Long noncoding RNA LUCAT1 enhances the survival and therapeutic effects of mesenchymal stromal cells post-myocardial infarction.
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ABSTRACT:
SUBMITTER: Tao Y
PROVIDER: S-EPMC8733180 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Outstanding progress has been achieved in developing therapeutic options for reasonably alleviating symptoms and prolonging the lifespan of patients suffering from myocardial infarction (MI). Current treatments, however, only partially address the functional recovery of post-infarcted myocardium, which is in fact the major goal for effective primary care. In this context, we largely investigated novel cell and TE tissue engineering therapeutic approaches for cardiac repair, particularly using multipotent mesenchymal stromal cells (MSC) and natural extracellular matrices, from pre-clinical studies to clinical application. A further step in this field is offered by MSC-derived extracellular vesicles (EV), which are naturally released nanosized lipid bilayer-delimited particles with a key role in cell-to-cell communication. Herein, in this review, we further describe and discuss the rationale, outcomes and challenges of our evidence-based therapy approaches using Wharton's jelly MSC and derived EV in post-MI management.
| S-EPMC8471243 | biostudies-literature
Project description:The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSCs) into a cardiac progenitor phenotype and assess therapeutic benefit in chronic myocardial infarction.Adult stem cells, delivered in their naïve state, demonstrate a limited benefit in patients with ischemic heart disease. Pre-emptive lineage pre-specification may optimize therapeutic outcome.hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of transforming growth factor-beta(1), bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-6 was formulated to engage hMSC into cardiopoiesis. Derived hMSC were injected into the myocardium of a nude infarcted murine model and followed over 1 year for functional and structural end points.Although the majority of patient-derived hMSC in their native state demonstrated limited effect on ejection fraction, stem cells from rare individuals harbored a spontaneous capacity to improve contractile performance. This reparative cytotype was characterized by high expression of homeobox transcription factor Nkx-2.5, T-box transcription factor TBX5, helix-loop-helix transcription factor MESP1, and myocyte enhancer factor MEF2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared with unguided counterparts, cardiopoietic hMSC delivered into infarcted myocardium achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric, and gap junction content along with induction of myocardial cell cycle activity.Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived hMSC in chronic ischemic cardiomyopathy.
| S-EPMC2932958 | biostudies-literature
Project description:Growth differentiation factor 11 (GDF11) has been shown to promote stem cell activity, but little is known about the effect of GDF11 on viability and therapeutic efficacy of cardiac mesenchymal stem cells (MSCs) for cardiac injury. To understand the roles of GDF11 in MSCs, mouse heart-derived MSCs were transduced with lentiviral vector carrying genes for both GDF11 and green fluorescent protein (GFP) (MSCsLV-GDF11 ) or cultured with recombinant GDF11 (MSCsrGDF11 ). Either MSCsrGDF11 or MSCs LV-GDF11 displayed less cell apoptosis and better paracrine function, as well as preserved mitochondrial morphology and function under hypoxic condition as compared with control MSCs. GDF11 enhanced phosphorylation of Smad2/3, which upregulated expression of YME1L, a mitochondria protease that balances OPA1 processing. Inhibitors of TGF-β receptor (SB431542) or Smad2/3 (SIS3) attenuated the effects of GDF11 on cell viability, mitochondrial function, and expression of YME1L. Transplantation of MSCsGDF11 into infarct heart resulted in improved cell survival and retention, leading to more angiogenesis, smaller scar size, and better cardiac function in comparison with control MSCs. GDF11 enhanced viability and therapeutic efficiency of MSCs by promoting mitochondrial fusion through TGF-β receptor/Smad2/3/YME1L-OPA1 signaling pathway. This novel role of GDF11 may be used for a new approach of stem cell therapy for myocardial infarction.
| S-EPMC7519765 | biostudies-literature
Project description:Both weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.
