Ex Vivo Molecular Rejuvenation Improves the Therapeutic Activity of Senescent Human Cardiac Stem Cells in a Mouse Model of Myocardial Infarction. (18th August 2014)

• Record Type: Journal Article
• Authors: Avolio, Elisa; Gianfranceschi, Giuseppe; Cesselli, Daniela; Caragnano, Angela; Athanasakis, Emmanouil; Katare, Rajesh; Meloni, Marco; Palma, Anita; Barchiesi, Arianna; Vascotto, Carlo; Toffoletto, Barbara; Mazzega, Elisa; Finato, Nicoletta; Aresu, Giuseppe; Livi, Ugolino; Emanueli, Costanza; Scoles, Giacinto; Beltrami, Carlo Alberto; Madeddu, Paolo; Beltrami, Antonio Paolo
• Is Part Of: Stem cells. Volume 32:Number 9(2014:Sep.)
• Page Start: 2373
• Page End: 2385
• Publication Date: 2014-08-18
• Subjects: Stem cells -- Myocardial infarction -- Cellular senescence -- Heart failure; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.1728
• Languages: English
• ISSNs: 1066-5099

Abstract

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 investigated 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 IL1 β compared with D-CSC. Using blocking antibodies, we verified that IL1 β hampers the paracrine protective action of E-CSC on cardiomyocyte viability. IL1 β acts intracranially inducing IKK β signaling, a mechanism that via nuclear factor-κB upregulates the expression of IL1 β itself. Moreover, E-CSC show reduced levels of AMP protein kinase (AMPK) activating phosphorylation. This latter event, together with enhanced IKK β signaling, increases TORC1 activity, thereby impairing the autophagic flux and inhibiting the phosphorylation of Akt and cAMP response element-binding protein. The combined use of rapamycin and resveratrol enhanced AMPK, thereby restoring downstream signaling and reducing IL1 β 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 endogenous c-Kit + 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. Stem Cells 2014;32:2373–2385