Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored. Consensus document of the ESC Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart

Cardiovascular Research, Journal Year: 2022, Volume and Issue: 118(15), P. 3016 - 3051

Published: Jan. 5, 2022

Abstract Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, discover test novel preventive curative therapies, all which warrant experimental models that recapitulate human disease. The translation basic science results clinical practice is challenging task, in particular for complex conditions such as cardiovascular diseases, often result from multiple risk factors comorbidities. This difficulty might lead some individuals question the value animal research, citing translational ‘valley death’, largely reflects fact studies rodents are difficult translate humans. also influenced by new, human-derived vitro can aspects disease processes. However, it would be mistake think do not vital step pathway they provide important pathophysiological insights into mechanisms particularly on an organ systemic level. While stem cell-derived have potential become key testing toxicity effectiveness new drugs, we need realistic, carefully validate human-like models. In this position paper, highlight recent advances trying reduce number animals ranging situ modelling heart properties, bioinformatic based large datasets, state-of-the-art models, show clinically relevant characteristics observed patients with We aim guide help researchers their design bench findings routine taking replacement, reduction, refinement (3R) guiding concept.

Language: Английский

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Serine biosynthesis as a novel therapeutic target for dilated cardiomyopathy

European Heart Journal, Journal Year: 2022, Volume and Issue: 43(36), P. 3477 - 3489

Published: June 21, 2022

Abstract Aims Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. Despite significant progress in understanding the genetic aetiologies DCM, molecular mechanisms underlying pathogenesis familial DCM remain unknown, translating to lack disease-specific therapies. The discovery novel targets for treatment was sought using phenotypic sceening assays induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) that recapitulate disease phenotypes vitro. Methods and results Using patient-specific iPSCs carrying pathogenic TNNT2 gene mutation (p.R183W) CRISPR-based genome editing, faithful model vitro developed. An unbiased screening mutant iPSC-derived with small molecule kinase inhibitors (SMKIs) performed identify therapeutic targets. Two SMKIs, Gö 6976 SB 203580, were discovered whose combinatorial rescued contractile dysfunction iPSC-CMs mutations various ontologies (TNNT2, TTN, LMNA, PLN, TPM1, LAMA2). SMKI upregulated expression genes encode serine, glycine, one-carbon metabolism enzymes significantly increased intracellular levels glucose-derived serine glycine iPSC-CMs. Furthermore, mitochondrial respiration defects tricarboxylic acid cycle metabolites ATP Finally, rescue mediated by activating transcription factor 4 (ATF4) its downstream effector genes, phosphoglycerate dehydrogenase (PHGDH), which encodes critical enzyme biosynthesis pathway, Tribbles 3 (TRIB3), pseudokinase pleiotropic cellular functions. Conclusions A platform established target discovery. combination SMKIs ameliorated metabolic via ATF4-dependent pathway. Together, these findings suggest modulation signalling may represent genotype-agnostic strategy DCM.

Language: Английский

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Human Engineered Heart Tissue Models for Disease Modeling and Drug Discovery

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: March 31, 2022

The emergence of human induced pluripotent stem cells (hiPSCs) and efficient differentiation hiPSC-derived cardiomyocytes (hiPSC-CMs) from diseased donors have the potential to recapitulate molecular functional features heart. Although immaturity hiPSC-CMs, including structure, gene expression, conduct, ion channel density, Ca 2+ kinetics, is a major challenge, various attempts promote maturation been effective. Three-dimensional cardiac models using hiPSC-CMs achieved these morphological maturations, disease patient-specific furthered our understanding underlying mechanisms effective therapies for diseases. Aside diseases drug responses, also evaluate safety efficacy drugs in context before candidate enters market many phases clinical trials. In fact, novel testing paradigms suggested that can be used better predict proarrhythmic risk drugs. this review, we overview current strategies engineered heart tissue with focus on discuss perspectives future directions real application modeling, development, trials, cardiotoxicity tests.

Language: Английский

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Histone lactylation-derived LINC01127 promotes the self-renewal of glioblastoma stem cells via the cis-regulating the MAP4K4 to activate JNK pathway

Cancer Letters, Journal Year: 2023, Volume and Issue: 579, P. 216467 - 216467

Published: Oct. 29, 2023

Language: Английский

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Silencing of Long Non-coding RNA GAS5 Suppresses Neuron Cell Apoptosis and Nerve Injury in Ischemic Stroke Through Inhibiting DNMT3B-Dependent MAP4K4 Methylation

Translational Stroke Research, Journal Year: 2020, Volume and Issue: 11(5), P. 950 - 966

Published: Jan. 29, 2020

Language: Английский

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Particle-based artificial three-dimensional stem cell spheroids for revascularization of ischemic diseases

Science Advances, Journal Year: 2020, Volume and Issue: 6(19)

Published: May 6, 2020

Development of new approaches to biomimetically reconstruct vasculature networks remains challenging in regenerative medicine. We introduce a particle-based artificial stem cell spheroid (ASSP) technology that recapitulates paracrine functions three-dimensional (3D) SSPs for regeneration. Specifically, we used facile method induce the aggregation cells into 3D spheroids, which benefited from hypoxia microenvironment-driven and enhanced secretion proangiogenic bioactive factors. Furthermore, artificially reconstructed spheroids (i.e., ASSP) by integration SSP-secreted factors micro-/nanoparticles with membrane-derived surface coatings. The easily controllable sizes ASSP particles provided superior revascularization effects on ischemic tissues hindlimb ischemia models through local administration microparticles myocardial infarction via systemic delivery nanoparticles. strategy offers promising therapeutic option tissue regeneration addresses issues faced bottlenecked development therapies.