| S-EPMC8131743 | biostudies-literature
Project description:PURPOSE:Exercise-induced skeletal muscle deoxygenation is startling by its absence in early post-myocardial infarction (MI) patients. Exercise training early post-MI is associated with reduced cardiovascular risk and increased aerobic capacity. We therefore investigated whether aerobic training could enhance the muscle deoxygenation in early post-MI patients. METHODS:21 ± 8 days after the first MI patients (n = 16) were divided into 12-week aerobic training (TR, n = 10) or non-training (CON, n = 6) groups. Before and after intervention, patients performed ramp bicycle exercise until exhaustion. Muscle deoxygenation was measured at vastus lateralis by near-infrared spectroscopy during exercise. RESULTS:Aerobic training significantly increased peak oxygen uptake (VO2) (18.1 ± 3.0 vs. 22.9 ± 2.8 mL/kg/min), decreased the change in muscle oxygen saturation from rest to submaximal and peak exercise (?SmO2; 2.4 ± 5.7 vs. -7.0 ± 3.4 %), and increased the relative change in deoxygenated hemoglobin/myoglobin concentration from rest to submaximal (-1.5 ± 2.3 vs. 3.0 ± 3.6 ?mol/L) and peak exercise (1.1 ± 4.5 vs. 8.2 ± 3.5 ?mol/L). Change in total hemoglobin/myoglobin concentration in muscle was not significantly affected by training. In CON, no significant alterations were found after 12 weeks in either muscle deoxygenation or peak VO2 (18.6 ± 3.8 vs. 18.9 ± 4.6 mL/kg/min). An increase in peak VO2 was significantly negatively correlated with change in ?SmO2 (r = -0.65) and positively associated with change in ?deoxy-Hb/Mb at peak exercise (r = 0.64) in TR. CONCLUSIONS:In early post-MI patients, aerobic training enhanced skeletal muscle deoxygenation, and the enhancement was related to increased aerobic capacity.
| S-EPMC4819748 | biostudies-other
Project description:BackgroundMesenchymal stromal cells (MSCs) activated with IFN-γ elicit stronger physical effects. Exosomes (Exos) secreted from MSCs show protective effects against myocardial injury. This study aimed to determine whether Exos derived from IFN-γ-treated MSCs exhibit more potent cardioprotective function and the underlying mechanisms.MethodsH9c2 cells or human umbilical vein endothelial cells (HUVECs) were treated with Exos isolated from MSCs (Ctrl-Exo) or IFN-γ-primed MSCs (IFN-γ-Exo) under oxygen and glucose deprivation (OGD) conditions in vitro and in vivo in an infarcted rat heart. RNA sequencing was used to identify differentially expressed functional transcription factors (TFs). Quantitative reverse transcription-PCR (qPCR) was used to confirm the upregulated TFs and miRNA in IFN-γ-primed MSCs. Dual-luciferase reporter gene assay was used to analyze the transcriptional regulation of miRNAs by STAT1. The target of miR-21-5p (miR-21) was determined by luciferase reporter assays and qPCR. The function of BTG2 was verified in vitro under OGD conditions.ResultIFN-γ-Exo accelerated migration and tube-like structure formation and prevented OGD-induced apoptosis in H9c2. Similarly, IFN-γ-Exo treatment caused a decrease in fibrosis, reduced cardiomyocyte apoptosis, and improved cardiac function compared to Ctrl-Exo treatment. MiR-21 was significantly upregulated in IFN-γ-primed MSCs and IFN-γ-Exo. STAT1 transcriptionally induced miR-21 expression. Up-regulated miR-21 could inhibit BTG anti-proliferation factor 2 (BTG2) expressions. BTG2 promoted H9c2 cell apoptosis and reversed the protective effects of miR-21 under OGD conditions.ConclusionIFN-γ-Exo showed enhanced therapeutic efficacy against acute MI, possibly by promoting angiogenesis and reducing apoptosis by upregulating miR-21, which directly targeted BTG2.
| S-EPMC9308256 | biostudies-literature
Project description:AimTo examine the contribution of treatment resistant depression (TRD) to mortality in depressed post-myocardial infarction (MI) patients independent of biological and social predictors.MethodsThis secondary analysis study utilizes the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial data. From 1834 depressed patients in the ENRICHD study, there were 770 depressed post-MI patients who were treated for depression. In this study, TRD is defined as having a less than 50% reduction in Hamilton Depression (HAM-D) score from baseline and a HAM-D score of greater than 10 in 6 mo after depression treatment began. Cox regression analysis was used to examine the independent contributions of TRD to mortality after controlling for the biological and social predictors.ResultsTRD occurred in 13.4% (n = 103) of the 770 patients treated for depression. Patients with TRD were significantly younger in age (P = 0.04) (mean = 57.0 years, SD = 11.7) than those without TRD (mean = 59.2 years, SD = 12.0). There was a significantly higher percentage of females with TRD (57.3%) compared to females without TRD (47.4%) [χ(2) (1) = 4.65, P = 0.031]. There were significantly more current smokers with TRD (44.7%) than without TRD (33.0%) [χ(2) (1) = 7.34, P = 0.007]. There were no significant differences in diabetes (P = 0.120), history of heart failure (P = 0.258), prior MI (P = 0.524), and prior stroke (P = 0.180) between patients with TRD and those without TRD. Mortality was 13% (n = 13) in patients with TRD and 7% (n = 49) in patients without TRD, with a mean follow-up of 29 mo (18 mo minimum and maximum of 4.5 years). TRD was a significant independent predictor of mortality (HR = 1.995; 95%CI: 1.011-3.938, P = 0.046) after controlling for age (HR = 1.036; 95%CI: 1.011-1.061, P = 0.004), diabetes (HR = 2.912; 95%CI: 1.638-5.180, P < 0.001), heart failure (HR = 2.736; 95%CI: 1.551-4.827, P = 0.001), and smoking (HR = 0.502; 95%CI: 0.228-1.105, P = 0.087).ConclusionThe analysis of TRD in the ENRICHD study shows that the effective treatment of depression reduced mortality in depressed post-MI patients. It is important to monitor the effectiveness of depression treatment and change treatments if necessary to reduce depression and improve cardiac outcomes in depressed post-MI patients.
