Cell Therapy For Myocardial Infarction Research Articles

Caspase-1 mediates hyperlipidemia-weakened progenitor cell vessel repair.

Caspase-1 activation senses metabolic danger-associated molecular patterns (DAMPs) and mediates the initiation of inflammation in endothelial cells. Here, we examined whether the caspase-1 pathway is responsible for sensing hyperlipidemia as a DAMP in bone marrow (BM)-derived Stem cell antigen-1 positive (Sca-(1+)) stem/progenitor cells and weakening their angiogenic ability. Using biochemical methods, gene knockout, cell therapy and myocardial infarction (MI) models, we had the following findings: 1) Hyperlipidemia induces caspase-1 activity in mouse Sca-(1+) progenitor cells in vivo; 2) Caspase-1 contributes to hyperlipidemia-induced modulation of vascular cell death-related gene expression in vivo; 3) Injection of Sca-1+ progenitor cells from caspase-1(-/-) mice improves endothelial capillary density in heart and decreases cardiomyocyte death in a mouse model of MI; and 4) Caspase-1(-/-) Sca-(1+) progenitor cell therapy improves mouse cardiac function after MI. Our results provide insight on how hyperlipidemia activates caspase-1 in Sca-(1+) progenitor cells, which subsequently weakens Sca-(1+) progenitor cell repair of vasculature injury. These results demonstrate the therapeutic potential of caspase-1 inhibition in improving progenitor cell therapy for MI.

Abstract 17412: Paracrine Role of B Lymphocytes in Successful Bone Marrow Cell Therapy for Myocardial Infarction

Introduction: Treatment of myocardial infarction (MI) with bone marrow cells (BMCs) or cell-free BMC lysate substantially improves post-MI cardiac function in rodent experiments. However, clinical trials of BMC therapy have been less successful. While most mouse experiments use young healthy BMC donors, MI patients undergoing autologous cell therapy (i.e., receiving their own BMCs) are older and are post-MI. We have previously demonstrated that BMCs from aged and post-MI donor mice are therapeutically impaired, that donor MI induces inflammation leading to changes in BMC composition, and that BMCs from aged or post-MI mice have reduced levels of B cells, which reportedly can be a therapeutic BMC subpopulation. We recently observed that partial depletion of B cells from young healthy donor BMCs reduces the BMCs’ therapeutic effect, mimicking the effects of donor age or MI. Hypothesis: B cells play a crucial role in BMC therapy for MI, and B cell lysate is also therapeutic. Methods: We induced permanent coronary artery ligation MI, and implanted purified CD19+ bone marrow B cells from young healthy donors into the recipient infarct border zone 3 days post-MI via ultrasound guidance. CD3ε+ T cells and vehicle (HBSS) were injected as negative controls. A similar experiment was carried out with B cell lysate and T cell lysate. Results: In all groups, recipient left ventricular ejection fraction (EF) declined uniformly from baseline to day 2 post-MI, before cell injection. Injection of B cells significantly improved day 28 EF (p<.0005 adjusted for multiple comparisons). In contrast, T cells provided little or no benefit relative to HBSS. Notably, B cell lysate, but not T cell lysate, increased EF comparably to intact B cells. *p<.05 in figure. Conclusions: Bone marrow B cells play a crucial role in BMC therapy for MI via a paracrine mechanism. Reduction of bone marrow B cells by age or MI may explain why autologous BMC therapy in patients has not matched the success of rodent experiments.

Myocardial infarction: stem cell transplantation for cardiac regeneration.

It is estimated that by 2030, almost 23.6 million people will perish from cardiovascular disease, according to the WHO. The review discusses advances in stem cell therapy for myocardial infarction, including cell sources, methods of differentiation, expansion selection and their route of delivery. Skeletal muscle cells, hematopoietic cells and mesenchymal stem cells (MSCs) and embryonic stem cells (ESCs)-derived cardiomyocytes have advanced to the clinical stage, while induced pluripotent cells (iPSCs) are yet to be considered clinically. Delivery of cells to the sites of injury and their subsequent retention is a major issue. The development of supportive scaffold matrices to facilitate stem cell retention and differentiation are analyzed. The review outlines clinical translation of conjugate stem cell-based cellular therapeutics post-myocardial infarction.

