Silica-coated magnetic nanoparticles labeled endothelial progenitor cells alleviate ischemic myocardial injury and improve long-term cardiac function with magnetic field guidance in rats with myocardial infarction

Low retention of endothelial progenitor cells (EPCs) in the infarct area has been suggested to be responsible for the poor clinical efficacy of EPC therapy for myocardial infarction (MI). This study aimed to evaluate whether magnetized EPCs guided through an external magnetic field could augment the aggregation of EPCs in an ischemia area, thereby enhancing therapeutic efficacy. EPCs from male rats were isolated and labeled with silica-coated magnetic iron oxide nanoparticles to form magnetized EPCs. Then, the proliferation, migration, vascularization, and cytophenotypic markers of magnetized EPCs were analyzed. Afterward, the magnetized EPCs (1 × 10⁶) were transplanted into a female rat model of MI via the tail vein at 7 days after MI with or without the guidance of an external magnet above the infarct area. Cardiac function, myocardial fibrosis, and the apoptosis of cardiomyocytes were observed at 4 weeks after treatment. In addition, EPC retention and the angiogenesis of ischemic myocardium were evaluated. Labeling with magnetic nanoparticles exhibited minimal influence to the biological functions of EPCs. The transplantation of magnetized EPCs guided by an external magnet significantly improved the cardiac function, decreased infarction size, and reduced myocardial apoptosis in MI rats. Moreover, enhanced aggregations of magnetized EPCs in the infarcted border zone were observed in rats with external magnet-guided transplantation, accompanied by the significantly increased density of microvessels and upregulated the expression of proangiogenic factors, when compared with non-external-magnet-guided rats. The magnetic field-guided transplantation of magnetized EPCs was associated with the enhanced aggregation of EPCs in the infarcted border zone, thereby improving the therapeutic efficacy of MI.     

Bradykinin protects cardiac c-kit positive cells from high-glucose-induced senescence through B2 receptor signaling pathway

Cardiac c-kit positive cells are cardiac-derived cells that exist within the heart and have a great many protective effects. The senescence of cardiac c-kit positive cells probably leads to cell dysfunction. Bradykinin plays a key role in cell protection. However, whether bradykinin prevents cardiac c-kit positive cells from high-glucose-induced senescence is unknown. Here, we found that glucose treatment causes the premature senescence of cardiac c-kit positive cells. Bradykinin B2 receptor (B2R) expression was declined by glucose-induced senescence. Bradykinin treatment inhibited senescence and reduced intracellular oxygen radicals according to senescence-associated β-galactosidase staining and 2′,7′-dichlorodihydrofluorescein diacetate staining. Moreover, the mitochondrial membrane potential was damaged, as measured by JC-1 staining. The mitochondrial membrane potential was preserved under bradykinin treatment. The concentration of superoxide was decreased, and the concentration of intracellular adenosine triphosphate was increased after bradykinin treatment. Western blot showed that bradykinin leads to AKT and mammalian target of rapamycin (mTOR) phosphorylation and decreased levels of P53 and P16 when compared with glucose treatment alone. Antagonists of B2R, phosphoinositide 3-kinase (PI3K), mTOR, and B2R small interfering RNA prevented the protective effect of bradykinin. P53 antagonist also inhibited the glucose-induced senescence of cardiac c-kit positive cells. In conclusion, bradykinin prevents the glucose-induced premature senescence of cardiac c-kit positive cells through the B2R/PI3K/AKT/mTOR/P53 signal pathways.     

Mineralocorticoid receptor deficiency improves the therapeutic effects of mesenchymal stem cells for myocardial infarction via enhanced cell survival

The poor survival of stem cells seriously limits their therapeutic efficacy for myocardial infarction (MI). Mineralocorticoid receptor (MR) activation plays an important role in the pathogenesis of multiple cardiovascular diseases. Here, we examined whether MR silencing in bone marrow derived mesenchymal stem cells (MSCs) could improve MSCs’ survival and enhance their cardioprotective effects in MI. MSCs from male Sprague‐Dawley rats were transfected with adenoviral small interfering RNA to silence MR (siRNA‐MR). MR silencing decreased hypoxia‐induced MSCs’ apoptosis, as demonstrated by Annexin V/7‐AAD staining. The mechanisms contributing to the beneficial effects of MR depletion were associated with inhibiting intracellular reactive oxygen species production and increased Bcl‐2/Bax ratio. In vivo study, 1 × 10⁶ of MSCs with or without siRNA‐MR were injected into rat hearts immediately after MI. Depletion of MR could improve the MSCs’ survival significantly in infarcted myocardium, associated with more cardiac function improvement and smaller infarct size. Capillary density were also significantly higher in siRNA group with increased expression of vascular endothelial growth factor. Our study demonstrated that silencing MR promoted MSCs’ survival and repair efficacy in ischaemic hearts. MR might be a potential target for enhancing the efficacy of cell therapy in ischaemic heart disease.     

