Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Encapsulating Bioactive Hydrogels Improve Rat Heart Function Post Myocardial Infarction.
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ABSTRACT:
SUBMITTER: Chow A
PROVIDER: S-EPMC5830963 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) hold great promise for the repair of the injured heart, but optimal cell production in a fully chemically defined and cost-effective system is essential for the efficacy and safety of cell transplantation therapies. In this study, we provided a simple and efficient strategy for cardiac differentiation from hPSCs and performed functional evaluation in a rat model of myocardial infarction. Using a chemically defined medium including four components, recombinant human albumin, ascorbic acid, human transferrin, and RPMI 1640, we developed a manageable and cost-effective protocol for robust generation of CMs from hPSCs. Interestingly, the addition of transferrin helped hPSCs to transit from TeSR-E8 medium to the simple cardiac differentiation medium and successfully initiated mesoderm differentiation without significant cell death. The CM generation efficiency was up to 85% based on cTnT expression. We performed transcriptome profiling from differentiation day 0 to 35, and characterized interesting dynamic change of cardiac genes. CMs derived from transferrin-supplemented simple medium have similar transcriptome and the maturation level compared to those generated in B27 minus insulin medium as well as their in vivo counterparts. Importantly, after transplantation, hPSC-derived CMs survived in the infarcted rat heart, significantly improved the physiological function and reduced fibrosis. Our study offers an easy-to-use and cost-effective method for cardiac differentiation and facilitates the translational application of hPSC-derived CMs for heart repair.
| S-EPMC7790792 | biostudies-literature
Project description:Injury due to myocardial infarction (MI) is largely irreversible. Once an infarct has occurred, the clinical goal becomes limiting remodeling, preserving left ventricular function, and preventing heart failure. Although traditional approaches (e.g., ?-blockers) partially preserve left ventricular function, novel strategies are needed to limit ventricular remodeling post-MI.The aim of this study was to determine the role of glycogen synthase kinase-3? (GSK-3?) in post-MI remodeling.Mice with cardiomyocyte-specific conditional deletion of Gsk3? and littermate controls underwent sham or MI surgery. Heart function was assessed using serial M-mode echocardiography.Gsk3? deletion in the heart markedly limits remodeling and preserves left ventricular function post-MI. This is due at least in part to dramatic thinning and expansion of the scar in the control hearts, which was less in the heart of knockout (KO) mice. In contrast, the border zone in the KO mice demonstrated a much thicker scar, and there were more viable cardiomyocytes within the scar/border zone. This was associated with less apoptosis and more proliferation of cardiomyocytes in the KO mice. Mechanistically, reduced apoptosis was due, at least in part, to a marked decrease in the Bax/Bcl-2 ratio, and increased cardiomyocyte proliferation was mediated through cyclin E1 and E2F-1 in the hearts of the KO mice.Taken together, these findings show that reducing GSK-3? expression in cardiomyocytes limits ventricular remodeling and preserves cardiac function post-MI. Specifically targeting GSK-3? could be a novel strategy to limit adverse remodeling and heart failure.
| S-EPMC4142642 | biostudies-literature
Project description:The inflammatory response is associated with cardiac repair and ventricular remodeling after myocardial infarction (MI). The key inflammation regulatory factor thymic stromal lymphopoietin (TSLP) plays a critical role in various diseases. However, its role in cardiac repair after MI remains uncertain. In this study, we elucidated the biological function and mechanism of action of TSLP in cardiac repair and ventricular remodeling following MI. Wild-type and TSLP receptor (TSLPR)-knockout (Crlf2-/-) mice underwent MI induction via ligation of the left descending artery. TSLP expression was upregulated in the infarcted heart, with a peak observed on day 7 post-MI. TSLP expression was enriched in the cardiomyocytes of infarcted hearts, with the highest expression observed in dendritic cells. Crlf2-/- mice exhibited significantly reduced survival and worsened cardiac function, increased interstitial fibrosis and cardiomyocyte cross-sectional area, and reduced CD31+ staining, with no change in the proportion of apoptotic cardiomyocytes within the border zone. Mechanistically, a reduction in regulatory T cells and more innate immune cells and their subsets were observed in the infarcted hearts of Crlf2-/- mice, accompanied by a systemic reduction in T cell activation and proliferation. Simultaneously, RNA sequencing analysis of the infarcted hearts revealed significant downregulation of genes in Crlf2-/- mice. Our findings indicate that TSLP plays a pivotal role in regulating T cell responses, specifically T regulatory cells, thus promoting cardiac repair, which may provide a potential novel therapeutic approach for managing heart failure after MI.
