Induced Pluripotent Stem Cells in Cardiomyopathy: Advancing Disease Modeling, Therapeutic Development, and Regenerative Therapy

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(11), P. 4984 - 4984

Published: May 22, 2025

Cardiomyopathies are a heterogeneous group of heart muscle diseases that can lead to failure, arrhythmias, and sudden cardiac death. Traditional animal models in vitro systems have limitations replicating the complex pathology human cardiomyopathies. Induced pluripotent stem cells (iPSCs) offer transformative platform by enabling generation patient-specific cardiomyocytes, thus opening new avenues for disease modeling, drug discovery, regenerative therapy. This process involves reprogramming somatic into iPSCs subsequently differentiating them functional which be characterized using techniques such as electrophysiology, contractility assays, gene expression profiling. iPSC-derived cardiomyocyte (iPSC-CM) platforms also being explored screening personalized medicine, including high-throughput testing cardiotoxicity identification patient-tailored therapies. While iPSC-CMs already serve valuable understanding mechanisms drugs, ongoing advances maturation bioengineering bringing iPSC-based therapies closer clinical application. Furthermore, integration multi-omics approaches artificial intelligence (AI) is enhancing predictive power iPSC models. technologies paving way era cardiology, with potential revolutionize management cardiomyopathies through insights strategies.

Language: Английский

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Polyphenols-Enriched Diet Prevents Muscle Atrophy in an Inflamed Zebrafish (Danio Rerio) Model

Published: Jan. 1, 2025

Language: Английский

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Intermediate filaments at a glance

Journal of Cell Science, Journal Year: 2024, Volume and Issue: 137(16)

Published: Aug. 15, 2024

Intermediate filaments (IFs) comprise a large family of versatile cytoskeletal proteins, divided into six subtypes with tissue-specific expression patterns. IFs have wide repertoire cellular functions, including providing structural support to cells, as well active roles in mechanical and signaling pathways. Consequently, defects are associated more than 100 diseases. In this Cell Science at Glance article, we discuss the established classes their general features, functions beyond support, recent advances field. We also highlight involvement disease potential use clinical markers pathological conditions. Finally, provide our view on current knowledge gaps future directions IF

Language: Английский

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Amyloidogenic immunoglobulin light chains disturb contractile function and calcium transients in a human cardiac spheroid model of light chain (AL) amyloidosis

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 4, 2025

Light chain (AL) amyloidosis is a serious systemic disease caused by the deposition of free misfolded immunoglobulin light chains (LCs) in form amyloid fibrils within tissues. Cardiac involvement determines prognosis and mortality. An important cytotoxic impact amyloidogenic prefibrillar LC oligomers on cardiomyocytes now established isolated rodent cardiomyocytes, simple animal models, or cardiomyocyte-like cell lines. However, response human to this pathogenic condition currently unknown. In work, we have set up cellular model AL cardiac (AL-CA) spheroids, study effects LCs with regard contractile function calcium handling. To mimic reconstituted system, soluble purified from urine AL-CA patients were added mixture induced pluripotent stem cell-issued (hiPSC-CM) primary fibroblasts, which resulted formation spheroids 7 days. This procedure ensured uniform pericellular distribution spheroids. LC-treated hiPSC-CM cultures LC-containing presented structural functional defects including: (1) decreased levels subcellular disorganization sarcomeric protein alpha-actinin; (2) abnormal accumulation handling SERCA2a protein; (3) impaired contractility altered transients. Three independent patient-derived had similar effects, albeit varying degrees, highlighting patient-specific properties type amyloids. Taken together, these results indicate that present spheroid could be appropriate cytotoxicity different patients, contributing better understanding therapeutic disease.