Acute aerobic exercise increases exogenously infused bone marrow cell retention in the heart.

Stem cell therapy for myocardial infarction (MI) has been shown to improve cardiac function and reduce infarct size. Exercise training, in the form of cardiac rehabilitation, is an essential part of patient care post-MI. Hence, we tested the effects of acute and chronic aerobic exercise on stem cell retention and cardiac remodeling post-MI. Small epicardial MI’s were induced in 12-month-old C57BL/6 mice via cryoinjury. Two weeks post-MI, vehicle infusion (N = 4) or GFP+ bone marrow-derived cells (BMC) were injected (tail vein I.V.) immediately after acute exercise (N = 14) or sedentary conditions (N = 14). A subset of mice continued a 5-week intervention of chronic treadmill exercise (10–13 m/min; 45 min/day; 4 days/week; N = 7) or remained sedentary (N = 6). Exercise tolerance was assessed using a graded exercise test, and cardiac function was assessed with echocardiography. Acute exercise increased GFP+ BMC retention in the infarcted zone of the heart by 30% versus sedentary (P < 0.05). This was not associated with alterations in myocardial function or gene expression of key cell adhesion molecules. Animals treated with chronic exercise increased exercise capacity (P < 0.05) and cardiac mass (P < 0.05) without change in left ventricular ejection fraction (LVEF), infarct size, or regional wall thickness (P = NS) compared with sedentary. While BMC’s alone did not affect exercise capacity, they increased LVEF (P < 0.05) and Ki67+ nuclei number in the border zone of the heart (P < 0.05), which was potentiated with chronic exercise training (P < 0.05). We conclude that acute exercise increases BMC retention in infarcted hearts and chronic training increases exogenous BMC-mediated effects on stimulating the cardiomyocyte cell cycle. These preclinical results suggest that exercise may help to optimize stem cell therapeutics following MI.

Identification of apoptosis-related microRNAs and their target genes in myocardial infarction post-transplantation with skeletal myoblasts.

BackgroundSkeletal myoblasts (SkMs) has provided a promising treatment for myocardial infarction (MI). Functioning as posttranscriptional regulators, microRNAs (miRNAs) play important roles in cardiac repairment and stem cell regulation. However, the correlation between miRNAs and their targeted genes in SkM cell therapy for MI was not fully understood.MethodsWe explored the cardioprotection by SkMs in infracted rats and determined cardiac functions at 4 weeks. In addition, we compared the expression profiles of miRNAs and mRNAs in post-MI rats with or without SkM cell therapy using microarray. The concordance between miRNA expression and mRNA levels of potential target genes was confirmed by quantitative real-time PCR.ResultsQuantitative echocardiography and histology showed improved cardiac function, attenuated heart infarcted area and inhibited cardiomyocyte apoptosis in the SkM group, compared with MI group. We identified that 160 miRNAs were differentially expressed in MI group as compared to the control group and 78 miRNAs were differentially expressed in the SkM treated group as compared to the untreated post-MI. We focused on a novel set of apoptosis-associated miRNAs and their target genes, among which 4 miRNAs (miR-30a-5p, miR-30c-5p, miR-145-5p, miR-140-3p), except one (miR-143-3p), were downregulated in the SkM treated group as compared to the untreated group. Furthermore, we found seven genes including Angptl4, Dpep1, Egr1, Eif5a, Tsc22d3, Irs2 and Cebpb that showed a linear correlation with which miRNAs.ConclusionsThe downregulation of apoptosis-regulatory miRNAs and in turn upregulation of target genes may partially account for rescue effect of SKM therapy for MI.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0603-0) contains supplementary material, which is available to authorized users.

Stem Cell Therapy for Myocardial Infarction 2001-2013 Revisited.

