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 language | English |
|---|---|
| Pages (from-to) | 2373-2385 |
| Number of pages | 13 |
| Journal | Stem Cells |
| Volume | 32 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 2014 |
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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 journal › Article
}
TY - JOUR
T1 - Ex vivo molecular rejuvenation improves the therapeutic activity of senescent human cardiac stem cells in a mouse model of myocardial infarction
AU - Avolio, Elisa
AU - Gianfranceschi, Giuseppe
AU - Cesselli, Daniela
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
AU - Scoles, Giacinto
AU - Beltrami, Carlo Alberto
AU - Madeddu, Paolo
AU - Beltrami, Antonio Paolo
PY - 2014
Y1 - 2014
N2 - 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
AB - 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
KW - Cellular senescence
KW - Heart failure
KW - Myocardial infarction
KW - Stem cells
UR - http://www.scopus.com/inward/record.url?scp=84906275800&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84906275800&partnerID=8YFLogxK
U2 - 10.1002/stem.1728
DO - 10.1002/stem.1728
M3 - Article
VL - 32
SP - 2373
EP - 2385
JO - Stem Cells
JF - Stem Cells
SN - 1066-5099
IS - 9
ER -