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Title:Ex Vivo Molecular Rejuvenation Improves the Therapeutic Activity of Senescent Human Cardiac Stem Cells in a Mouse Model of Myocardial Infarction
Authors:Avolio, Elisa (Author)
Gianfranceschi, Giuseppe (Author)
Caragnano, Angela (Author)
Athanasakis, Emmanouil (Author)
Katare, Rajesh (Author)
Cesselli, Daniela (Author)
Meloni, Marco (Author)
Palma, Anita (Author)
Barchiesi, Arianna (Author)
Vascotto, Carlo (Author)
Toffoletto, Barbara (Author)
Mazzega, Elisa (Author)
Finato, Nicoletta (Author)
Aresu, Giuseppe (Author)
Livi, Ugolino (Author)
Emanueli, Costanza (Author)
Scoles, Giacinto (Author)
Beltrami, Carlo Alberto (Author)
Madeddu, Paolo (Author)
Beltrami, Antonio Paolo (Author)
Files:This document has no files. This document may have a phisical copy in the library of the organization, check the status via COBISS. Link is opened in a new window
Work type:Not categorized (r6)
Tipology:1.01 - Original Scientific Article
Organization:UNG - University of Nova Gorica
Abstract:Cardiac stem cells (CSC) from explanted decompensated hearts (E-CSC) are, with respect to those obtained from healthy donors (D-CSC), senescent and functionally impaired. We aimed to identify alterations in signaling pathways that are associated with CSC senescence. Additionally, we inves- tigated if pharmacological modulation of altered pathways can reduce CSC senescence in vitro and enhance their reparative ability in vivo. Measurement of secreted factors showed that E-CSC release larger amounts of proinflammatory cytokine IL1b compared with D-CSC. Using blocking antibodies, we verified that IL1b hampers the paracrine protective action of E-CSC on cardiomyo- cyte viability. IL1b acts intracranially inducing IKKb signaling, a mechanism that via nuclear factor-jB upregulates the expression of IL1b itself. Moreover, E-CSC show reduced levels of AMP protein kinase (AMPK) activating phosphorylation. This latter event, together with enhanced IKKb signaling, increases TORC1 activity, thereby impairing the autophagic flux and inhibiting the phos- phorylation of Akt and cAMP response element-binding protein. The combined use of rapamycin and resveratrol enhanced AMPK, thereby restoring downstream signaling and reducing IL1b secretion. These molecular corrections reduced E-CSC senescence, re-establishing their protective activity on cardiomyocytes. Moreover ex vivo treatment with rapamycin and resveratrol improved E-CSC capacity to induce cardiac repair upon injection in the mouse infarcted heart, leading to reduced cardiomyocyte senescence and apoptosis and increased abundance of endog- enous c-Kit1 CSC in the peri-infarct area. Molecular rejuvenation of patient-derived CSC by short pharmacologic conditioning boosts their in vivo reparative abilities. This approach might prove useful for refinement of CSC-based therapies.
Keywords:Stem cells, Myocardial infarction, Cellular senescence, Heart failure
Year of publishing:2014
Number of pages:2373-2385
Numbering:May 6
COBISS_ID:4723963 Link is opened in a new window
DOI:10.1002/stem.1728 Link is opened in a new window
License:CC BY-NC-ND 4.0
This work is available under this license: Creative Commons Attribution Non-Commercial No Derivatives 4.0 International
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Title:STEM CELLSStem cells
Publisher:AlphaMed Press
Year of publishing:2014