Dual stem cell therapy synergistically improves cardiac function and vascular regeneration following myocardial infarction.
Ontology highlight
ABSTRACT:
SUBMITTER: Park SJ
PROVIDER: S-EPMC6635499 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
Publications
Dual stem cell therapy synergistically improves cardiac function and vascular regeneration following myocardial infarction.
Park Soon-Jung SJ Kim Ri Youn RY Park Bong-Woo BW Lee Sunghun S Choi Seong Woo SW Park Jae-Hyun JH Choi Jong Jin JJ Kim Seok-Won SW Jang Jinah J Cho Dong-Woo DW Chung Hyung-Min HM Moon Sung-Hwan SH Ban Kiwon K Park Hun-Jun HJ
Nature communications 20190716 1
Since both myocardium and vasculature in the heart are excessively damaged following myocardial infarction (MI), therapeutic strategies for treating MI hearts should concurrently target both so as to achieve true cardiac repair. Here we demonstrate a concomitant method that exploits the advantages of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) and human mesenchymal stem cell-loaded patch (hMSC-PA) to amplify cardiac repair in a rat MI model. Epicardially implante ...[more]
Similar Datasets
Project description:Vascular regeneration in ischemic hearts has been considered a target for new therapeutic strategies. It has been reported that ETV2 is essential for vascular development, injury-induced neovascularization and direct cell reprogramming of non-endothelial cells into endothelial cells. Thus, the objective of this study was to explore the therapeutic potential of ETV2 in murine models of myocardial infarction in vivo. Direct myocardial delivery of lentiviral ETV2 into rodents undergoing myocardial infarction dramatically upregulated the expression of markers for angiogenesis as well as anti-fibrosis and anti-inflammatory factors in vivo. Consistent with these findings, echocardiography showed significantly improved cardiac function in hearts with induced myocardial infarction upon ETV2 injection compared to that in the control virus-injected group as determined by enhanced ejection fraction and fractional shortening. In addition, ETV2-injected hearts were protected against massive fibrosis with a remarkable increase in capillary density. Interestingly, major fractions of capillaries were stained positive for ETV2. In addition, ECs infected with ETV2 showed enhanced proliferation, suggesting a direct role of ETV2 in vascular regeneration in diseased hearts. Furthermore, culture media from ETV2-overexpressing cardiac fibroblasts promoted endothelial cell migration based on scratch assay. Importantly, intramyocardial injection of the adeno-associated virus form of ETV2 into rat hearts with induced myocardial infarction designed for clinical applicability consistently resulted in significant augmentation of cardiac function. We provide compelling evidence that ETV2 has a robust effect on vascular regeneration and enhanced cardiac repair after myocardial infarction, highlighting a potential therapeutic function of ETV2 as an efficient means to treat failing hearts.
| S-EPMC6372609 | biostudies-literature
Project description:Myocardial fibrosis is a major determinant of clinical outcomes in heart failure (HF) patients. It is characterized by the emergence of myofibroblasts and early activation of pro-fibrotic signaling pathways before adverse ventricular remodeling and progression of HF. Boron has been reported in recent years to augment the innate immune system and cell proliferation, which play an important role in the repair and regeneration of the injured tissue. Currently, the effect of boron on cardiac contractility and remodeling is unknown. In this study, we investigated, for the first time, the effect of boron supplementation on cardiac function, myocardial fibrosis, apoptosis and regeneration in a rat model myocardial infarction (MI)-induced HF. MI was induced in animals and borax, a sodium salt of boron, was administered for 7 days, p.o., 21 days post-injury at a dose level of 4 mg/kg body weight. Transthoracic echocardiographic analysis showed a significant improvement in systolic and diastolic functions with boron treatment compared to saline control. In addition, boron administration showed a marked reduction in myocardial fibrosis and apoptosis in the injured hearts, highlighting a protective effect of boron in the ischemic heart. Interestingly, we observed a tenfold increase of nuclei in thin myocardial sections stained positive for the cell cycle marker Ki67 in the MI boron-treated rats compared to saline, indicative of increased cardiomyocyte cell cycle activity in MI hearts, highlighting its potential role in regeneration post-injury. We similarly observed increased Ki67 and BrdU staining in cultured fresh neonatal rat ventricular cardiomyocytes. Collectively, the results show that boron positively impacted MI-induced HF and attenuated cardiac fibrosis and apoptosis, two prominent features of HF. Importantly, boron has the potential to induce cardiomyocyte cell cycle entry and potentially cardiac tissue regeneration after injury. Boron might be beneficial as a supplement in MI and may be a good candidate substance for anti-fibrosis approach.
