Aging induces cardiac mesenchymal stromal cell senescence and promotes endothelial cell fate of the CD90 + subset

Martini, Hélène; Iacovoni, Jason S.; Maggiorani, Damien; Dutaur, Marianne; Marsal, Dimitri; Roncalli, Jérôme; Itier, Romain; Dambrin, Camille; Pizzinat, Nathalie; Mialet‐Perez, Jeanne; Cussac, Daniel; Parini, Angelo; Lefèvre, Lise; Douin‐Echinard, Victorine

doi:10.1111/acel.13015

Cited by 37 publications

(50 citation statements)

References 36 publications

(42 reference statements)

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“…The main function of the SASP is to reinforce cell senescence by secreting pro-senescent cytokines such as IL1, IL6, and IL8 [ 130 , 131 , 132 ]. Furthermore, the SASP induces paracrine senescence in neighboring cells [ 133 ].…”

Section: Sasp and Stem Cell Senescence And Agingmentioning

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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Section: Sasp and Stem Cell Senescence And Agingmentioning

confidence: 99%

Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

Cianflone

Torella

Biamonte

et al. 2020

Cells

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“…The results showed that mIgG bound KRT10 to form complexes (Figure 3 E). Furthermore, we also found the CD31 + endothelial cells in the heart 23 expressed KRT10 ( Figure S3 ). The results indicate that mIgG can specifically bind KRT10 in vascular endothelial cells in the heart.…”

Section: Resultsmentioning

confidence: 60%

House Dust Mite Specific Antibodies induce Neutrophilic Inflammation in the Heart

Chen

Zhang

et al. 2020

Theranostics

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Rationale : Inflammatory heart disorders are among the causes of human death. The causative factors of heart inflammation are to be further elucidated. House dust mite (HDM)-derived protein antigens are involved in the pathogenesis of many human diseases. This study aims to investigate the role of HDM-specific autoantibodies in the pathogenesis of heart inflammation. Methods : Human heart tissue samples were obtained from surgically removed hearts in heart transplantation. The interaction of the heart tissues with HDM-specific antibodies was assessed by pertinent immune analysis. The role of HDM-specific autoantibodies in the induction of heart inflammation was assessed with a murine model. Results : HDM-specific IgG (mIgG) was detected in the serum of patients with myocarditis (Mcd); the mIgG titers were positively correlated with the neutrophil counts in the heart tissues. The mIgG specifically bound to keratin-10 (KRT10) in heart vascular endothelial cells and the heart tissue protein extracts. The amounts of C3a, C5a and C5b-9 were increased in the mouse heart tissues after exposing to mIgG. In the presence of the complement-containing serum, mIgG bound cardiovascular epithelial monolayers to impair the barrier functions. Administration of mIgG or HDM induced the Mcd-like inflammation in the heart, in which neutrophils were the dominant cellular components in the infiltration of inflammatory cells. Conclusions : Mcd patients with neutrophilic inflammation in the heart had higher serum levels of mIgG. The mIgG bound heart endothelial cells to impair the endothelial barrier functions and induce neutrophilic inflammation in the heart.

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“…In the adult heart, C-MSCs participate in stromal cardiac tissue renewal by differentiating into SMCs and ECs and releasing a variety of paracrine factors responsible for trophic, angiogenic, and anti-inflammatory effects (Martini et al, 2019). Here we report that transplantation of C-MSCs after N1ICD overexpression has a superior and significant effect on cardiac function improvement and attenuation of cardiac fibrosis compared with C-MSCs.…”

Section: Discussionmentioning

confidence: 99%

“…It appears that Notch1 activation boosts the function of C-MSCs in the regenerative process. However, Notch1 is altered in aging (Rizzo et al, 2018), which also compromises the function of C-MSCs (Martini et al, 2019). How Notch signaling is affected in the aging heart has not been extensively investigated yet.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles From Notch Activated Cardiac Mesenchymal Stem Cells Promote Myocyte Proliferation and Neovasculogenesis

Wang

Khan

Ashraf

2020

Front. Cell Dev. Biol.

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Cardiac mesenchymal stem cells (C-MSCs) are a novel mesenchymal stem cell (MSC) subpopulation derived from cardiac tissue, which are reported to be responsible for cardiac regeneration. Notch signaling is believed to aid in cardiac repair following myocardial injury. In this study, we have investigated the role of extracellular vesicles (EVs) from Notch1 engineered C-MSCs on angiogenesis and cardiomyocyte (CM) proliferation in ischemic myocardium. C-MSCs were isolated from Notch1 flox mice (C-MSC Notch1FF). Notch1 gene deletion was accomplished by adenoviral vectormediated Cre recombination, and Notch1 overexpression was achieved by overexpression of Notch1 intracellular domain (N1ICD). EVs were isolated by using the size exclusion column method. Proteomic composition of EV was carried out by mass spectrometry. A mouse myocardial infarction (MI) model was generated by permanent left anterior descending (LAD) coronary artery ligation. Intramyocardial transplantation of Notch1 knockout C-MSCs (C-MSCs Notch1KO) did not have any effect on cardiac function and scar size. On the other hand, transplantation of N1ICD-overexpressing C-MSCs (C-MSCs N1ICD) showed significant improvement in cardiac function and attenuation of fibrosis as compared to the control (PBS) group and non-modified C-MSC groups. C-MSCs N1ICD differentiated into smooth muscle cells and formed new vessels. Proteomics profiling identified several proteins, such as lysyl oxidase homolog-2 and biglycan, as highly enriched proteins in EV-C-MSCs N1ICD. Go term analysis indicated that EV-C-MSCs N1ICD were enriched with bioactive factors, potent prorepair proteins responsible for cell migration and proliferation. EV-C-MSCs Notch1FF and EV-C-MSCs N1ICD were strongly proangiogenic under both in vitro and in vivo conditions. EV-C-MSCs N1ICD caused dense tube formation in vitro and increased neovasculogenesis in the peri-infarct area in vivo. Furthermore, EV-C-MSCs N1ICD attenuated endothelial cell (EC) and CM apoptosis under oxidative stress and ischemic injury. Similarly, EV-C-MSC Notch1FF and EV-C-MSC N1ICD treatment improved cardiac

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Aging induces cardiac mesenchymal stromal cell senescence and promotes endothelial cell fate of the CD90 + subset

Cited by 37 publications

References 36 publications

Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

House Dust Mite Specific Antibodies induce Neutrophilic Inflammation in the Heart

Extracellular Vesicles From Notch Activated Cardiac Mesenchymal Stem Cells Promote Myocyte Proliferation and Neovasculogenesis

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