心肌梗死大鼠钙敏感受体表达与心肌细胞凋亡的变化

目的:观察大鼠急性心肌梗死后不同时间心肌钙敏感受体(CaSR)的表达和心肌细胞凋亡的变化情况。方法:健康Wistar大鼠随机分为假手术组(Sham)和心肌梗死(AMI)组,通过结扎左侧冠状动脉前降支的方法,建立大鼠心肌梗死模型,分别在手术后1、2、4周(每组成功存活n=5)检测心脏形态学和血流动力学的改变,检测心肌组织中CaSRmRNA和蛋白的表达,以及Bax、Bcl-2、caspase-3和caspase-9蛋白的表达,检测血清中乳酸脱氢酶(LDH)、肌酸激酶(CK)活性和肌钙蛋白(cTnT)水平,观察心肌细胞凋亡情况。结果:和Sham组相比,随着心肌梗死的发展,AMI组大鼠心肌组织CaSR的mRNA和蛋白的表达、细胞凋亡指数均明显增加(P<0.05),心肌细胞超微结构损伤严重;左心室收缩压(LVSP)、左心室内压最大上升速率(+dp/dtmax)(mmHg/s)和最大下降速率(-dp/dtmax)(mmHg/s)减少,左心室舒张末期压(LVEDP)明显增大(P<0.05);AMI组血清cTnT水平、CK和LDH活性均升高(P<0.05),随着心肌梗死的发展,cTnT水平和CK活性逐渐降低,LDH变化不明显。心肌组织中促凋亡相关蛋白Bax、caspase-3、caspase-9表达增多,抑制凋亡的相关蛋白(或因子)Bcl-2表达减少(P<0.05)。结论:随着AMI的发展,AMI组大鼠心肌组织中CaSR的mRNA和蛋白的表达增多,细胞凋亡数增加,表明CaSR参与了心肌梗死的发展,其机制可能与促进细胞凋亡有关。     

Functions of beta2-adrenergic receptor in human periodontal ligament cells

Adrenergic receptors (ARs) are receptors of noradrenalin and adrenalin, of which there are nine different subtypes. In particular, β2 adrenergic receptor (β2-AR) is known to be related to the restoration and maintenance of homeostasis in bone and cardiac tissues; however, the functional role of signaling through β2-AR in periodontal ligament (PDL) tissue has not been fully examined. In this report, we investigated that β2-AR expression in PDL tissues and their features in PDL cells. β2-AR expressed in rat PDL tissues and human PDL cells (HPDLCs) derived from two different patients (HPDLCs-2G and -3S). Rat PDL tissue with occlusal loading showed high β2-AR expression, while its expression was downregulated in that without loading. In HPDLCs, β2-AR expression was increased exposed to stretch loading. The gene expression of PDL-related molecules was investigated in PDL clone cells (2-23 cells) overexpressing β2-AR. Their gene expression and intracellular cyclic adenosine monophosphate (cAMP) levels were also investigated in HPDLCs treated with a specific β2-AR agonist, fenoterol (FEN). Overexpression of β2-AR significantly promoted the gene expression of PDL-related molecules in 2 to 23 cells. FEN led to an upregulation in the expression of PDL-related molecules and increased intracellular cAMP levels in HPDLCs. In both HPDLCs, inhibition of cAMP signaling by using protein kinase A inhibitor suppressed the FEN-induced gene expression of α-smooth muscle actin. Our findings suggest that the occlusal force is important for β2-AR expression in PDL tissue and β2-AR is involved in fibroblastic differentiation and collagen synthesis of PDL cells. The signaling through β2-AR might be important for restoration and homeostasis of PDL tissue.     