| S-EPMC7553911 | biostudies-literature
Project description:Pericytes have been implicated in regulation of inflammatory, reparative, fibrogenic and angiogenic responses in several different organs and pathologic conditions. Although the adult mammalian heart contains abundant pericytes, their fate and involvement in myocardial disease remains unknown. We used NG2Dsred;PDGFRaEGFP pericyte-fibroblast dual reporter mice and inducible NG2CreER mice to study the fate and phenotypic modulation of pericytes in a model of myocardial infarction. The transcriptomic profile of pericyte-derived fibroblasts was studied using PCR arrays. The transcriptomic profile of NG2 lineage cells (pericytes) was studied in control and infarcted hearts using single cell RNA-sequencing analysis. The role of TGF-b signaling in regulation of pericyte phenotype in vivo was investigated using pericyte-specific Tgfbr2 knockout mice. In vitro, the effects of TGF-b were studied in cultured human placental pericytes.In normal mouse hearts, NG2 and PDGFRa identified distinct non-overlapping populations of pericytes and fibroblasts respectively. Following myocardial infarction, a population of cells expressing both pericyte and fibroblast markers emerged. These cells expressed large amounts of extracellular matrix (ECM) genes. Lineage tracing demonstrated that in the infarcted region, a subpopulation of pericytes underwent fibroblast conversion. Single cell RNA-seq experiments demonstrated expansion and diversification of pericyte-derived cells in the infarct, associated with emergence of subpopulations exhibiting accentuated matrix gene synthesis. In vitro studies and the profile of pericyte-derived fibroblasts identified TGF-b as a potentially causative mediator in fibrogenic activation of infarct pericytes. However, pericyte-specific Tgfbr2 disruption had no significant effects on myofibroblast infiltration and collagen deposition in the infarct. Pericyte-specific TGF-b signaling was involved in vascular maturation, mediating formation of a mural cell coat investing infarct neovessels. These reparative effects of infarct pericytes protected the infarcted heart from dilative remodeling.
2023-11-03 | GSE222417 | GEO
Project description:RATIONALE:In response to injury, the rodent heart is capable of virtually full regeneration via cardiomyocyte proliferation early in life. This regenerative capacity, however, is diminished as early as 1 week postnatal and remains lost in adulthood. The mechanisms that dictate postinjury cardiomyocyte proliferation early in life remain unclear. OBJECTIVE:To delineate the role of miR-34a, a regulator of age-associated physiology, in regulating cardiac regeneration secondary to myocardial infarction (MI) in neonatal and adult mouse hearts. METHODS AND RESULTS:Cardiac injury was induced in neonatal and adult hearts through experimental MI via coronary ligation. Adult hearts demonstrated overt cardiac structural and functional remodeling, whereas neonatal hearts maintained full regenerative capacity and cardiomyocyte proliferation and recovered to normal levels within 1-week time. As early as 1 week postnatal, miR-34a expression was found to have increased and was maintained at high levels throughout the lifespan. Intriguingly, 7 days after MI, miR-34a levels further increased in the adult but not neonatal hearts. Delivery of a miR-34a mimic to neonatal hearts prohibited both cardiomyocyte proliferation and subsequent cardiac recovery post MI. Conversely, locked nucleic acid-based anti-miR-34a treatment diminished post-MI miR-34a upregulation in adult hearts and significantly improved post-MI remodeling. In isolated cardiomyocytes, we found that miR-34a directly regulated cell cycle activity and death via modulation of its targets, including Bcl2, Cyclin D1, and Sirt1. CONCLUSIONS:miR-34a is a critical regulator of cardiac repair and regeneration post MI in neonatal hearts. Modulation of miR-34a may be harnessed for cardiac repair in adult myocardium.
