Molecular mechanisms of cardioprotective effects mediated by transplanted cardiac ckitcells through the activation of an inflammatory hypoxia-dependent reparative response

Giovanni Puddighinu, Domenico D'Amario, Eleonora Foglio, Melissa Manchi, Andrea Siracusano, Elena Pontemezzo, Martina Cordella, Francesco Facchiano, Laura Pellegrini, Antonella Mangoni, Marco Tafani, Filippo Crea, Antonia Germani, Matteo Antonio Russo, Federica Limana

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The regenerative effects of cardiac ckit+stem cells (ckit+CSCs) in acute myocardial infarction (MI) have been studied extensively, but how these cells exert a protective effect on cardiomyocytes is not well known. Growing evidences suggest that in adult stem cells injury triggers inflammatory signaling pathways which control tissue repair and regeneration. Aim of the present study was to determine the mechanisms underlying the cardioprotective effects of ckit+CSCs following transplantation in a murine model of MI. Following isolation andin vitroexpansion, cardiac ckit+CSCs were subjected to normoxic and hypoxic conditions and assessed at different time points. These cells adapted to hypoxia as showed by the activation of HIF-1α and the expression of a number of genes, such as VEGF, GLUT1, EPO, HKII and, importantly, of alarmin receptors, such as RAGE, P2X7R, TLR2 and TLR4. Activation of these receptors determined an NFkB-dependent inflammatory and reparative gene response (IRR). Importantly, hypoxic ckit+CSCs increased the secretion of the survival growth factors IGF-1 and HGF. To verify whether activation of the IRR in a hypoxic microenvironment could exert a beneficial effectin vivo, autologous ckit+CSCs were transplanted into mouse heart following MI. Interestingly, transplantation of ckit+CSCs lowered apoptotic rates and induced autophagy in the peri-infarct area; further, it reduced hypertrophy and fibrosis and, most importantly, improved cardiac function. ckit+CSCs are able to adapt to a hypoxic environment and activate an inflammatory and reparative response that could account, at least in part, for a protective effect on stressed cardiomyocytes following transplantation in the infarcted heart.

Original languageEnglish
Pages (from-to)937-957
Number of pages21
JournalOncotarget
Volume9
Issue number1
DOIs
Publication statusPublished - 2017

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Transplantation
Myocardial Infarction
Cardiac Myocytes
Genes
Adult Stem Cells
Autophagy
Insulin-Like Growth Factor I
Hypertrophy
Vascular Endothelial Growth Factor A
Regeneration
Intercellular Signaling Peptides and Proteins
Fibrosis
Stem Cells
Wounds and Injuries
Hypoxia
Alarmins

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Molecular mechanisms of cardioprotective effects mediated by transplanted cardiac ckitcells through the activation of an inflammatory hypoxia-dependent reparative response. / Puddighinu, Giovanni; D'Amario, Domenico; Foglio, Eleonora; Manchi, Melissa; Siracusano, Andrea; Pontemezzo, Elena; Cordella, Martina; Facchiano, Francesco; Pellegrini, Laura; Mangoni, Antonella; Tafani, Marco; Crea, Filippo; Germani, Antonia; Russo, Matteo Antonio; Limana, Federica.

In: Oncotarget, Vol. 9, No. 1, 2017, p. 937-957.

Research output: Contribution to journalArticle

Puddighinu, G, D'Amario, D, Foglio, E, Manchi, M, Siracusano, A, Pontemezzo, E, Cordella, M, Facchiano, F, Pellegrini, L, Mangoni, A, Tafani, M, Crea, F, Germani, A, Russo, MA & Limana, F 2017, 'Molecular mechanisms of cardioprotective effects mediated by transplanted cardiac ckitcells through the activation of an inflammatory hypoxia-dependent reparative response', Oncotarget, vol. 9, no. 1, pp. 937-957. https://doi.org/10.18632/oncotarget.22946
Puddighinu, Giovanni ; D'Amario, Domenico ; Foglio, Eleonora ; Manchi, Melissa ; Siracusano, Andrea ; Pontemezzo, Elena ; Cordella, Martina ; Facchiano, Francesco ; Pellegrini, Laura ; Mangoni, Antonella ; Tafani, Marco ; Crea, Filippo ; Germani, Antonia ; Russo, Matteo Antonio ; Limana, Federica. / Molecular mechanisms of cardioprotective effects mediated by transplanted cardiac ckitcells through the activation of an inflammatory hypoxia-dependent reparative response. In: Oncotarget. 2017 ; Vol. 9, No. 1. pp. 937-957.
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AU - Foglio, Eleonora

AU - Manchi, Melissa

AU - Siracusano, Andrea

AU - Pontemezzo, Elena

AU - Cordella, Martina

AU - Facchiano, Francesco

AU - Pellegrini, Laura

AU - Mangoni, Antonella

AU - Tafani, Marco

AU - Crea, Filippo

AU - Germani, Antonia

AU - Russo, Matteo Antonio

AU - Limana, Federica

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