Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids

Mariangela Scalise; Eleonora Cianflone; Claudia Quercia; Loredana Pagano; Antonio Chiefalo; Antonio Stincelli; Annalaura Torella; Barbara Puccio; Gianluca Santamaria; Hiram P Guzzi; Pierangelo Veltri; Antonella De Angelis; Konrad Urbanek; Georgina M Ellison-Hughes; Daniele Torella; Fabiola Marino

doi:10.1016/j.mad.2024.112007

Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids

Mech Ageing Dev. 2024 Nov 30:223:112007. doi: 10.1016/j.mad.2024.112007. Online ahead of print.

Authors

Mariangela Scalise¹, Eleonora Cianflone², Claudia Quercia³, Loredana Pagano⁴, Antonio Chiefalo⁴, Antonio Stincelli³, Annalaura Torella⁵, Barbara Puccio³, Gianluca Santamaria⁴, Hiram P Guzzi³, Pierangelo Veltri⁶, Antonella De Angelis⁵, Konrad Urbanek⁷, Georgina M Ellison-Hughes⁸, Daniele Torella⁹, Fabiola Marino⁴

Affiliations

¹ 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.
² Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro 88100, Italy. Electronic address: [email protected].
³ Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro 88100, Italy.
⁴ Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro 88100, Italy.
⁵ Department of Experimental Medicine, University of Campania "L. Vanvitelli", Naples 80138, Italy.
⁶ DIMES Department of Informatics, Modeling, Electronics and Systems, UNICAL, Rende, Cosenza, Italy.
⁷ Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", and CEINGE-Advanced Biotechnologies, Naples 80131, Italy.
⁸ Centre for Human and Applied Physiological, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
⁹ Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro 88100, Italy. Electronic address: [email protected].

PMID: 39622416
DOI: 10.1016/j.mad.2024.112007

Abstract

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.