2024-09-21 | GSE265931 | GEO
Project description:The aim of the present study was to identify the mechanisms underlying the development of post-myocardial infarction (post-MI) heart failure. The left anterior descending coronary artery of rats was occluded to mimic human ischemic heart disease. Linear Trap Quadropole OrbiTrap mass spectrometry was used to profile the expressions of energy metabolism‑associated and calcium‑binding proteins in the post‑MI and control groups. Using the online Protein Analysis Through Evolutionary Relationships classification system, 78 differentially expressed proteins were identified, including 50 downregulated proteins and 28 upregulated proteins in post‑MI group when compared with the control group. The differentially expressed proteins were closely associated with energy metabolism, contractile function, calcium handling, pathological hypertrophy and cardiac remodeling. These results were further validated using western blotting. At different postoperative time points (1st and 14th day following surgery) during the progression of advanced heart failure post‑MI, dynamic alterations in differential protein expression were identified. The expression of the vitamin D protein was significantly upregulated on the 1st day post‑MI however, was then downregulated with progression of the disease on the 14th day post‑MI. These results identified various target proteins associated with the disease, which may be used as diagnostic markers.
| S-EPMC5561871 | biostudies-literature
Project description:Numerous studies have proposed that glycogen synthase kinase (GSK)-3beta is a central regulator of the hypertrophic response of cardiomyocytes. However, all of this work has relied on overexpression of GSK-3beta, expression of constitutively active mutants, or small molecule inhibitors with documented off-target effects. Genetic loss of function approaches have not been used in the adult mouse because germ-line deletion of GSK-3beta is embryonic-lethal.This study was designed to define the role played by GSK-3beta in pressure overload (PO)-induced hypertrophy and remodeling following myocardial infarction (MI).We used a mouse model that allows inducible, cardiomyocyte-specific deletion of GSK-3beta in the adult knockout. Surprisingly, we find that knockout mice exposed to PO induced by thoracic aortic constriction exhibit a normal hypertrophic response. Thus, in contrast to virtually all prior published studies, GSK-3beta appears to play at most a minor role in the hypertrophic response to PO stress. However, GSK-3beta does regulate post-MI remodeling because the GSK-3beta knockouts had less left ventricular dilatation and better-preserved left ventricular function at up to 8 weeks post-MI despite demonstrating significantly more hypertrophy in the remote myocardium. Deletion of GSK-3beta also led to increased cardiomyocyte proliferation following PO and MI.Deletion of GSK-3beta protects against post-MI remodeling and promotes stress-induced cardiomyocyte proliferation in the adult heart. These studies suggest that inhibition of GSK-3beta could be a strategy to both prevent remodeling and to promote cardiac regeneration in pathological states.
| S-EPMC2895414 | biostudies-literature
Project description:AIMS:Cellular processes in the heart rely mainly on studies from experimental animal models or explanted hearts from patients with terminal end-stage heart failure (HF). To address this limitation, we provide data on excitation contraction coupling, cardiomyocyte contraction and relaxation, and Ca2+ handling in post-myocardial-infarction (MI) patients at mid-stage of HF. METHODS AND RESULTS:Nine MI patients and eight control patients without MI (non-MI) were included. Biopsies were taken from the left ventricular myocardium and processed for further measurements with epifluorescence and confocal microscopy. Cardiomyocyte function was progressively impaired in MI cardiomyocytes compared with non-MI cardiomyocytes when increasing electrical stimulation towards frequencies that simulate heart rates during physical activity (2 Hz); at 3 Hz, we observed almost total breakdown of function in MI. Concurrently, we observed impaired Ca2+ handling with more spontaneous Ca2+ release events, increased diastolic Ca2+ , lower Ca2+ amplitude, and prolonged time to diastolic Ca2+ removal in MI (P < 0.01). Significantly reduced transverse-tubule density (-35%, P < 0.01) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase 2a (SERCA2a) function (-26%, P < 0.01) in MI cardiomyocytes may explain the findings. Reduced protein phosphorylation of phospholamban (PLB) serine-16 and threonine-17 in MI provides further mechanisms to the reduced function. CONCLUSIONS:Depressed cardiomyocyte contraction and relaxation were associated with impaired intracellular Ca2+ handling due to impaired SERCA2a activity caused by a combination of alteration in the PLB/SERCA2a ratio and chronic dephosphorylation of PLB as well as loss of transverse tubules, which disrupts normal intracellular Ca2+ homeostasis and handling. This is the first study that presents these mechanisms from viable and intact cardiomyocytes isolated from the left ventricle of human hearts at mid-stage of post-MI HF.
