Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids

被引:2
作者
Scalise, Mariangela [1 ,2 ]
Cianflone, Eleonora [3 ]
Quercia, Claudia [3 ]
Pagano, Loredana [1 ]
Chiefalo, Antonio [1 ]
Stincelli, Antonio [3 ]
Torella, Annalaura [4 ]
Puccio, Barbara [3 ]
Santamaria, Gianluca [1 ]
Guzzi, Hiram P. [3 ]
Veltri, Pierangelo [5 ]
De Angelis, Antonella [4 ]
Urbanek, Konrad [6 ,7 ]
Ellison-Hughes, Georgina M. [2 ]
Torella, Daniele [1 ]
Marino, Fabiola [1 ]
机构
[1] Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, I-88100 Catanzaro, Italy
[2] Kings Coll London, Fac Life Sci & Med, Ctr Human & Appl Physiol, Sch Basic & Med Biosci, London, England
[3] Magna Graecia Univ Catanzaro, Dept Med & Surg Sci, I-88100 Catanzaro, Italy
[4] Univ Campania L Vanvitelli, Dept Expt Med, I-80138 Naples, Italy
[5] UNICAL, DIMES Dept Informat Modeling Elect & Syst, Arcavacata Di Rende, Cosenza, Italy
[6] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, I-80131 Naples, Italy
[7] CEINGE Adv Biotechnol, I-80131 Naples, Italy
关键词
SENESCENT CELLS; CELLULAR SENESCENCE; STEM-CELLS; IN-VITRO; HEART; AGE; MODEL; MULTIPOTENT; EXPRESSION; APOPTOSIS;
D O I
10.1016/j.mad.2024.112007
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 (p16INK4A) 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.
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页数:17
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