Ex vivo molecular rejuvenation improves the therapeutic activity of senescent human cardiac stem cells in a mouse model of myocardial infarction

Elisa Avolio, Giuseppe Gianfranceschi, Daniela Cesselli, Angela Caragnano, Emmanouil Athanasakis, Rajesh Katare, Marco Meloni, Anita Palma, Arianna Barchiesi, Carlo Vascotto, Barbara Toffoletto, Elisa Mazzega, Nicoletta Finato, Giuseppe Aresu, Ugolino Livi, Costanza Emanueli, Giacinto Scoles, Carlo Alberto Beltrami, Paolo Madeddu, Antonio Paolo Beltrami

Research output: Contribution to journalArticle

32 Citations (Scopus)

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 IL1β compared with D-CSC. Using blocking antibodies, we verified that IL1β hampers the paracrine protective action of E-CSC on cardiomyocyte viability. IL1β acts intracranially inducing IKKβ signaling, a mechanism that via nuclear factor-κB upregulates the expression of IL1β itself. Moreover, E-CSC show reduced levels of AMP protein kinase (AMPK) activating phosphorylation. This latter event, together with enhanced IKKβ 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 IL1β 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

Original languageEnglish
Pages (from-to)2373-2385
Number of pages13
JournalStem Cells
Volume32
Issue number9
DOIs
Publication statusPublished - 2014

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Rejuvenation
Human Activities
Stem Cells
Myocardial Infarction
Therapeutics
Cell Aging
Cardiac Myocytes
Adenylate Kinase
Sirolimus
Protein Kinases
Phosphorylation
Cyclic AMP Response Element-Binding Protein
Blocking Antibodies
Cell- and Tissue-Based Therapy

Keywords

  • Cellular senescence
  • Heart failure
  • Myocardial infarction
  • Stem cells

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine
  • Medicine(all)

Cite this

Ex vivo molecular rejuvenation improves the therapeutic activity of senescent human cardiac stem cells in a mouse model of myocardial infarction. / 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.

In: Stem Cells, Vol. 32, No. 9, 2014, p. 2373-2385.

Research output: Contribution to journalArticle

Avolio, E, Gianfranceschi, G, Cesselli, D, Caragnano, A, Athanasakis, E, Katare, R, Meloni, M, Palma, A, Barchiesi, A, Vascotto, C, Toffoletto, B, Mazzega, E, Finato, N, Aresu, G, Livi, U, Emanueli, C, Scoles, G, Beltrami, CA, Madeddu, P & Beltrami, AP 2014, 'Ex vivo molecular rejuvenation improves the therapeutic activity of senescent human cardiac stem cells in a mouse model of myocardial infarction', Stem Cells, vol. 32, no. 9, pp. 2373-2385. https://doi.org/10.1002/stem.1728
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. / Ex vivo molecular rejuvenation improves the therapeutic activity of senescent human cardiac stem cells in a mouse model of myocardial infarction. In: Stem Cells. 2014 ; Vol. 32, No. 9. pp. 2373-2385.
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AU - Caragnano, Angela

AU - Athanasakis, Emmanouil

AU - Katare, Rajesh

AU - Meloni, Marco

AU - Palma, Anita

AU - Barchiesi, Arianna

AU - Vascotto, Carlo

AU - Toffoletto, Barbara

AU - Mazzega, Elisa

AU - Finato, Nicoletta

AU - Aresu, Giuseppe

AU - Livi, Ugolino

AU - Emanueli, Costanza

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