Period 2 is essential to maintain early endothelial progenitor cell function in vitro and angiogenesis after myocardial infarction in mice

Cellular therapeutic neovascularization has been successfully performed in clinical trials for patients with ischaemia diseases. Despite the vast knowledge of cardiovascular disease and circadian biology, the role of the circadian clock in regulating angiogenesis in myocardial infarction (MI) remains poorly understood. In this study, we aimed to investigate the role and underlying mechanisms of Period 2 (Per2) in endothelial progenitor cell (EPC) function. Flow cytometry revealed lower circulating EPC proportion in per2^−/− than in wild-type (WT) mice. PER2 was abundantly expressed in early EPCs in mice. In vitro, EPCs from per2^−/− mice showed impaired proliferation, migration, tube formation and adhesion. Western blot analysis demonstrated inhibited PI3k/Akt/FoxO signalling and reduced C-X-C chemokine receptor type 4 (CXCR4) protein level in EPCs of per2^−/− mice. The impaired proliferation was blocked by activated PI3K/Akt/FoxO signalling. Direct interaction of CXCR4 and PER2 was detected in WT EPCs. To further study the effect of per2 on in vivo EPC survival and angiogenesis, we injected saline or DiI-labelled WT or per2^−/− EPC intramyocardially into mice with induced MI. Per2^−/− reduced the retention of transplanted EPCs in the myocardium, which was associated with significantly reduced DiI expression in the myocardium of MI mice. Decreased angiogenesis in the myocardium of per2^−/− EPC-treated mice coincided with decreased LV function and increased infarct size in the myocardium. Per2 may be a key factor in maintaining EPC function in vitro and in therapeutic angiogenesis in vivo.     

ADRB2 polymorphisms predict the risk of myocardial infarction and coronary artery disease

Recently, the rs1042713 G > A and rs1042714 C > G polymorphisms in the beta-2adrenergic receptor (ADRB2) gene were shown to be related to atherosclerosisdiseases. Therefore, we performed a systemic meta-analysis to determine whether thetwo functional polymorphisms are related to the risk of myocardial infarction (MI)and coronary artery disease (CAD). We identified published studies that are relevantto our topic of interest. Seven case-control studies, with a total of 6,843 subjects,were incorporated into the current meta-analysis. Our analysis showed a higherfrequency of rs1042713 G > A variant in patients with MI or CAD compared tohealthy controls. A similar result was also obtained with the rs1042714 C > Gvariant under both the allele and dominant models. Ethnicity-stratified subgroupanalysis suggested that the rs1042714 C > G variant correlated with an increasedrisk of the two diseases in both Asians and Caucasians, while rs1042713 G > A onlycontributes to the risk of two diseases in Asians. In the disease type-stratifiedsubgroups, the frequencies of both the rs1042713 G > A and rs1042714 C > Gvariants were higher in the cases than in the controls in both the MI and CADsubgroups. Collectively, our data contribute towards understanding the correlationbetween the rs1042713 G > A and rs1042714 C > G polymorphisms inADRB2 and the susceptibility to MI and CAD.     

Migration of bone marrow-derived cells and improved perfusion after treatment with erythropoietin in a murine model of myocardial infarction

Erythropoietin (EPO) was shown to have protective effects after myocardial infarction (MI) by neovascularization and antiapoptotic mechanisms. Beside direct receptor-dependent mechanisms, mobilization and homing of bone marrow-derived cells (BMCs) may play a pivotal role in this regard. In this study, we intended to track different subpopulations of BMCs and to assess serially myocardial perfusion changes in EPO-treated mice after MI. To allow tracking of BMCs, we used a chimeric mouse model. Therefore, mice (C57BL/6J) were sublethally irradiated, and bone marrow (BM) from green fluorescent protein transgenic mice was transplanted. Ten weeks later coronary artery ligation was performed to induce MI. EPO was injected for 3 days with a total dose of 5000 IU/kg. Subpopulations (CD31, c-kit, CXCR-4 and Sca-1) of EGFP(+) cells were studied in peripheral blood, bone marrow and hearts by flow cytometry. Myocardial perfusion was serially investigated in vivo by pinhole single-photon emission computed tomography (SPECT) at days 6 and 30 after MI. EPO-treated animals revealed an enhanced mobilization of BMCs into peripheral blood. The numbers of these cells in BM remained unchanged. Homing of all BMCs subpopulations to the ischaemic myocardium was significantly increased in EPO-treated mice. Among the investigated subpopulations, EPO predominantly affected migration of CXCR-4(+) (4.3-fold increase). Repetitively SPECT analyses revealed a reduction of perfusion defects after EPO treatment over time. Our study shows that EPO treatment after MI enhances the migration capacity of BMCs into ischaemic tissue, which may attribute to an improved perfusion and reduced size of infarction, respectively.     