| S-EPMC4769861 | biostudies-literature
Project description:Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit+ cardiac stem cells (CSCs) enhances their cardioreparative properties.The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI).Human cardiac stem cells (hCSCs, n = 10), hckit+ CSCs overexpressing Pim1 (Pim1+; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration.Whereas both hCSCs reduced MI size compared to placebo, Pim1+ cells produced a ?3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (-29.2 ± 2.7% vs. -8.4 ± 0.7%; p < 0.003). Pim1+ hCSCs also produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 ± 7.2% vs. 65.6 ± 6.8%; p <0.003), and a greater increase in regional contractility in both infarct and border zones (both p < 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1+ group at 8 weeks compared to placebo. Both hCSC and Pim1+ hCSC treatment reduced afterload (p = 0.02 and p = 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1+ hCSC group (p = 0.005).Pim1 overexpression enhanced the effect of intramyocardial delivery of CSCs to infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials.
| S-EPMC5223744 | biostudies-other
Project description:BACKGROUND:Stem cell factor (SCF), a ligand of the c-kit receptor, is a critical cytokine, which contributes to cell migration, proliferation, and survival. It has been shown that SCF expression increases after myocardial infarction (MI) and may be involved in cardiac repair. The aim of this study was to determine whether gene transfer of membrane-bound human SCF improves cardiac function in a large animal model of MI. METHODS AND RESULTS:A transmural MI was created by implanting an embolic coil in the left anterior descending artery in Yorkshire pigs. One week after the MI, the pigs received direct intramyocardial injections of either a recombinant adenovirus encoding for SCF (Ad.SCF, n=9) or ?-gal (Ad.?-gal, n=6) into the infarct border area. At 3 months post-MI, ejection fraction increased by 12% relative to baseline after Ad.SCF therapy, whereas it decreased by 4.2% (P=0.004) in pigs treated with Ad.?-gal. Preload-recruitable stroke work was significantly higher in pigs after SCF treatment (Ad.SCF, 55.5±11.6 mm Hg versus Ad.?-gal, 31.6±12.6 mm Hg, P=0.005), indicating enhanced cardiac function. Histological analyses confirmed the recruitment of c-kit(+) cells as well as a reduced degree of apoptosis 1 week after Ad.SCF injection. In addition, increased capillary density compared with pigs treated with Ad.?-gal was found at 3 months and suggests an angiogenic role of SCF. CONCLUSIONS:Local overexpression of SCF post-MI induces the recruitment of c-kit(+) cells at the infarct border area acutely. In the chronic stages, SCF gene transfer was associated with improved cardiac function in a preclinical model of ischemic cardiomyopathy.
| S-EPMC4303518 | biostudies-literature
Project description:BACKGROUND:In heart failure the myocardium becomes insulin resistant which negatively influences cardiac energy metabolism and function, while increasing cardiac insulin signalling improves cardiac function and prevents adverse remodelling in the failing heart. Glucagon's action on cardiac glucose and lipid homeostasis counteract that of insulin's action. We hypothesised that pharmacological antagonism of myocardial glucagon action, using a human monoclonal antibody (mAb A) against glucagon receptor (GCGR), a G-protein coupled receptor, will enhance insulin sensitivity and improve cardiac energy metabolism and function post myocardial infarction (MI). METHODS:Male C57BL/6 mice were subjected to a permanent left anterior descending coronary artery ligation to induce MI, following which they received either saline or mAb A (4 mg kg-1 week-1 starting at 1 week post-MI) for 3 weeks. RESULTS:Echocardiographic assessment at 4 weeks post-MI showed that mAb A treatment improved % ejection fraction (40.0?±?2.3% vs 30.7?±?1.7% in vehicle-treated MI heart, p?<?0.05) and limited adverse remodelling (LV mass: 129?±?7 vs 176?±?14 mg in vehicle-treated MI hearts, p?<?0.05) post MI. In isolated working hearts an increase in insulin-stimulated glucose oxidation was evident in the mAb A-treated MI hearts (1661?±?192 vs 924?±?165 nmol g dry wt-1 min-1 in vehicle-treated MI hearts, p?<?0.05), concomitant with a decrease in ketone oxidation and fatty acid oxidation rates. The increase in insulin stimulated glucose oxidation was accompanied by activation of the IRS-1/Akt/AS160/GSK-3? pathway, an increase in GLUT4 expression and a reduction in pyruvate dehydrogenase phosphorylation. This enhancement in insulin sensitivity occurred in parallel with a reduction in cardiac branched chain amino acids content (374?±?27 vs 183?±?41 µmol g protein-1 in vehicle-treated MI hearts, p?<?0.05) and inhibition of the mTOR/P70S6K hypertrophic signalling pathway. The MI-induced increase in the phosphorylation of transforming growth factor ?-activated kinase 1 (p-TAK1) and p38 MAPK was also reduced by mAb A treatment. CONCLUSIONS:mAb A-mediated cardioprotection post-myocardial infarction is associated with improved insulin sensitivity and a selective enhancement of glucose oxidation via, at least in part, enhancing branched chain amino acids catabolism. Antagonizing glucagon action represents a novel and effective pharmacological intervention to alleviate cardiac dysfunction and adverse remodelling post-myocardial infarction.
