Bartelmez SH, Poppa V et al: Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004,428(6983):664-668.
90. Nygren JM, Jovinge S, Breitbach M, Sawen P, Roll W, Hescheler J, Taneera J, Fleischmann BK, Jacobsen SE:Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nature medicine 2004,10(5):494-501.
91. Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW:Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002,416(6880):542-545.
92. Ying QL, Nichols J, Evans EP, Smith AG:Changing potency by spontaneous fusion. Nature 2002,416(6880):545-548.
93. Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A:Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003, 425(6961):968-973.
94. Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ et al: Cardiac progenitor cells from adult myocardium:homing, differentiation, and fusion after infarction. Proceedings of the National Academy of Sciences of the United States of America 2003,100(21):12313-12318.
95. Janse MJ, Schwartz PJ, Wilms-Schopman F, Peters RJ, Durrer D:Effects of unilateral stellate ganglion stimulation and ablation on electrophysiologic changes induced by acute myocardial ischemia in dogs. Circulation 1985, 72(3):585-595.
96. Pak HN, Qayyum M, Kim DT, Hamabe A, Miyauchi Y, Lill MC, Frantzen M, Takizawa K, Chen LS, Fishbein MC et al: Mesenchymal stem cell injection induces cardiac nerve sprouting and increased tenascin expression in a Swine model of myocardial infarction. Journal of cardiovascular electrophysiology 2003,14(8):841-848.
97. Cao JM, Chen LS, KenKnight BH, Ohara T, Lee MH, Tsai J, Lai WW, Karagueuzian HS, Wolf PL, Fishbein MC et al: Nerve sprouting and sudden cardiac death. Circulation research 2000,86(7):816-821.
98.
.
99. Opthof T, Misier AR, Coronel R, Vermeulen JT, Verberne HJ, Frank RG, Moulijn AC, van Capelle FJ, Janse MJ:Dispersion of refractoriness in canine ventricular myocardium. Effects of sympathetic stimulation. Circulation research 1991,68(5):1204-1215.
100. Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers DM:Arrhythmogenesis and contractile dysfunction in heart failure:Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circulation research 2001,88(11):1159-1167.
101. Siminiak T, Kurpisz M:Myocardial replacement therapy. Circulation 2003, 108(10):1167-1171.
102. Bel A, Messas E, Agbulut O, Richard P, Samuel JL, Bruneval P, Hagege AA, Menasche P:Transplantation of autologous fresh bone marrow into infarcted myocardium:a word of caution. Circulation 2003,108 Suppl 1:11247-252.
103. Agbulut O, Menot ML, Li Z, Marotte F, Paulin D, Hagege AA, Chomienne C, Samuel JL, Menasche P:Temporal patterns of bone marrow cell differentiation following transplantation in doxorubicin-induced cardiomyopathy. Cardiovascular research 2003,58(2):451-459.
104. Haider H, Ashraf M:Bone marrow stem cell transplantation for cardiac repair. American journal of physiology Heart and circulatory physiology 2005, 288(6):H2557-2567.
105. Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI:The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells, tissues, organs 2001,169(1):12-20.
106. Bittira B, Shum-Tim D, Al-Khaldi A, Chiu RC:Mobilization and homing of bone marrow stromal cells in myocardial infarction. European journal of cardio-thoracic surgery:official journal of the European Association for Cardio-thoracic Surgery 2003,24(3):393-398.
107. Wang JS, Shum-Tim D, Galipeau J, Chedrawy E, Eliopoulos N, Chiu RC: Marrow stromal cells for cellular cardiomyoplasty:feasibility and potential clinical advantages. The Journal of thoracic and cardiovascular surgery 2000, 120(5):999-1005.
108. Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, Miller L, Guetta E, Zipori D, Kedes LH et al: Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium:feasibility, cell migration, and body distribution. Circulation 2003,108(7):863-868.
109. Saito T, Kuang JQ, Lin CC, Chiu RC:Transcoronary implantation of bone marrow stromal cells ameliorates cardiac function after myocardial infarction. The Journal of thoracic and cardiovascular surgery 2003, 126(1):114-123.
110. Dick AJ, Guttman MA, Raman VK, Peters DC, Pessanha BS, Hill JM, Smith S, Scott G, McVeigh ER, Lederman RJ:Magnetic resonance fluoroscopy allows targeted delivery of mesenchymal stem cells to infarct borders in Swine. Circulation 2003,108(23):2899-2904.
111. Hill JM, Dick AJ, Raman VK, Thompson RB, Yu ZX, Hinds KA, Pessanha BS, Guttman MA, Varney TR, Martin BJ et al: Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation 2003, 108(8):1009-1014.
112. Kraitchman DL, Heldman AW, Atalar E, Amado LC, Martin BJ, Pittenger MF, Hare JM, Bulte JW:In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 2003,107(18):2290-2293.