Stem cell therapy for ischemic heart disease was an emerging concept in the early 2000s. First hopes were largely overshadowed by rather inconsistent results in human trials conducted in the middle of the decade. We aimed at investigating how the field of stem cell research expanded worldwide over the years using scientometric methods. We performed a PubMed inquiry and screened a total of 2609 publications dealing with stem cell therapy for myocardial infarction in the years 2001-2013. Density equalizing maps were used to visualize important centres of stem cell research worldwide. This systematic bibliometric study revealed an increasing research interest in the field of stem cell research in the context of ischemic heart disease over the last decade. Though some of the large human trials failed to show significant effects of stem cell therapy, especially basic science represents an ever growing field that evolved promising new concepts over the last couple of years. The scientific principle of protective paracrine mediators released from transplanted stem cells seems to bear great potential for future cell-free therapeutic use. However, further mechanistic insights are needed before transition from bench to bedside should be attempted, taking the lessons learned from previous studies into account.

Isosorbide dinitrate improves the efficacy of bone mesenchymal stem cell transplantation via endothelial nitric oxide synthase-dependent mechanism

This study investigated the effect of treatment wientry isosorbide dinitrate (Isoket) on bone mesenchymal stem cell (BMSC) transplantation in a rat model of myocardial infarction (MI) and its possible mechanism. Sprague-Dawley (SD) rats were randomized to a sham operation group, MI control group, BMSC transplantation group, and Isoket-BMSCs transplantation group. Isosorbide dinitrate (Isoket, 5 μg/m) was administered by intraperitoneal injection (10 ml/kg) at 0, 12, and 24 hours following ischemia/reperfusion induction of MI models. Left ventricular function, myocardial infarct size (MIS), the survival of engrafted BMSCs, and expression of vascular endothelial growentry factor (VEGF), inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) proteins were detected 2 weeks post-transplantation. The results showed isosorbide dinitrate attenuated cardiac dysfunction, increased the survival of engrafted cells in the ischemic heart and promoted iNOS, eNOS, and VEGF protein expression. It is suggested that isosorbide dinitrate enhances mesenchymal stem cell therapy for MI via an eNOS-dependent mechanism.

Adenovirus-mediated expression of human sodium-iodide symporter gene permits in vivo tracking of adipose tissue-derived stem cells in a canine myocardial infarction model

IntroductionIn vivo tracking of the transplanted stem cells is important in pre-clinical research of stem cell therapy for myocardial infarction. We examined the feasibility of adenovirus-mediated sodium iodide symporter (NIS) gene to cell tracking imaging of transplanted stem cells in a canine infarcted myocardium by clinical single photon emission computed tomography (SPECT). MethodsBeagle dogs were injected intramyocardially with NIS-expressing adenovirus-transfected canine stem cells (Ad-hNIS-canine ADSCs) a week after myocardial infarction (MI) development. 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) and 99mTc-pertechnetate (99mTcO4−) SPECT imaging were performed for assessment of infarcted myocardium and viable stem cell tracking. Transthoracic echocardiography was performed to monitor any functional cardiac changes. ResultsLeft ventricular ejection fraction (LVEF) was decreased after LAD ligation. There was no significant difference in EF between the groups with the stem cell or saline injection. 125I uptake was higher in Ad-hNIS-canine ADSCs than in non-transfected ADSCs. Cell proliferation and differentiation were not affected by hNIS-carrying adenovirus transfection. 99mTc-MIBI myocardial SPECT imaging showed decreased radiotracer uptake in the infarcted apex and mid-anterolateral regions. Ad-hNIS-canine ADSCs were identified as a region of focally increased 99mTcO4− uptake at the lateral wall and around the apex of the left ventricle, peaked at 2 days and was observed until day 9. ConclusionsCombination of adenovirus-mediated NIS gene transfection and clinical nuclear imaging modalities enables to trace the fate of transplanted stem cells in infarcted myocardium for translational in vivo cell tracking study for prolonged duration.