Timing of transplantation of autologous bone marrow derived mesenchymal stem cells for treating myocardial infarction

It is still unclear whether the timing of intracoronary stem cell therapy affects the therapeutic response in patients with myocardial infarction.The natural course of healing the infarction and the presence of putative homing signals within the damaged myocardium appear to favor cell engraftment during the transendothelial passage in the early days after reperfusion.However,the adverse inflammatory environment,with its high oxidative stress,might be deleterious if cells are administered too early after reperfusion.Here we highlight several aspects of the timing of intracoronary stem cell therapy.Our results showed that transplantation of bone marrow mesenchymal stem cells at 2 4 weeks after myocardial infarction is more favorable for reduction of the scar area,inhibition of left ventricular remodeling,and recovery of heart function.Coronary injection of autologous bone marrow mesenchymal stem cells at 2 4 weeks after acute myocardial infarction is safe and does not increase the incidence of complications.     

海马齿状回内beta肾上腺素能受体对睡眠剥夺大鼠空间学习记忆的作用及其机制*

目的: 探究海马齿状回(DG)内beta肾上腺素能受体(beta-AR)对睡眠剥夺(SD)大鼠空间学习记忆的作用及其机制。方法: 本研究应用剥夺杆式睡眠剥夺仪建立21 d(18 h/d)慢性SD模型。动物分为4组(n=6):对照组,ISO组(异丙肾上腺素组),SD组和SD+ISO组。每天训练前30 min,以0.5 ml/min速度向DG区微量注入ISO (2 mg/μl) 或盐水1 ml。Morris水迷宫检测大鼠空间学习记忆能力。免疫组织化学和免疫印迹法检测海马DG区c-Fos和脑源性神经营养因子(BDNF)表达。结果: 与对照组相比, SD组大鼠前4 d逃逸时间显著增加(P＜0.01),且第5日目标象限时间比和穿台次数明显减少(P＜0.05),与SD组相比SD+ISO组上述行为学指标显著改善(P均＜0.05)。与对照组比较,SD组大鼠海马DG区c-Fos和BDNF蛋白表达水平均显著降低(P均＜0.05),然而与SD组比较,SD+ISO组两蛋白表达水平明显增加(P均＜0.05)。结论: 海马DG区beta-AR激活可改善SD诱发的空间学习和记忆障碍,其机制可能与上调DG区c-Fos和BDNF蛋白表达有关。     

Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart

Cannabinoid receptor type 2(CB2)activation is recently reported to promote proliferation of some types of resident stem cells(e.g.,hematopoietic stem/progenitor cell or neural progenitor cell).Resident cardiac progenitor cell(CPC)activation and proliferation are crucial for endogenous cardiac regeneration and cardiac repair after myocardial infarction(MI).This study aims to explore the role and possible mechanisms of CB2receptor activation in enhancing myocardial repair.Our results revealed that CB2receptor agonist AM1241 can significantly increase CPCs by c-kit and Runx1 staining in ischemic myocardium as well as improve cardiomyocyte proliferation.AM1241 also decreased serum levels of MDA,TNF-αand IL-6 after MI.In addition,AM1241 can ameliorate left ventricular ejection fraction and fractional shortening,and reduce fibrosis.Moreover,AM1241 treatment markedly increased p-Akt and HO-1 expression,and promoted Nrf-2 nuclear translocation.However,PI3K inhibitor wortmannin eliminated these cardioprotective roles of AM1241.In conclusion,AM1241 could induce myocardial regeneration and improve cardiac function,which might be associated with PI3K/Akt/Nrf2 signaling pathway activation.Our findings may provide a promising strategy for cardiac endogenous regeneration after MI.     