Language: Английский

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Natural History, Phenotype Spectrum, and Clinical Outcomes of Desmin ( DES )-Associated Cardiomyopathy

Circulation Genomic and Precision Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

BACKGROUND: Pathogenic/likely pathogenic (LP) desmin ( DES ) variants cause heterogeneous cardiomyopathy and skeletal myopathy phenotypes. Limited data suggest a high incidence of major adverse cardiac events (MACEs), including conduction disease, sustained ventricular arrhythmias (VA), heart failure (HF) (HF hospitalization, left assist device/cardiac transplant, HF-related death) in patients with pathogenic/LP variants. However, pleiotropic presentation small cohort sizes have limited clinical phenotype outcome characterization. We aimed to describe the natural history, spectrum, familial penetrance outcomes through systematic review individual patient meta-analysis using published reports. METHODS: searched Medline (PubMed) Embase for studies that evaluated phenotypes Cardiomyopathy diagnosis or occurrence MACE was considered evidence involvement/penetrance. Lifetime event-free survival from VA, HF events, composite assessed. RESULTS: Of 4212 screened publications, 71 met inclusion criteria. A total 230 were included (52.6% male, 52.2% probands, median age: 31 years [22.0–42.8] at first evaluation, follow-up: 3 [0–11.0]). Overall, 124 (53.9%) diagnosed cardiomyopathy, predominantly dilated (14.8%), followed by restrictive (13.5%), whereas other forms less common: arrhythmogenic (7.0%), hypertrophic (6.1%), right (5.2%), (7.4%). 132 (57.4%) developed MACE, 96 (41.7%) having 36 (15.7%) 43 (18.7%) events. Familial disease 63.6% among relatives Male sex associated an increased risk VA (hazard ratio, 2.28; P =0.02) 2.45; =0.008). CONCLUSIONS: exhibits distinct characterized substantial burden. face higher

Language: Английский

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Dilated cardiomyopathy: from genes and molecules to potential treatments

Molecular and Cellular Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 29, 2025

Language: Английский

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Characteristics and pharmacological responsiveness in hiPSC models of inherited cardiomyopathy

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108845 - 108845

Published: April 1, 2025

Inherited cardiomyopathies are a major cause of heart failure in all age groups, often with an onset adolescence or early adult life. More than thousand variants approximately one hundred genes associated cardiomyopathies. Interestingly, many genetic display overlapping phenotypical defects patients, despite the diversity initial pathogenic variants. Understanding how underlying pathophysiology leads to these phenotypes, will improve insights into patient's disease course and creates opportunity for conceiving treatment strategies. Moreover, therapeutic strategies can be used treat multiple based on shared phenotypes. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer reliable, high-throughput models studying molecular cellular characteristics hereditary hiPSC-CMs produced relatively easily, either by directly originating them from introducing patient-specific healthy lines. This review evaluates 90 studies 24 cardiomyopathy-associated systematically summarises morphological functional phenotypes observed hiPSC-CMs. Additionally, applied cardiomyopathic compiled scored effectiveness. Multiple phenotypic were identified different variants, whereas certain only specific Based findings, common mechanisms, prospects, considerations future research discussed aim clinical translation patients.

Language: Английский

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Pathophysiological mechanisms of cardiomyopathies induced by desmin gene variants located in the C‐Terminus of segment 2B

Journal of Cellular Physiology, Journal Year: 2024, Volume and Issue: 239(5)

Published: March 19, 2024

Abstract Desmin, the most abundant intermediate filament in cardiomyocytes, plays a key role maintaining cardiomyocyte structure by interconnecting intracellular organelles, and facilitating interactions with extracellular matrix neighboring cardiomyocytes. As consequence, mutations desmin gene ( DES ) can lead to desminopathies, group of diseases characterized variable often severe cardiomyopathies along skeletal muscle disorders. The basic is composed four segments separated linkers that further assemble into dimers, tetramers eventually unit‐length filaments compact radially give final form filament. Each step this process critical for proper formation allow specific within cell. Mutations disrupt formation, as seen aggregate thus have cardiac outcomes, depending on locus mutation. focus review outline molecular consequences located C‐terminal part segment 2B. This region crucial ensuring known hotspot significantly impact function.

Language: Английский

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Impact of MG132 induced-proteotoxic stress on αB-crystallin and desmin phosphorylation and O-GlcNAcylation and their partition towards cytoskeleton

Biochimie, Journal Year: 2024, Volume and Issue: 226, P. 121 - 135

Published: April 16, 2024

Language: Английский

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Natural History, Phenotype Spectrum and Clinical Outcomes of Desmin (DES)-Associated Cardiomyopathy

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 26, 2024

Pathogenic/likely pathogenic (P/LP) desmin (

Language: Английский

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