Stem Cell Therapy for Myocardial Infarction: Challenges and Prospects

Myocardial infarction causes death worldwide with the greatest incidence being in the United States. Although there have been many advances in myocardial re-perfusion strategies and novel pharmacological approaches, therapies for treating acute and chronic myocardial ischemic damage remain limited. This means that no currently available heart failure treatment has demonstrated an ability to generate new muscle tissue within the scared regions of the heart. Stem cell, however, offers new hope to patients who have otherwise limited choices. Therefore, this review aims at exploring the use and peculiarities of stem cell therapy for myocardial infarction. But the success of stem cell therapy for clinical use needs the validation of several issues ranging from selection of appropriate stem cells, routes of transfer, establishment of conducive trans-differentiation milieu with associated cytokines, means to evaluate/track response to cell therapy to compliance with regulatory and ethical issues besides addressing biological and technical issues surrounding stem cell therapy.

GW25-e0810 Intravenous ferumoxytol before mesenchymal stem cell harvest: a new method for tracking stem cell with MR imaging in cell therapy for myocardial infarction

GW25-e0810 Intravenous ferumoxytol before mesenchymal stem cell harvest: a new method for tracking stem cell with MR imaging in cell therapy for myocardial infarction

Abstract 20: Manipulating PHD2 to Promote Efficacy of Stem Cell Therapy for Myocardial Infarction

OBJECTIVE: Stem cell transplantation has had modest success as a treatment for myocardial infarction (MI). One of the limitations is the poor stem cell survival and function in the diseased microenvironment. We studied whether and how prolyl hydroxylase domain protein 2 (PHD2), a cellular oxygen sensor, enhances stem cell cardioprotective effects after transplantation into infarcted hearts. METHODS and RESULTS: Both adipose-derived stem cells (ADSCs) and bone marrow mesenchymal stem cells (BM-MSCs) were used. Stem cells were transduced with lentiviral short hairpin RNA to silence PHD2 (shPHD2) and intramyocardially injected into infarcted heart in mice. ADSCs reduced cardiomyocyte apoptosis, fibrosis, and infarct size (MI+ADSCs: 39.4±3.3%;MI+PBS: 48.4±4.5%) and improved cardiac function (MI+ADSCs: 43.8±5.6%; MI+PBS: 37.2±3.0%). shPHD2-ADSCs exerted significantly more protection (infarct size: 22.6±3.0%; LVEF: 67.3±6.8%; p&lt;0.05 vs. MI+ADSCs). PHD2 silencing induced greater ADSC survival (survival rate at 7 days post-transplantation: shPHD2-ADSCs: 14.7±4.2% vs. ADSCs: 3.4±0.8%, p&lt;0.05), which was abolished by HIF-1alpha silencing. No ADSC gave rise to cardiomyocyte and ADSCs induced cardioprotection was mainly induced by paracrine function. Conditioned medium from shPHD2-ADSCs decreased cardiomyocyte apoptosis. Insulin-like growth factor-1 (IGF-1) levels were 3.8 times higher in the conditioned medium of shPHD2-ADSCs than ADSCs, and depletion of IGF-1 attenuated the cardioprotective effects of shPHD2-ADSC-conditioned medium. NF-kappaB activation was induced by shPHD2 to stimulate IGF-1 secretion via binding to the IGF-1 gene promoter. A combination of HIF-1alpha silencing and IGF-1 neurtralization blocked the beneficial effects of shPHD2-ADSCs for MI. Similar findings were observed with BM-MSCs. CONCLUSIONS: PHD2 silencing promotes stem cell survival in infarcted hearts and enhances their paracrine function to protect cardiomyocytes. Its prosurvival effect on stem cells is HIF-1alpha dependent, while it enhances stem cell paracrine function through NF-kappaB-mediated IGF-1 upregulation. PHD2 silencing in stem cells may be a novel strategy for enhancing the effectiveness of stem cell therapy after MI.

Potential Applications of PET/MR Imaging in Cardiology.