113. Min JY, Sullivan MF, Yang Y, Zhang JP, Converso KL, Morgan JP, Xiao YF: Significant improvement of heart function by cotransplantation of human mesenchymal stem cells and fetal cardiomyocytes in postinfarcted pigs. The Annals of thoracic surgery 2002,74(5):1568-1575.
114. Vulliet PR, Greeley M. Halloran SM, MacDonald KA, Kittleson MD: Intra-coronary arterial injection of mesenchymal stromal cells and microinfarction in dogs. Lancet 2004,363(9411):783-784.
115. Kovacic JC, Graham RM:Stem-cell therapy for myocardial diseases. Lancet2004,363(9422)：1735-1736.
116. Assmus B, Schachinger V. Teupe C, Britten M, Lehmann R, Dobert N, Grunwald F, Aicher A, Urbich C, Martin H et al: Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 2002,106(24):3009-3017.
117. Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D et al: Intracoronary autologous bone-marrow cell transfer after myocardial infarction:the BOOST randomised controlled clinical trial. Lancet 2004,364(9429):141-148.
118. Jaquet K, Krause KT, Denschel J, Faessler P, Nauerz M, Geidel S, Boczor S, Lange C, Stute N, Zander A et al: Reduction of myocardial scar size after implantation of mesenchymal stem cells in rats:what is the mechanism? Stem cells and development 2005,14(3):299-309.
119. Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P:Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002, 106(15):1913-1918.
120. Menasche P, Hagege AA, Vilquin JT, Desnos M, Abergel E, Pouzet B, Bel A, Sarateanu S, Scorsin M, Schwartz K et al: Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. Journal of the American College of Cardiology 2003,41(7):1078-1083.
121. Pagani FD, DerSimonian H, Zawadzka A, Wetzel K, Edge AS, Jacoby DB, Dinsmore JH, Wright S, Aretz TH, Eisen HJ et al: Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation. Journal of the American College of Cardiology 2003,41(5):879-888.
122. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, Rossi MI, Carvalho AC, Dutra HS, Dohmann HJ et al: Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003,107(18):2294-2302.
123. Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, Schumichen C, Nienaber CA, Freund M, Steinhoff G:Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003,361(9351):45-46.
124. Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP:Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003,361(9351):47-49.
125. Rafii S, Avecilla S, Shmelkov S, Shido K, Tejada R, Moore MA, Heissig B, Hattori K:Angiogenic factors reconstitute hematopoiesis by recruiting stem cells from bone marrow microenvironment. Annals of the New York Academy of Sciences 2003,996:49-60.
126. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM:Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circulation research 1999,85(3):221-228.
127. Kawamoto A, Asahara T, Losordo DW:Transplantation of endothelial progenitor cells for therapeutic neovascularization. Cardiovascular radiation medicine 2002,3(3-4):221-225.
128. Tepper OM, Capla JM, Galiano RD, Ceradini DJ, Callaghan MJ, Kleinman ME, Gurtner GC:Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. Blood 2005,105(3):1068-1077.
129. Yoshida S, Ono M, Shono T, Izumi H, Ishibashi T, Suzuki H, Kuwano M: Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. Molecular and cellular biology 1997,17(7):4015-4023.
130. Presta M, Dell'Era P, Mitola S, Moroni E, Ronca R, Rusnati M:Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine & growth factor reviews 2005,16(2):159-178.
131. Yoshioka T, Ageyama N, Shibata H, Yasu T, Misawa Y, Takeuchi K, Matsui K, Yamamoto K, Terao K, Shimada K et al: Repair of infarcted myocardium mediated by transplanted bone marrow-derived CD34+stem cells in a nonhuman primate model. Stem cells 2005,23(3):355-364.
132. Chen SL, Fang WW, Ye F, Liu YH, Qian J. Shan SJ. Zhang JJ, Chunhua RZ, Liao LM, Lin S et al: Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. The American journal of cardiology 2004,94(1):92-95.
133. Florenzano F, Minguell JJ:Autologous mesenchymal stem cell transplantation after acute myocardial infarction. The American journal of cardiology'2005, 95(3):435.
134. Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, Amano K, Kishimoto Y, Yoshimoto K, Akashi H et al: Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells:a pilot study and a randomised controlled trial. Lancet 2002,360(9331):427-435.
135. Benavente CA, Sierralta WD, Conget PA, Minguell JJ:Subcellular distribution and mitogenic effect of basic fibroblast growth factor in mesenchymal uncommitted stem cells. Growth Factors 2003,21(2):87-94.
136. Haynesworth SE, Baber MA, Caplan AI:Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro:effects of dexamethasone and IL-1 alpha. J Cell Physiol 1996,166(3):585-592.
137. Erices A, Conget P, Rojas C, Minguell JJ:Gp130 activation by soluble interleukin-6 receptor/interleukin-6 enhances osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells. Experimental cell research 2002,280(1):24-32.
138. Tang YL, Zhao Q, Qin X, Shen L, Cheng L, Ge J, Phillips MI: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 2005,80(1):229-236; discussion 236-227.