Critical role of lysosomes in the dysfunction of human Cardiac Stem Cells obtained from failing hearts

Gianfranceschi, Giuseppe; Caragnano, Angela; Piazza, Silvano; Manini, Ivana; Ciani, Yari; Verardo, Roberto; Toffoletto, Barbara; Finato, Nicoletta; Livi, Ugolino; Beltrami, Carlo Alberto; Scoles, G.; Sinagra, Gianfranco; Aleksova, Aneta; Cesselli, Daniela; Beltrami, Antonio Paolo

doi:10.1016/j.ijcard.2016.04.155

Cited by 16 publications

(15 citation statements)

References 36 publications

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“…Cardiac progenitor cells from failing human hearts, compared with those from healthy donors, display impaired autophagy in cultures. This impairment was recently found to associate with depressed TFEB signaling [52]. Elderly patients are generally more vulnerable to sepsis than younger patients.…”

Section: Discussionmentioning

confidence: 99%

TFEB activation protects against cardiac proteotoxicity via increasing autophagic flux

Pan

Zhang

Cui

et al. 2017

Journal of Molecular and Cellular Cardiology

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Insufficient lysosomal removal of autophagic cargoes in cardiomyocytes has been suggested as a main cause for the impairment of the autophagic-lysosomal pathway (ALP) in many forms of heart disease including cardiac proteinopathy and may play an important pathogenic role; however, the molecular basis and the correcting strategy for the cardiac ALP insufficiency require further investigation. The present study was sought to determine whether myocardial expression and activity of TFEB, the recently identified ALP master regulator, are impaired in a cardiac proteinopathy mouse model and to determine the effect of genetic manipulation of TFEB expression on autophagy and proteotoxicity in a cardiomyocyte model of proteinopathy. We found that increased myocardial TFEB mRNA levels and a TFEB protein isoform switch were associated with marked decreases in the mRNA levels of representative TFEB target genes and increased mTORC1 activation, in mice with cardiac transgenic expression of a missense (R120G) mutant αB-crystallin (CryABR120G), a well-established model of cardiac proteinopathy. Using neonatal rat ventricular cardiomyocyte cultures, we demonstrated that downregulation of TFEB decreased autophagic flux in cardiomyocytes both at baseline and during CryABR120G overexpression and increased CryABR120G protein aggregates. Conversely, forced TFEB overexpression increased autophagic flux and remarkably attenuated the CryABR120G overexpression- induced accumulation of ubiquitinated proteins, caspase 3 cleavage, LDH leakage, and decreases in cell viability. Moreover, these protective effects of TFEB were dramatically diminished by inhibiting autophagy. We conclude that myocardial TFEB signaling is impaired in cardiac proteinopathy and forced TFEB overexpression protects against proteotoxicity in cardiomyocytes through improving ALP activity.

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Section: Discussionmentioning

confidence: 99%

TFEB activation protects against cardiac proteotoxicity via increasing autophagic flux

Pan

Zhang

Cui

et al. 2017

Journal of Molecular and Cellular Cardiology

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“…Chronic heart failure is associated with a functional decline of the resident CSCs that progressively reduce their potential to preserve tissue homeostasis and to contribute new cardiac cells upon myocardial damage [ 189 ]. We and others have thus assessed whether the progressive accumulation of dysfunctional and senescent CSCs plays a crucial role in the pathogenesis of cardiac aging and failure [ 27 , 28 , 29 , 189 , 190 , 191 , 192 ]. Though cell senescence has been classically associated with the development of HF, even for this condition, an acute raise of senescent fibroblasts after myocardial infarction has been linked to a reduced fibrotic response of the myocardium, postulating a pro-regenerative effect from the acute and transient exposure to senescence program [ 96 ].…”

Section: Cardiac Stem Cell Senescencementioning

confidence: 99%

Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

Cianflone

Torella

Biamonte

et al. 2020

Cells

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Adult stem/progenitor are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Adult cardiac stem/progenitor cell (CSC) senescence has been accordingly associated with physiological and pathological processes encompassing both non-age and age-related decline in cardiac tissue repair and organ dysfunction and disease. Senescence is a highly active and dynamic cell process with a first classical hallmark represented by its replicative limit, which is the establishment of a stable growth arrest over time that is mainly secondary to DNA damage and reactive oxygen species (ROS) accumulation elicited by different intrinsic stimuli (like metabolism), as well as external stimuli and age. Replicative senescence is mainly executed by telomere shortening, the activation of the p53/p16INK4/Rb molecular pathways, and chromatin remodeling. In addition, senescent cells produce and secrete a complex mixture of molecules, commonly known as the senescence-associated secretory phenotype (SASP), that regulate most of their non-cell-autonomous effects. In this review, we discuss the molecular and cellular mechanisms regulating different characteristics of the senescence phenotype and their consequences for adult CSCs in particular. Because senescent cells contribute to the outcome of a variety of cardiac diseases, including age-related and unrelated cardiac diseases like diabetic cardiomyopathy and anthracycline cardiotoxicity, therapies that target senescent cell clearance are actively being explored. Moreover, the further understanding of the reversibility of the senescence phenotype will help to develop novel rational therapeutic strategies.

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“…Accumulation of undegraded substrates on lysosomes may have a great impact on cells and tissues, highlighting the importance of lysosome dysfunction and impaired proteostasis as a major outcome of failure of autophagy and a key feature of senescence. This particularly relevant in metabolic tissues such as liver and heart (Schneider et al, 2015 ; Gianfranceschi et al, 2016 ), but might also be true in musculoskeletal tissues.…”

Section: Autophagy In Oamentioning

confidence: 99%

Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

et al. 2018

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Osteoarthritis is the most common musculoskeletal disease causing chronic disability in adults. Studying cartilage aging, chondrocyte senescence, inflammation, and autophagy mechanisms have identified promising targets and pathways with clinical translatability potential. In this review, we highlight the most recent mechanistic and therapeutic preclinical models of aging with particular relevance in the context of articular cartilage and OA. Evidence supporting the role of metabolism, nuclear receptors and transcription factors, cell senescence, and circadian rhythms in the development of musculoskeletal system degeneration assure further translational efforts. This information might be useful not only to propose hypothesis and advanced models to study the molecular mechanisms underlying joint degeneration, but also to translate our knowledge into novel disease-modifying therapies for OA.

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Critical role of lysosomes in the dysfunction of human Cardiac Stem Cells obtained from failing hearts

Cited by 16 publications

References 36 publications

TFEB activation protects against cardiac proteotoxicity via increasing autophagic flux

TFEB activation protects against cardiac proteotoxicity via increasing autophagic flux

Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

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