Recent advances in hybrid PET/MR imaging have opened new perspectives for cardiovascular applications. Although cardiac MR imaging has gained wider adoption for routine clinical applications, PET images remain the reference in many applications for which objective analysis of metabolic and physiologic parameters is needed. In particular, in cardiovascular diseases-more specifically, coronary artery disease-the use of quantitative and measurable parameters in a reproducible way is essential for the management of therapeutic decisions and patient follow-up. Functional MR images and dynamic assessment of myocardial perfusion from transit of intravascular contrast medium can provide useful criteria for identifying areas of decreased myocardial perfusion or for assessing tissue viability from late contrast enhancement of scar tissue. PET images, however, will provide more quantitative data on true tissue perfusion and metabolism. Quantitative myocardial flow can also lead to accurate assessment of coronary flow reserve. The combination of both modalities will therefore provide complementary data that can be expected to improve the accuracy and reproducibility of diagnostic procedures. But the true potential of hybrid PET/MR imaging may reside in applications beyond the domain of coronary artery disease. The combination of both modalities in assessment of other cardiac diseases such as inflammation and of other systemic diseases can also be envisioned. It is also predicted that the 2 modalities combined could help characterize atherosclerotic plaques and differentiate plaques with a high risk of rupture from stable plaques. In the future, the development of new tracers will also open new perspectives in evaluating myocardial remodeling and in assessing the kinetics of stem cell therapy in myocardial infarction. New tracers will also provide new means for evaluating alterations in cardiac innervation, angiogenesis, and even the assessment of reporter gene technologies. The fusion of 2 potentially competing modalities can certainly offer the best of each modality in a single procedure. The impact of such advanced technology in routine clinical practice will still need to be demonstrated. Beyond the expected improvement in patient management and the potential impact on patient outcome, PET/MR imaging will also need to establish its medicoeconomic justification in an era of health-care economic restrictions.

Incremental benefits of repeated mesenchymal stromal cell administration compared with solitary intervention after myocardial infarction

Background aimsTraditionally, stem cell therapy for myocardial infarction (MI) has been administered as a single treatment in the acute or subacute period after MI. These time intervals coincide with marked differences in the post-infarct myocardial environment, raising the prospect that repeat cell dosing could provide incremental benefit beyond a solitary intervention. This prospect was evaluated with the use of mesenchymal stromal cells (MSCs). MethodsThree groups of rats were studied. Single-therapy and dual-therapy groups received allogeneic, prospectively isolated MSCs (1 × 106 cells) by trans-epicardial injection immediately after MI, with additional dosing 1 week later in the dual-therapy cohort. Control animals received cryopreservant solution only. Left ventricular (LV) dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance immediately before MI and at 1, 2 and 4 weeks after MI. ResultsImmediate MSC treatment attenuated early myocardial damage with EF of 35.3 ± 3.1% (dual group, n = 12) and 35.2 ± 2.2% (single group, n = 15) at 1 week after MI compared with 22.1 ± 1.9% in controls (n = 17, P < 0.01). In animals receiving a second dose of MSCs, EF increased to 40.7 ± 3.1% by week 4, which was significantly higher than in the single-therapy group (EF 35.9 ± 1.8%, P < 0.05). Dual MSC treatment was also associated with greater myocardial mass and arteriolar density, with trends toward reduced myocardial fibrosis. These incremental benefits were especially observed in remote (non-infarct) segments of LV myocardium. ConclusionsRepeated stem cell intervention in both the acute and the sub-acute period after MI provides additional improvement in ventricular function beyond solitary cell dosing, largely owing to beneficial changes remote to the area of infarction.

GW24-e2201 Role of cardiotrophin-1 on cardiac differentiation of mouse induced pluripotent stem cells

ObjectivesInducedpluripotent stem cell (iPSC), which demonstrates the stem cell characteristics like clonogenicity, self-renewal and multipotency, could differentiate into all three germ layer cell types including cardiomyocytes. The cytokinecardiotrophin-1, a member...