Language: Английский

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LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway

Stem Cell Research & Therapy, Journal Year: 2020, Volume and Issue: 11(1)

Published: Jan. 21, 2020

Abstract Aims Extracellular vesicles, especially exosomes, have emerged as key mediators of intercellular communication with the potential to improve cardiac function part cell-based therapies. We previously demonstrated that cardioprotective factor, macrophage migration inhibitory factor (MIF), had an optimizing effect on mesenchymal stem cells (MSCs). The aim this study was determine protective exosomes derived from MIF-pretreated MSCs in cardiomyocytes and explore underlying mechanisms. Methods results Exosomes were isolated control (exosome) (exosome MIF ), delivered subjected H 2 O vitro. Regulatory long non-coding RNAs (lncRNAs) activated by pretreatment explored using genomics approaches. Exosome protected -induced apoptosis. Mechanistically, we identified lncRNA-NEAT1 a mediator exosome regulating expression miR-142-3p activating Forkhead class O1 (FOXO1). effects consistently abrogated depletion lncRNA-NEAT1, overexpression miR-142-3p, or FOXO1 silencing. Furthermore, inhibited apoptosis through modulating oxidative stress. Conclusions obtained cardiomyocytes. functions anti-apoptotic molecule via competitive endogenous RNA activity towards miR-142-3p. LncRNA-NEAT1/miR-142-3p/FOXO1 at least partially mediates roles protecting

Language: Английский

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Human iPSC modeling of heart disease for drug development

Cell chemical biology, Journal Year: 2021, Volume and Issue: 28(3), P. 271 - 282

Published: March 1, 2021

Human induced pluripotent stem cells (hiPSCs) have emerged as a promising platform for pharmacogenomics and drug development. In cardiology, they make it possible to produce unlimited numbers of patient-specific human that reproduce hallmark features heart disease in the culture dish. Their potential applications include discovery mechanism-specific therapeutics, evaluation safety efficacy context before candidate reaches patients, stratification patients clinical trials. Although this new technology has revolutionize discovery, translational hurdles hindered its widespread adoption pharmaceutical Here we discuss recent progress overcoming these should facilitate use hiPSCs develop medicines individualize therapies disease.

Language: Английский

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Generating 3D human cardiac constructs from pluripotent stem cells

EBioMedicine, Journal Year: 2022, Volume and Issue: 76, P. 103813 - 103813

Published: Jan. 27, 2022

Human pluripotent stem cell (hPSC) technology has offered nearly infinite opportunities to model all kinds of human diseases in vitro. Cardiomyocytes derived from hPSCs have proved be efficient tools for cardiac disease modeling, drug screening and pathological mechanism studies. In this review, we discuss the advantages limitations 2D hPSC-cardiomyocyte (hPSC-CM) system, introduce recent development three-dimensional (3D) culture platforms hPSCs. Although bioengineering technologies greatly improved 3D platform construction, there are certainly challenges room further in-depth research.

Language: Английский

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Targeting miR-30d reverses pathological cardiac hypertrophy

EBioMedicine, Journal Year: 2022, Volume and Issue: 81, P. 104108 - 104108

Published: June 22, 2022

Pathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological are highly needed.The expression level of miR-30d was analyzed models serum patients with chronic by qRT-PCR. Gain loss-of-function experiments were performed vitro. gain function vivo. Bioinformatics, western blot, luciferase assay, qRT-PCR, immunofluorescence examine the molecular mechanisms miR-30d.miR-30d decreased both murine neonatal rat cardiomyocytes (NRCMs) hypertrophy. overexpression ameliorated phenylephrine (PE) angiotensin II (Ang II) induced NRCMs, whereas opposite phenotype observed when downregulated. Consistently, transgenic found protect against isoproterenol (ISO)-induced Mechanistically, methyltransferase EZH2 could promote H3K27me3 methylation promotor region suppress its during prevented via negatively regulating target genes MAP4K4 GRP78 inhibiting pro-hypertrophic nuclear factor activated T cells (NFAT). Adeno-associated virus (AAV) serotype 9 mediated-miR-30d exhibited beneficial effects hypertrophic model. Notably, reduced significantly human embryonic stem cell-derived cardiomyocytes.Overexpression may be a potential approach treat hypertrophy.This work supported grants from National Key Research Development Project (2018YFE0113500 J Xiao), Natural Science Foundation China (82020108002 Xiao, 81900359 Li), grant Technology Commission Shanghai Municipality (20DZ2255400 21XD1421300 22010500200 Sailing Program (19YF1416400 "Dawn" Education (19SG34 "Chen Guang" project Municipal (19CG45 Li).

Language: Английский

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