Beyond cardiomyocyte loss: Role of Notch in cardiac aging

Rizzo, Paola; Bertero, Edoardo; Ferrari, Roberto; Ameri, Pietro

doi:10.1002/jcp.26417

Cited by 7 publications

(7 citation statements)

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“…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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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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“…A few pathways have been reported in previous studies to determine the stemness of active rapid cycling and dormant stem cells, such as Wnt (Li and Clevers, 2010) and PI3K-Akt (Richmond et al, 2015). Meanwhile, Notch signaling was involved in multiple diseases associated with advanced aging (Sun et al, 2013;Rizzo et al, 2018). Here, we found that Notch activation mimicking by NICD overexpression could restore the neuronal differentiation of Lgr5+ cells in aged OE (Figure 6), while aging weakened capacity to generate progenies from Lgr5+ cells compared with the young OE ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent Activation and Neuronal Differentiation of Lgr5+ Basal Cells in Injured Olfactory Epithelium via Notch Signaling Pathway

Tong²,

Wang

et al. 2020

Front. Aging Neurosci.

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Aging is an important factor affecting function of smell, leading to the degeneration of mature olfactory sensory neurons and inducing the occurrence of smell loss. The mammalian olfactory epithelium (OE) can regenerate when subjected to chemical assaults. However, this capacity is not limitless. Inactivation of globose basal cells and failure to generate sensory neurons are the main obstacles to prevent the OE regeneration. Here, we found the significant attenuation in mature sensory neuronal generation and apparent transcriptional alternation in the OE from aged mice compared with young ones. The recruitment of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-positive cells in injured OE was weakened in aged mice, and more Lgr5+ cells remained quiescence in aged OE postinjury. Lineage-traced progenies from Lgr5+ cells were significantly fewer in the OE with aging. Moreover, Notch activation enhanced the neuronal regeneration in aged OE, making the regenerative capacity of aged OE comparable with that of young animals after injury. The growth and morphology of three-dimensional (3D)-cultured organoids from the OE of young and aged mice varied and was modulated by small molecules regulating the Notch signaling pathway. Thus, we concluded that activation of Lgr5+ cells in injured OE was age dependent and Notch activation could enhance the capacity of neuronal generation from Lgr5+ cells in aged OE after injury.

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“…Notch signaling pathway seems indispensable for functional activities controlling tissue formation in cardiogenesis ( Kratsios et al, 2010 ). Moreover, it is an important cell–cell communication system and its activation after the damage has been demonstrated in several tissues ( Kratsios et al, 2010 ; Rizzo et al, 2017 ). It has been reported that Notch signaling plays a regulatory role in adult cardiac damage and in the cardioprotection preserving cardiac function after ischemia.…”

Section: Discussionmentioning

confidence: 99%

Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat Hearts

et al. 2018

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G protein-coupled estrogen receptor (GPER) is an estrogen receptor expressed in the cardiovascular system. G1, a selective GPER ligand, exerts cardiovascular effects through activation of the PI3K-Akt pathway and Notch signaling in normotensive animals. Here, we investigated whether the G1/GPER interaction is involved in the limitation of infarct size, and improvement of post-ischemic contractile function in female spontaneous hypertensive rat (SHR) hearts. In this model, we also studied Notch signaling and key components of survival pathway, namely PI3K-Akt, nitric oxide synthase (NOS) and mitochondrial K+-ATP (MitoKATP) channels. Rat hearts isolated from female SHR underwent 30 min of global, normothermic ischemia and 120 min of reperfusion. G1 (10 nM) alone or specific inhibitors of GPER, PI3K/NOS and MitoKATP channels co-infused with G1, just before I/R, were studied. The involvement of Notch1 was studied by Western blotting. Infarct size and left ventricular pressure were measured. To confirm endothelial-independent G1-induced protection by Notch signaling, H9c2 cells were studied with specific inhibitor, N-[N-(3,5 difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT, 5 μM), of this signaling. Using DAPT, we confirmed the involvement of G1/Notch signaling in limiting infarct size in heart of normotensive animals. In the hypertensive model, G1-induced reduction in infarct size and improvement of cardiac function were prevented by the inhibition of GPER, PI3K/NOS, and MitoKATP channels. The involvement of Notch was confirmed by western blot in the hypertensive model and by the specific inhibitor in the normotensive model and cardiac cell line. Our results suggest that GPERs play a pivotal role in mediating preconditioning cardioprotection in normotensive and hypertensive conditions. The G1-induced protection involves Notch1 and is able to activate the survival pathway in the presence of comorbidity. Several pathological conditions, including hypertension, reduce the efficacy of ischemic conditioning strategies. However, G1-induced protection can result in significant reduction of I/R injury also female in hypertensive animals. Further studies may ascertain the clinical translation of the present results.

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Beyond cardiomyocyte loss: Role of Notch in cardiac aging

Cited by 7 publications

References 131 publications

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

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

Age-Dependent Activation and Neuronal Differentiation of Lgr5+ Basal Cells in Injured Olfactory Epithelium via Notch Signaling Pathway

Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat Hearts

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