Local activation of cardiac stem cells for post‐myocardial infarction cardiac repair

The prognosis of patients with myocardial infarction (MI) and resultant chronic heart failure remains extremely poor despite continuous advancements in optimal medical therapy and interventional procedures. Animal experiments and clinical trials using adult stem cell therapy following MI have shown a global improvement of myocardial function. The emergence of stem cell transplantation approaches has recently represented promising alternatives to stimulate myocardial regeneration. Regarding their tissue‐specific properties, cardiac stem cells (CSCs) residing within the heart have advantages over other stem cell types to be the best cell source for cell transplantation. However, time‐consuming and costly procedures to expanse cells prior to cell transplantation and the reliability of cell culture and expansion may both be major obstacles in the clinical application of CSC‐based transplantation therapy after MI. The recognition that the adult heart possesses endogenous CSCs that can regenerate cardiomyocytes and vascular cells has raised the unique therapeutic strategy to reconstitute dead myocardium via activating these cells post‐MI. Several strategies, such as growth factors, mircoRNAs and drugs, may be implemented to potentiate endogenous CSCs to repair infarcted heart without cell transplantation. Most molecular and cellular mechanism involved in the process of CSC‐based endogenous regeneration after MI is far from understanding. This article reviews current knowledge opening up the possibilities of cardiac repair through CSCs activation in situ in the setting of MI.     

Repair mechanisms of bone marrow mesenchymal stem cells in myocardial infarction

The prognosis of patients with myocardial infarction (MI) and resultant chronic heart failure remains extremely poor despite advances in optimal medical therapy and interventional procedures. Animal experiments and clinical trials using adult stem cell therapy following MI have shown a global improvement of myocardial function. Bone marrow-derived mesenchymal stem cells (MSCs) hold promise for cardiac repair following MI, due to their multilineage, self-renewal and proliferation potential. In addition, MSCs can be easily isolated, expanded in culture, and have immunoprivileged properties to the host tissue. Experimental studies and clinical trials have revealed that MSCs not only differentiate into cardiomyocytes and vascular cells, but also secrete amounts of growth factors and cytokines which may mediate endogenous regeneration via activation of resident cardiac stem cells and other stem cells, as well as induce neovascularization, anti-inflammation, anti-apoptosis, anti-remodelling and cardiac contractility in a paracrine manner. It has also been postulated that the anti-arrhythmic and cardiac nerve sprouting potential of MSCs may contribute to their beneficial effects in cardiac repair. Most molecular and cellular mechanisms involved in the MSC-based therapy after MI are still unclear at present. This article reviews the potential repair mechanisms of MSCs in the setting of MI.     

心梗后心肌重构过程中AT_(1A)、AT_2受体表达的变化

为探讨AT1、AT2 受体在心肌重构演变过程中的作用 ,本实验应用免疫组化、电镜技术和图像分析方法 ,观察了大鼠心梗后心肌重构过程中非梗塞区AT1、AT2 受体表达的动态变化。结果显示 ,心梗术后 3d ,电镜显示非梗塞区心肌细胞肌原纤维横纹消失 ,线粒体肿胀 ,成纤维细胞增多 ,免疫组化显示AT1A受体在非梗塞区心肌组织表达明显升高 (P <0 0 0 1) ,AT2 受体表达无明显变化 (P >0 0 5 ) ;心梗术后 14d ,可见心肌细胞肌原纤维横纹 ,心肌细胞间胶原纤维明显增多 ,同时AT1A受体在心肌的表达比心梗术后 3d时减弱 ,但仍高于对照组 (P <0 0 5 ) ,AT2 受体表达明显增加 (P <0 0 0 1)。结果提示 :心梗后非梗塞区心肌AT1A、AT2 受体表达先后上调 ,可能参与介导心肌重构过程     

Inhibition of gut pacemaker cell formation from mouse ES cells by the c-kit inhibitor

Using an embryoid body (EB) culture system, we developed a functional organ-like cluster, a "gut", from mouse embryonic stem (ES) cells (ES gut). Each ES gut exhibited various types of spontaneous movements. In these spontaneously contracting ES guts, dense distributions of interstitial cells of Cajal (ICC) (c-kit, a transmembrane receptor that has tyrosine kinase activity, positive cells; gut pacemaker cells) and smooth muscle cells were discernibly identified. By adding Glivec 10(-5)M, a tyrosine kinase receptor c-kit inhibitor, only during EB formation, we for the first time succeeded in suppressing in vitro formation of ICC in the ES gut. The ES gut without ICC did not exhibit any movements. However, it appeared that Glivec 10(-6)-10(-7)M rather increased number of ES guts with spontaneous movements associated with increase of intracellular Ca(2+) concentration ([Ca(2+)](i)). These results suggest ICC is critical for in vitro formation of ES guts with spontaneous movements.     

