Cardiac stromal cells (CSCs) embrace multiple phenotypes and are a contributory factor in tissue homeostasis and repair. They can be utilized as therapeutic mediators against cardiac fibrosis and remodeling, but their survival and cardioprotective properties can be decreased by microenvironmental cues. We evaluated the impact of autophagy modulation by different pharmacological/genetic approaches on the viability and phenotype of murine CSCs, which had been subjected to nutrient deprivation or hyperglycemia, in order to mimic relevant stress conditions and risk factors of cardiovascular diseases. Our results show that autophagy is activated in CSCs by nutrient deprivation, and that autophagy induction by trehalose or autophagy-related protein 7 (ATG7)-overexpression can significantly preserve CSC viability. Furthermore, autophagy induction is associated with a higher proportion of primitive, non-activated stem cell antigen 1 (Sca1) positive cells, and with a reduced fibrotic fraction (positive for the discoidin domain-containing receptor 2, DDR2) in the CSC pool after nutrient deprivation. Hyperglycemia, on the other hand, is associated with reduced autophagic flux in CSCs, and with a significant reduction in primitive Sca1+ cells. Autophagy induction by adenoviral-mediated ATG7 overexpression maintains a cardioprotective, anti-inflammatory and pro-angiogenic paracrine profile of CSCs exposed to hyperglycemia for 1 week. Finally, autophagy induction by ATG7 overexpression during hyperglycemia can significantly preserve cell viability in CSCs, which were subsequently exposed to nutrient deprivation, reducing hyperglycemia-induced impairment of cell resistance to stress. In conclusion, our results show that autophagy stimulation preserves CSC viability and function in response to metabolic stressors, suggesting that it may boost the beneficial functions of CSCs in cardiac regeneration.

The impact of autophagy modulation on phenotype and survival of cardiac stromal cells under metabolic stress / Chimenti, Isotta; Picchio, Vittorio; Pagano, Francesca; Schirone, Leonardo; Schiavon, Sonia; D'Ambrosio, Luca; Valenti, Valentina; Forte, Maurizio; di Nonno, Flavio; Rubattu, Speranza Donatella; Peruzzi, Mariangela; Versaci, Francesco; Greco, Ernesto; Calogero, Antonella; DE FALCO, Elena; Frati, Giacomo; Sciarretta, Sebastiano. - In: CELL DEATH DISCOVERY. - ISSN 2058-7716. - 8:1(2022). [10.1038/s41420-022-00924-7]

The impact of autophagy modulation on phenotype and survival of cardiac stromal cells under metabolic stress

Isotta Chimenti
;
Vittorio Picchio;Leonardo Schirone;Sonia Schiavon;Luca D’Ambrosio;Valentina Valenti;Speranza Rubattu;Mariangela Peruzzi;Ernesto Greco;Antonella Calogero;Elena De Falco;Giacomo Frati;Sebastiano Sciarretta
2022

Abstract

Cardiac stromal cells (CSCs) embrace multiple phenotypes and are a contributory factor in tissue homeostasis and repair. They can be utilized as therapeutic mediators against cardiac fibrosis and remodeling, but their survival and cardioprotective properties can be decreased by microenvironmental cues. We evaluated the impact of autophagy modulation by different pharmacological/genetic approaches on the viability and phenotype of murine CSCs, which had been subjected to nutrient deprivation or hyperglycemia, in order to mimic relevant stress conditions and risk factors of cardiovascular diseases. Our results show that autophagy is activated in CSCs by nutrient deprivation, and that autophagy induction by trehalose or autophagy-related protein 7 (ATG7)-overexpression can significantly preserve CSC viability. Furthermore, autophagy induction is associated with a higher proportion of primitive, non-activated stem cell antigen 1 (Sca1) positive cells, and with a reduced fibrotic fraction (positive for the discoidin domain-containing receptor 2, DDR2) in the CSC pool after nutrient deprivation. Hyperglycemia, on the other hand, is associated with reduced autophagic flux in CSCs, and with a significant reduction in primitive Sca1+ cells. Autophagy induction by adenoviral-mediated ATG7 overexpression maintains a cardioprotective, anti-inflammatory and pro-angiogenic paracrine profile of CSCs exposed to hyperglycemia for 1 week. Finally, autophagy induction by ATG7 overexpression during hyperglycemia can significantly preserve cell viability in CSCs, which were subsequently exposed to nutrient deprivation, reducing hyperglycemia-induced impairment of cell resistance to stress. In conclusion, our results show that autophagy stimulation preserves CSC viability and function in response to metabolic stressors, suggesting that it may boost the beneficial functions of CSCs in cardiac regeneration.
2022
cardiac stromal cells; autophagy; trehalose; hyperglycemia; paracrine mechanisms; cardiac repair; cardiac fibrosis.
01 Pubblicazione su rivista::01a Articolo in rivista
The impact of autophagy modulation on phenotype and survival of cardiac stromal cells under metabolic stress / Chimenti, Isotta; Picchio, Vittorio; Pagano, Francesca; Schirone, Leonardo; Schiavon, Sonia; D'Ambrosio, Luca; Valenti, Valentina; Forte, Maurizio; di Nonno, Flavio; Rubattu, Speranza Donatella; Peruzzi, Mariangela; Versaci, Francesco; Greco, Ernesto; Calogero, Antonella; DE FALCO, Elena; Frati, Giacomo; Sciarretta, Sebastiano. - In: CELL DEATH DISCOVERY. - ISSN 2058-7716. - 8:1(2022). [10.1038/s41420-022-00924-7]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1615940
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