| S-EPMC4404376 | biostudies-literature
Project description:BACKGROUND:The LIM-homeobox transcription factor islet-1 (ISL1) has been proposed as a marker for cardiovascular progenitor cells. This study investigated whether forced expression of ISL1 in human mesenchymal stem cells (hMSCs) improves myocardial infarction (MI) treatment outcomes. METHODS:The lentiviral vector containing the human elongation factor 1? promoter, which drives the expression of ISL1 (EF1?-ISL1), was constructed using the Multisite Gateway System and used to transduce hMSCs. Flow cytometry, immunofluorescence, Western blotting, TUNEL assay, and RNA sequencing were performed to evaluate the function of ISL1-overexpressing hMSCs (ISL1-hMSCs). RESULTS:The in vivo results showed that transplantation of ISL1-hMSCs improved cardiac function in a rat model of MI. Left ventricle ejection fraction and fractional shortening were greater in post-MI hearts after 4 weeks of treatment with ISL1-hMSCs compared with control hMSCs or phosphate-buffered saline. We also found that ISL1 overexpression increased angiogenesis and decreased apoptosis and inflammation. The greater potential of ISL1-hMSCs may be attributable to an increased number of surviving cells after transplantation. Conditioned medium from ISL1-hMSCs decreased the apoptotic effect of H2O2 on the cardiomyocyte cell line H9c2. To clarify the molecular basis of this finding, we employed RNA sequencing to compare the apoptotic-related gene expression profiles of control hMSCs and ISL1-hMSCs. The results showed that insulin-like growth factor binding protein 3 (IGFBP3) was the only gene in ISL1-hMSCs with a RPKM value higher than 100 and that the difference fold-change between ISL1-hMSCs and control hMSCs was greater than 3, suggesting that IGFBP3 might play an important role in the anti-apoptosis effect of ISL1-hMSCs through paracrine effects. Furthermore, the expression of IGFBP3 in the conditioned medium from ISL1-hMSCs was almost fourfold greater than that in conditioned medium from control hMSCs. Moreover, the IGFBP3 neutralization antibody reversed the apoptotic effect of ISL1-hMSCs-CM. CONCLUSIONS:These results suggest that overexpression of ISL1 in hMSCs promotes cell survival in a model of MI and enhances their paracrine function to protect cardiomyocytes, which may be mediated through IGFBP3. ISL1 overexpression in hMSCs may represent a novel strategy for enhancing the effectiveness of stem cell therapy after MI.