AT1receptor blockade alters metabolic,functional and structural proteins after reperfused myocardial infarction: Detection using proteomics

Angiotensin II (AngII) type 1 receptor (AT₁R) blockers (ARBs) limit left ventricular (LV) dysfunction and necrosis after reperfused myocardial infarction (RMI) and proteomics can detect changes in protein levels after injury. We applied proteomics to detect changes in levels of specific protein in the ischemic zone (IZ) and non-ischemic zone (NIZ) of dog hearts after in vivo RMI (90 min of anterior ischemia; 120 min of reperfusion) and treatment with intravenous vehicle (control) and the ARBs valsartan or irbesartan (10 mg/kg) over 30 min before RMI. We also assessed LV function, infarction and apoptosis. Both ARBs limited the RMI-induced LV dysfunction, infarct size and apoptosis. Proteomics detected differential expression of 5 randomly selected proteins in the IZ compared to the NIZ after RMI: decrease in subunit of ATP synthase isoform precursor (consistent with increased conversion to subunit under metabolic stress), M chain creatine kinase (consistent with cellular damage) and ventricular myosin light chain-1 (consistent with structural damage and decreased contractility); and increase in NAD⁺-isocitrate dehydrogenase (ICDH) and subunit and ATP synthase D chain (mitochondrial, consistent with metabolic dysfunction). Importantly, changes in NAD₊-ICDH and ATP synthase D chain were reversed by ARB therapy. Thus, proteomics can detect regional changes in metabolic, contractile, and structural proteins after RMI and several of these proteins are favorably modified by ARBs, suggesting that they may be novel therapeutic targets. (Mol Cell Biochem 263: 179–188, 2004)     

The importance of valine 114 in ligand binding in β2‐adrenergic receptor

G‐protein coupled receptors (GPCRs) are transmembrane signaling molecules, with a majority of them performing important physiological roles. β₂‐Adrenergic receptor (β₂‐AR) is a well‐studied GPCRs that mediates natural responses to the hormones adrenaline and noradrenaline. Analysis of the ligand‐binding region of β₂‐AR using the recently solved high‐resolution crystal structures revealed a number of highly conserved amino acids that might be involved in ligand binding. However, detailed structure‐function studies on some of these residues have not been performed, and their role in ligand binding remains to be elucidated. In this study, we have investigated the structural and functional role of a highly conserved residue valine 114, in hamster β₂‐AR by site‐directed mutagenesis. We replaced V114 in hamster β₂‐AR with a number of amino acid residues carrying different functional groups. In addition to the complementary substitutions V114I and V114L, the V114C and V114E mutants also showed significant ligand binding and agonist dependent G‐protein activation. However, the V114G, V114T, V114S, and V114W mutants failed to bind ligand in a specific manner. Molecular modeling studies were conducted to interpret these results in structural terms. We propose that the replacement of V114 influences not only the interaction of the ethanolamine side‐chains but also the aryl‐ring of the ligands tested. Results from this study show that the size and orientation of the hydrophobic residue at position V114 in β₂‐AR affect binding of both agonists and antagonists, but it does not influence the receptor expression or folding.     

Insulin-like growth factor 1 improves the efficacy of mesenchymal stem cells transplantation in a rat model of myocardial infarction

Background Previous study demonstrated the improvement of cardiac function was proportional to the number of cells implanted. Therefore, increasing cell survival in the infarcted myocardium might contribute to the improvement of the functional benefit of cell transplantation. Methods and results MSCs were treated with IGF-1 in vitro and infused into the acute myocardial infarction rats via the tail vein. After treatment of MSCs with IGF-1 for 48 h, flow cytometric analysis showed marked enhancement of expression of CXCR4 in the cell surface. After 4 weeks of transplantation, we found 1) a greater number of engrafted MSCs arrived and survived in the peri-infarct region; 2) TnT protein expression and capillary density were enhanced; 3) LV cavitary dilation, transmural infarct thinning, deposition of total collagen in the peri-infarct region and cardiac dysfunction were attenuated. Conclusion 1) IGF-1 treatment has time-dependent and dose-dependent effects on CXCR4 expression in MSCs in vitro. 2) IGF-1 improves the efficacy of MSCs transplantation in a rat model of myocardial infarction mainly via enhancement of the number of cells attracted into the infarcted heart. These findings provide a novel stem cell therapeutic avenue against ischemic heart disease.