| S-EPMC6325856 | biostudies-other
Project description:BACKGROUND:Macrophages are highly plastic cells that play an important role in the pathogenesis of cardiovascular disease. OBJECTIVES:This study investigated the role of GATA3-positive macrophages in modulating cardiac function after myocardial infarction (MI) or in response to pressure overload hypertrophy. METHODS:Myeloid-specific GATA3-deficient (mGATA3KO) mice were generated, MI or pressure overload was induced, and cardiac function was determined by echocardiography. GATA3-sufficient Cre mice were used as a control. Immunohistochemical staining, flow cytometry, MILLIPLEX Mouse Cytokine/Chemokine Assay, cultured macrophages, quantitative real-time polymerase chain reaction, and western blot were used to determine the role of GATA3 in macrophages. RESULTS:GATA3-positive macrophages rapidly accumulated in the infarcted region of the myocardium after acute MI. Deficiency of GATA3-positive macrophages led to a significant improvement of cardiac function in response to acute MI or pressure overload hypertrophy compared with the control mice. This improvement was associated with the presence of a large number of proinflammatory Ly6Chi monocytes/macrophages and fewer reparative Ly6Clo macrophages in the myocardium of mGATA3KO mice compared with control mice. Analysis of serum proteins from the 2 mouse genotypes revealed no major changes in the profile of serum growth factors and cytokines between the 2 mice genotypes before and after MI. GATA3 was found to be specifically and transiently induced by interleukin 4 in cultured macrophages through activity of the proximal promoter, whereas the distal promoter remained silent. In addition, the absence of GATA3 in macrophages markedly attenuated arginase-1 expression in cultured macrophages. CONCLUSIONS:We demonstrated that the presence of GATA3-positive macrophages adversely affects remodeling of the myocardium in response to ischemia or pressure overload, whereas the absence of these macrophages led to a significant improvement in cardiac function. Targeting of signaling pathways that lead to the expression of GATA3 in macrophages may have favorable cardiac outcomes.
| S-EPMC6145461 | biostudies-literature
Project description:AimsTo establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction.Methods and resultsRats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs.ConclusionsSubcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy.
| S-EPMC7898942 | biostudies-literature
Project description:Clinical trials with autologous adipose-derived stem cell (AdSC) therapy for ischemic heart diseases (IHDs) are ongoing. However, little is known about combinational therapeutic effect of AdSCs and statin poly(lactic-co-glycolic) acid (PLGA) nanoparticles on the ischemic myocardium. We investigated the hypothesis that statins, which have pleiotropic effects, augment the therapeutic potential of AdSCs and that AdSCs also act as drug delivery tools. Simvastatin-conjugated nanoparticles (SimNPs) significantly promoted migration activity without changing proliferation activity and upregulated growth factor gene expression in vitro. A small number of intravenously administered SimNP-loaded AdSCs (10,000 cells per mouse) improved cardiac function following myocardial infarction, inducing endogenous cardiac regeneration in the infarcted myocardium. The de novo regenerated myocardium was thought to be derived from epicardial cells, which were positive for Wilms' tumor protein 1 expression. These findings were attributed to the sustained, local simvastatin release from the recruited SimNP-loaded AdSCs in the infarcted myocardium rather than to the direct contribution of recruited AdSCs to tissue regeneration. SimNP-loaded AdSCs may lead to a novel somatic stem cell therapy for IHDs. Stem Cells Translational Medicine 2019;8:1055-1067.
| S-EPMC6766602 | biostudies-literature