Stem Cell Therapy in Myocardial Infarction: Latest Trends

Heart Diseases are a major cause of morbidity and mortality world wide. Myocardial infarction is the leading cause of congestive heart failure and death in the industrialized world. Current therapy is limited in preventing the progression of ventricular remodeling and congestive heart failure. Recent interest has focused on stem cells, which are undifferentiated and pleuropotent cells that can proliferate, potentially self-renew, and differentiate into cardiomyocytes. The article tries to underline the beneficial effects of the stem cell therapy for use in patients where other modes of therapy are not advisable and the multi purpose effects of such as therapy.

Effects of myocardial infarction on the distribution and transport of nutrients and oxygen in porcine myocardium.

One of the primary limitations of cell therapy for myocardial infarction is the low survival of transplanted cells, with a loss of up to 80% of cells within 3 days of delivery. The aims of this study were to investigate the distribution of nutrients and oxygen in infarcted myocardium and to quantify how macromolecular transport properties might affect cell survival. Transmural myocardial infarction was created by controlled cryoablation in pigs. At 30 days post-infarction, oxygen and metabolite levels were measured in the peripheral skeletal muscle, normal myocardium, the infarct border zone, and the infarct interior. The diffusion coefficients of fluorescein or FITC-labeled dextran (0.3-70 kD) were measured in these tissues using fluorescence recovery after photobleaching. The vascular density was measured via endogenous alkaline phosphatase staining. To examine the influence of these infarct conditions on cells therapeutically used in vivo, skeletal myoblast survival and differentiation were studied in vitro under the oxygen and glucose concentrations measured in the infarct tissue. Glucose and oxygen concentrations, along with vascular density were significantly reduced in infarct when compared to the uninjured myocardium and infarct border zone, although the degree of decrease differed. The diffusivity of molecules smaller than 40 kD was significantly higher in infarct center and border zone as compared to uninjured heart. Skeletal myoblast differentiation and survival were decreased stepwise from control to hypoxia, starvation, and ischemia conditions. Although oxygen, glucose, and vascular density were significantly reduced in infarcted myocardium, the rate of macromolecular diffusion was significantly increased, suggesting that diffusive transport may not be inhibited in infarct tissue, and thus the supply of nutrients to transplanted cells may be possible. in vitro studies mimicking infarct conditions suggest that increasing nutrients available to transplanted cells may significantly increase their ability to survive in infarct.

Periprocedural adverse events in cell therapy trials in myocardial infarction and cardiomyopathy: a systematic review

Cell therapy (CTh) is a promising novel therapy for myocardial infarction (MI) and ischemic cardiomyopathy (iCMP). Recognizing adverse events (AE) is important for safety evaluation, harm prevention and may aid in the design of future trials. To define the prevalence of periprocedural AE in CTh trials in MI and iCMP. A literature search was conducted using the MEDLINE database from January 1990 to October 2010. Controlled clinical trials that compared CTh with standard treatment in the setting of MI and/or iCMP were selected. AE related to CTh were analyzed. A total of 2,472 patients from 35 trials were included. There were 26 trials including 1,796 patients that used CTh in MI and 9 trials including 676 patients that used CTh in iCMP. Periprocedural arrhythmia monitoring protocols were heterogeneous and follow-up was short in most of the trials. In MI trials, the incidence of periprocedural adverse events (AE) related to intracoronary cell transplantation was 7.5% (95% CI 6.04-8.96%). AE related to granulocyte colony-stimulating factor (GCS-F) used for cell mobilization for peripheral apheresis was 16% (95% CI 9.44-22.56%). During intracoronary transplantation in iCMP, the incidence of periprocedural AE incidence was 2.6% (95% CI 0.53-4.67%). There were no AE reported during transepicardial transplantation and AE were rare during transendocardial transplantation. The majority of periprocedural AE in CTh trials in MI occurred during intracoronary transplantation and GCS-F administration. In iCMP, periprocedural AE were uncommon. Avoiding intracoronary route for CTh implantation may decrease the burden of periprocedural AE. Standardization of AE definition in CTh trials is needed.