| S-EPMC5828309 | biostudies-literature
Project description:BACKGROUND:Ischemia related inflammation is the most critical factor for the survival of transplanted mesenchymal stem cells (MSCs), and strategies for controlling excessive inflammation after acute myocardial infarction (AMI) are essential and necessary for cell transplantation therapy. Our present study tested the effect of decreased Ly6C(high) monocytes on mouse MSCs transplantation after AMI. METHODS:BALB/c AMI mice were treated systemically with a CCR2 antagonist (RS 504393, 2 mg/kg, subcutaneously) or normal saline (control group). Next, 10(5) EdU-labeled MSCs were administered by intramyocardial injection to the mice in each group. TUNEL kits were used to identify the apoptotic cardiomyocytes in the infarct. The slides of the infarct border zone were stained with wheat germ agglutinin to measure the vessel density, and anti-myosin heavy chain eFluor 660 was used to measure the cardiac myosin-positive area. A transwell chamber was used to examine the interactions between Ly6C(high) monocytes and MSCs. The inflammatory cytokines expressed by Ly6C(high) monocytes and the SDF-1 expressed by MSCs were detected using ELISA kits. MSC viability was further examined by MTT and mitochondrial membrane potential assays by flow cytometry using JC-1 kits. RESULTS:We first observed the increased survival of transplanted MSCs (11.2 ± 3.4/mm(2) vs. 3.5 ± 1.6/mm(2), p < 0.001), and the decreased apoptosis of cardiomyocytes (11.20% ± 3.55% vs. 20.51% ± 8.17%, p < 0.001) in the infarcts at 3 days in the CCR2 antagonist group. An increased number of capillaries and small arterioles (139.6 ± 21.7/mm(2) vs. 95.4 ± 17.6/mm(2), p < 0.001) and an increased cardiac myosin-positive area (17.9% ± 6.6% vs. 11.8% ± 3.5%, p < 0.001) were also observed in the infarct zone at 21 days post MSC infusion in the CCR2 antagonist group. In addition, a significantly increased LvEF% (50.17 ± 10.06 vs. 45.44 ± 9.45, p < 0.001) was detected at the same time compared to the control mice. We further demonstrated that both the mitochondrial membrane potential of the MSCs (0.45 ± 0.11 vs. 3.4 ± 0.3, p < 0.001) and stromal cell-derived factor-1 (SDF-1) secreted by the MSCs significantly decreased (80.77 ± 39.02 pg/ml vs. 435.5 ± 77.41 pg/ml, p < 0.001) when co-cultured with Ly6C(high) monocytes. This is possibly mediated by the over-expressed cytokines secreted by the Ly6C(high) monocytes compared to the Ly6C(low) monocytes, including IL-1 (139.45 ± 30.44 vs. 80.05 ± 19.33, p < 0.001), IL-6 (187.82 ± 40.43 vs. 135.5 ± 22.09, p < 0.001), TNF-α (121.77 ± 31.65 vs. 75.3 ± 22.14, p < 0.001) and IFN-γ (142.46 ± 27.55 vs. 88.25 ± 19.91, p < 0.001).
| S-EPMC4448197 | biostudies-literature
Project description:BackgroundMesenchymal Stromal Cells (MSC) have been widely used for their therapeutic properties in many clinical applications including myocardial infarction. Despite promising preclinical results and evidences of safety and efficacy in phases I/ II, inconsistencies in phase III trials have been reported. In a previous study, we have shown using MSC derived from the bone marrow of PPARβ/δ (Peroxisome proliferator-activated receptors β/δ) knockout mice that the acute cardioprotective properties of MSC during the first hour of reperfusion are PPARβ/δ-dependent but not related to the anti-inflammatory effect of MSC. However, the role of the modulation of PPARβ/δ expression on MSC cardioprotective and anti-apoptotic properties has never been investigated.ObjectivesThe aim of this study was to investigate the role of PPARβ/δ modulation (inhibition or activation) in MSC therapeutic properties in vitro and ex vivo in an experimental model of myocardial infarction.Methods and resultsNaïve MSC and MSC pharmacologically activated or inhibited for PPARβ/δ were challenged with H2O2. Through specific DNA fragmentation quantification and qRT-PCR experiments, we evidenced in vitro an increased resistance to oxidative stress in MSC pre-treated by the PPARβ/δ agonist GW0742 versus naïve MSC. In addition, PPARβ/δ-priming allowed to reveal the anti-apoptotic effect of MSC on cardiomyocytes and endothelial cells in vitro. When injected during reperfusion, in an ex vivo heart model of myocardial infarction, 3.75 × 105 PPARβ/δ-primed MSC/heart provided the same cardioprotective efficiency than 7.5 × 105 naïve MSC, identified as the optimal dose in our experimental model. This enhanced short-term cardioprotective effect was associated with an increase in both anti-apoptotic effects and the number of MSC detected in the left ventricular wall at 1 h of reperfusion. By contrast, PPARβ/δ inhibition in MSC before their administration in post-ischemic hearts during reperfusion decreased their cardioprotective effects.ConclusionAltogether these results revealed that PPARβ/δ-primed MSC exhibit an increased resistance to oxidative stress and enhanced anti-apoptotic properties on cardiac cells in vitro. PPARβ/δ-priming appears as an innovative strategy to enhance the cardioprotective effects of MSC and to decrease the therapeutic injected doses. These results could be of major interest to improve MSC efficacy for the cardioprotection of injured myocardium in AMI patients.
| S-EPMC9034535 | biostudies-literature