Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids.

Autor: Scalise M; Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro 88100, Italy; Centre for Human and Applied Physiological, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King's College London, London, UK., Cianflone E; Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro 88100, Italy. Electronic address: cianflone@unicz.it., Quercia C; Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro 88100, Italy., Pagano L; Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro 88100, Italy., Chiefalo A; Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro 88100, Italy., Stincelli A; Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro 88100, Italy., Torella A; Department of Experimental Medicine, University of Campania 'L. Vanvitelli', Naples 80138, Italy., Puccio B; Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro 88100, Italy., Santamaria G; Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro 88100, Italy., Guzzi HP; Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro 88100, Italy., Veltri P; DIMES Department of Informatics, Modeling, Electronics and Systems, UNICAL, Rende, Cosenza, Italy., De Angelis A; Department of Experimental Medicine, University of Campania 'L. Vanvitelli', Naples 80138, Italy., Urbanek K; Department of Molecular Medicine and Medical Biotechnologies, University of Naples 'Federico II', and CEINGE-Advanced Biotechnologies, Naples 80131, Italy., Ellison-Hughes GM; Centre for Human and Applied Physiological, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King's College London, London, UK., Torella D; Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro 88100, Italy. Electronic address: dtorella@unicz.it., Marino F; Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro 88100, Italy.
Jazyk: angličtina
Zdroj: Mechanisms of ageing and development [Mech Ageing Dev] 2024 Nov 30; Vol. 223, pp. 112007. Date of Electronic Publication: 2024 Nov 30.
DOI: 10.1016/j.mad.2024.112007
Abstrakt: Background: Human cardiac organoids closely replicate the architecture and function of the human heart, offering a potential accurate platform for studying cellular and molecular features of aging cardiomyopathy. Senolytics have shown potential in addressing age-related pathologies but their potential to reverse aging-related human cardiomyopathy remains largely unexplored.
Methods: We employed human iPSC-derived cardiac organoids (hCOs/hCardioids) to model doxorubicin(DOXO)-induced cardiomyopathy in an aged context. hCardioids were treated with DOXO and subsequently with a combination of two senolytics: dasatinib (D) and quercetin (Q).
Results: DOXO-treated hCardioids exhibited significantly increased oxidative stress, DNA damage (pH2AX), cellular senescence (p16 INK4A ) and decreased cell proliferation associated with a senescence-associated secretory phenotype (SASP). DOXO-treated hCardioids were considerably deprived of cardiac progenitors and displayed reduced cardiomyocyte proliferation as well as contractility. These distinctive aging-associated characteristics were confirmed by global RNA-sequencing analysis. Treatment with D+Q reversed these effects, reducing oxidative stress and senescence markers, alleviating SASP, and restoring hCardioids viability and function. Additionally, senolytics replenished cardiac progenitors and reversed the cardiomyocyte proliferation deficit.
Conclusions: Doxorubicin triggers an age-associated phenotype in hCardioids reliably modelling the main cellular and molecular features of aging cardiomyopathy. Senescence is a key mechanism of the aged-hCOs phenotype as senolytics rejuvenated aged-hCardioids restoring their structure and function while reverting the age-associated regenerative deficit.
Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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