Five-year results of intracoronary infusion of the mobilized peripheral blood stem cells by granulocyte colony-stimulating factor in patients with myocardial infarction

To evaluate the long-term effects of peripheral blood stem cell therapy in myocardial infarction (MI) patients. A total of 163 patients with MI who were successfully revascularized with drug-eluting stents were enrolled and randomly assigned to four groups: acute MI (AMI) cell infusion, AMI control, old MI (OMI) cell infusion, and OMI control. We compared 5 years' clinical outcomes between the cell infusion group (57 and 22 patients with AMI and OMI, respectively) and the control (60 and 24 patients with AMI and OMI, respectively). In the time-sequence comparison from baseline to 6 and 24 months follow-up after AMI, left ventricular ejection fraction (LVEF) by cardiac magnetic resonance imaging was significantly improved in the cell infusion group (n = 57), but not in the control group (n = 60). In the between-group comparison, the difference in improvement of LVEF for 2 years after AMI did not reach statistical significance between cell infusion and control groups. Intriguingly, the major adverse cardiac events for 5 years were significantly reduced in the cell infusion group (n = 79) compared with the control (n = 84; composite of cardiac death, non-fatal MI, hospitalization for heart failure and angina, and target vessel revascularization; 22.8 vs. 39.3%, P = 0.015). Peripheral blood stem cell therapy has potential to improve long-term cardiovascular outcomes in MI patients.

Regulation of Cardiac MicroRNAs by Bone Marrow Mononuclear Cell Therapy in Myocardial Infarction

Cell therapy with bone marrow-derived mononuclear cells (BMCs) can improve recovery of cardiac function after ischemia; however, the molecular mechanisms are not yet fully understood. MicroRNAs (miRNAs) are key regulators of gene expression and modulate the pathophysiology of cardiovascular diseases. We demonstrated that intramyocardial delivery of BMCs in infarcted mice regulates the expression of cardiac miRNAs and significantly downregulates the proapoptotic miR-34a. In vitro studies confirmed that the supernatant of BMC inhibited the expression of H(2)O(2)-induced miR-34a and cardiomyocytes apoptosis. These effects were blocked by neutralizing antibodies directed against insulin-like growth factor-1 (IGF-1). Indeed, IGF-1 significantly inhibited H(2)O(2)-induced miR-34a expression, and miR-34a overexpression abolished the antiapoptotic effect of IGF-1. Likewise, inhibition of IGF-1 signaling in vivo abolished the BMC-mediated inhibition of miR-34 expression and the protective effect on cardiac function and increased apoptosis and cardiac fibrosis. IGF-1 specifically blocked the expression of the precursor and the mature miR-34a, but did not interfere with the transcription of the primary miR-34a demonstrating that IGF-1 blocks the processing of miR-34a. Together, our data demonstrate that the paracrine regulation of cardiac miRNAs by transplanted BMCs contributes to the protective effects of cell therapy. BMCs release IGF-1, which inhibits the processing of miR-34a, thereby blocking cardiomyocyte apoptosis.

Challenges for heart disease stem cell therapy

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The use of stem cells to improve recovery of the injured heart after myocardial infarction (MI) is an important emerging therapeutic strategy. However, recent reviews of clinical trials of stem cell therapy for MI and ischemic heart disease recovery report that less than half of the trials found only small improvements in cardiac function. In clinical trials, bone marrow, peripheral blood, or umbilical cord blood cells were used as the source of stem cells delivered by intracoronary infusion. Some trials administered only a stem cell mobilizing agent that recruits endogenous sources of stem cells. Important challenges to improve the effectiveness of stem cell therapy for CVD include: (1) improved identification, recruitment, and expansion of autologous stem cells; (2) identification of mobilizing and homing agents that increase recruitment; and (3) development of strategies to improve stem cell survival and engraftment of both endogenous and exogenous sources of stem cells. This review is an overview of stem cell therapy for CVD and discusses the challenges these three areas present for maximum optimization of the efficacy of stem cell therapy for heart disease, and new strategies in progress.