| S-EPMC5933953 | biostudies-literature
Project description:BackgroundIschemia/reperfusion-mediated myocardial infarction (MIRI) is a major pathological factor implicated in the progression of ischemic heart disease, but the key factors dysregulated during MIRI have not been fully elucidated, especially those essential non-coding factors required for cardiovascular development.MethodsA murine MIRI model and RNA sequencing (RNA-seq) were used to identify key lncRNAs after myocardial infarction. qRT-PCR was used to validate expression in cardiac muscle tissues and myocardial cells. The role of Gm18840 in HL-1 cell growth was determined by flow cytometry experiments in vitro. Full-length Gm18840 was identified by using a rapid amplification of cDNA ends (RACE) assay. The subcellular distribution of Gm18840 was examined by nuclear/cytoplasmic RNA fractionation and qRT-PCR. RNA pulldown and RNA immunoprecipitation (RIP)-qPCR assays were performed to identify Gm18840-interacting proteins. Chromatin isolation by RNA purification (ChIRP)-seq (chromatin isolation by RNA purification) was used to identify the genome-wide binding of Gm18840 to chromatin. The regulatory activity of Gm18840 in transcriptional regulation was examined by a luciferase reporter assay and qRT-PCR.ResultsGm18840 was upregulated after myocardial infarction in both in vivo and in vitro MIRI models. Gm18840 was 1,471 nt in length and localized in both the cytoplasm and the nucleus of HL-1 cells. Functional studies showed that the knockdown of Gm18840 promoted the apoptosis of HL-1 cells. Gm18840 directly interacts with histones, including H2B, highlighting a potential function in transcriptional regulation. Further ChIRP-seq and RNA-seq analyses showed that Gm18840 is directly bound to the cis-regulatory regions of genes involved in developmental processes, such as Junb, Rras2, and Bcl3.ConclusionGm18840, a novel transcriptional regulator, promoted the apoptosis of myocardial cells via direct transcriptional regulation of essential genes and might serve as a novel therapeutic target for MIRI.
| S-EPMC8312575 | biostudies-literature
Project description:Highlights•The mechanical complications of acute myocardial infarction (AMI) can be catastrophic.•A Gerbode type defect after AMI is rare.•Surgery is the mainstay of treatment, but percutaneous options are available.•Gerbode defects can be congenital or acquired and can be closed percutaneously.•Echocardiography reliably evaluates the mechanical complications of AMI.
| S-EPMC6034478 | biostudies-other
Project description:Cell encapsulating poly(ethylene glycol) hydrogels represent a promising approach for constructing 3D cultures designed to more closely approximate in vivo tissue environment. Improved strategies are needed, however, to optimally balance hydrogel permeability to support metabolic activities of encapsulated cells, while maintaining patternability to restore key aspects of tissue architecture. Herein, we have developed one such strategy incorporating hydrophobic nanoparticles to partially induce looser cross-linking density at the particle-hydrogel interface. Strikingly, our network design significantly increased hydrogel permeability, while only minimally affecting the matrix mechanical strength or prepolymer viscosity. This structural advantage improved viability and functions of encapsulated cells and permitted micron-scale structures to control over spatial distribution of incorporated cells. We expect that this design strategy holds promise for the development of more advanced artificial tissues that can promote high levels of cell metabolic activity and recapitulate key architectural features.
| S-EPMC2996449 | biostudies-literature
Project description:Human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) hold great promise for the repair of the injured heart, but optimal cell production in a fully chemically defined and cost-effective system is essential for the efficacy and safety of cell transplantation therapies. In this study, we provided a simple and efficient strategy for cardiac differentiation from hPSCs and performed functional evaluation in a rat model of myocardial infarction. Using a chemically defined medium including four components, recombinant human albumin, ascorbic acid, human transferrin, and RPMI 1640, we developed a manageable and cost-effective protocol for robust generation of CMs from hPSCs. Interestingly, the addition of transferrin helped hPSCs to transit from TeSR-E8 medium to the simple cardiac differentiation medium and successfully initiated mesoderm differentiation without significant cell death. The CM generation efficiency was up to 85% based on cTnT expression. We performed transcriptome profiling from differentiation day 0 to 35, and characterized interesting dynamic change of cardiac genes. CMs derived from transferrin supplemented simple medium have similar transcriptome and the maturation level compared to cardiomyocytes generated in B27 minus insulin medium as well as their in vivo counterparts. Importantly, after transplantation, hPSC derived CMs survived in the infarcted rat heart, significantly improved the physiological function and reduced fibrosis. Our study offers an easy-to-use and cost-effective method for cardiac differentiation and facilitates the translational application of hPSC-derived CMs for heart repair.
2021-01-13 | GSE154294 | GEO