VITTORIO PICCHIO

Dottore di ricerca

ciclo: XXXIII


supervisore: Isotta Chimenti
relatore: Isotta Chimenti

Titolo della tesi: Effects of autophagy modulation on survival and phenotype of primitive cardiac stromal cells

BACKGROUND. Ischaemic heart disease leads to maladaptive remodelling and progressive heart failure (HF). Despite advancements in medical treatments, new therapies against HF progression are needed in order to reduce its morbidity and mortality burden. The natural history of the disease after myocardial infarction includes cardiomyocyte death, followed by scar formation operated by collagen-depositing interstitial cells. Cardiac interstitial and stromal cells embrace a variety of different phenotypes that play a primary role in cardiac homeostasis, injury, and repair mainly through paracrine action. Autophagy is a degradation process of damaged intracellular components that can be either cytoprotective or trigger cell death. Autophagy can sustain cardiomyocyte survival during ischemia, but its role in cardiac stromal cells (CSCs) biology still needs elucidation. AIM. This thesis project aimed at investigating whether autophagy enhancement may exert a protective and anti-fibrotic effect on a population of murine CSCs under conditions of metabolic stress. METHODS AND DESIGN. CSCs were isolated from atrial explants of four-week old C57BL/6J mice, and selected through spontaneous spheroid culture (cardiospheres) for a primitive phenotype. We have optimized pharmacological and genetic tools for autophagy modulation in this model: trehalose (disaccharide known to activate autophagy) or TAT-Beclin (cell permeable autophagy-inducer peptide) treatments; adeno-vector transduction of the autophagy promoter ATG7 (Ad-ATG7); transfection of a small interfering RNA against ATG7 (siATG7). CSCs have been subjected to acute nutrient deprivation for 32h, or acute and chronic hyperglycemia (HG; 50mM glucose). RESULTS. First, we have investigated in vitro the effects of autophagy modulation on CSC viability and phenotype after nutrient deprivation. Results have shown significantly higher CSC viability after stress associated with autophagy activation (by Ad-ATG7 or trehalose), and, conversely, increased cell death after autophagy inhibition through siATG7. Moreover, pre-treatment with trehalose significantly preserved the Sca1+/CD90+/DDR2- fraction of CSCs with cardiogenic potential, while reducing the Sca1-/CD90-/DDR2+ fibroblastoid fraction after stress. Next we tested whether intermediate autophagy activation (by Ad-ATG7 or TAT-beclin at day 3) preserves CSC cardiogenic immunophenotype and paracrine properties when exposed to 7 days of HG. We detected a significant reduction of the autophagic flux after HG, associated to reduction of the Sca1+ cardiogenic fraction, but this phenotypic shift could not be opposed by intermediate autophagy modulation. Nonetheless, screening of conditioned media after 7 days of HG revealed a consistent reduction in the secretion of several pro-inflammatory cytokines and chemokines in Ad-ATG7-transduced CSCs. We then investigated whether previous exposure to HG could impair CSC resistance to stress, and whether autophagy modulation may be protective. Results showed that exposure to HG significantly reduced CSC viability after nutrient deprivation, while autophagy activation during stress could significantly preserve subsequent CSC survival. CONCLUSIONS. Overall, results of this thesis project suggest that autophagy enhancement may represent a useful tool: 1) to oppose stromal pro-fibrotic shift during HF progression and dysmetabolic conditions; 2) to possibly increase the efficacy of cardiac cell therapy with endogenous primitive populations by improving cell survival and enrichment in beneficial cardiogenic cells.

Produzione scientifica

  • 11573/1667523 - 2022 - Sex-related differences in oxidative, platelet, and vascular function in chronic users of heat-not-burn vs. traditional combustion cigarettes (01a Articolo in rivista)
    SCHIRONE, LEONARDO; LOFFREDO, LORENZO; CARNEVALE, ROBERTO; PIZZOLO, STEFANO; BARTIMOCCIA, SIMONA; NOCELLA, CRISTINA; CAMMISOTTO, VITTORIA; SAADE, WAEL; TANZILLI, ALESSANDRA; SCIARRETTA, SEBASTIANO; CHIMENTI, ISOTTA; DE FALCO, ELENA; CAVARRETTA, ELENA; PICCHIO, VITTORIO; PERUZZI, MARIANGELA; MARULLO, ANTONINO; MIRALDI, FABIO; VIOLI, FRANCESCO; MORELLI, ANDREA; BIONDI ZOCCAI, GIUSEPPE; FRATI, GIACOMO
  • 11573/952552 - 2017 - Human lung spheroids as In vitro niches of lung progenitor cells with distinctive paracrine and plasticity properties (01a Articolo in rivista)
    CHIMENTI, ISOTTA; PAGANO, FRANCESCA; ANGELINI, FRANCESCO; SICILIANO, CAMILLA; MANGINO, GIORGIO; PICCHIO, VITTORIO; DE FALCO, ELENA; PERUZZI, MARIANGELA; CARNEVALE, ROBERTO; IBRAHIM, MOHSEN; BIONDI ZOCCAI, GIUSEPPE; MESSINA, ELISA; FRATI, GIACOMO
  • 11573/1016476 - 2017 - Getting old through the blood. Circulating molecules in aging and senescence of cardiovascular regenerative cells (01g Articolo di rassegna (Review))
    ANGELINI, FRANCESCO; PAGANO, FRANCESCA; BORDIN, ANTONELLA; PICCHIO, VITTORIO; DE FALCO, ELENA; CHIMENTI, ISOTTA
  • 11573/1173053 - 2018 - The biological mechanisms of action of cardiac progenitor cell therapy (01g Articolo di rassegna (Review))
    PAGANO, FRANCESCA; PICCHIO, VITTORIO; ANGELINI, FRANCESCO; IACCARINO, ALESSANDRA; PERUZZI, MARIANGELA; CAVARRETTA, ELENA; BIONDI ZOCCAI, GIUSEPPE; SCIARRETTA, SEBASTIANO; DE FALCO, ELENA; CHIMENTI, ISOTTA; FRATI, GIACOMO
  • 11573/1000116 - 2017 - Normal versus pathological cardiac fibroblast-derived extracellular matrix differentially modulates cardiosphere-derived cell paracrine properties and commitment (01a Articolo in rivista)
    PAGANO, FRANCESCA; ANGELINI, FRANCESCO; CASTALDO, CLOTILDE; PICCHIO, VITTORIO; MESSINA, ELISA; SCIARRETTA, SEBASTIANO; BIONDI ZOCCAI, GIUSEPPE; FRATI, GIACOMO; CHIMENTI, ISOTTA
  • 11573/1222231 - 2018 - CPCs and ECM. A good mix for cardiac regeneration (01g Articolo di rassegna (Review))
    PICCHIO, VITTORIO; DI RAIMO, TANIA; ANGELINI, FRANCESCO
  • 11573/1336408 - 2019 - On the road to regeneration. “Tools” and “Routes” towards efficient cardiac cell therapy for ischemic cardiomyopathy (01g Articolo di rassegna (Review))
    PAGANO, FRANCESCA; PICCHIO, VITTORIO; CHIMENTI, ISOTTA; DE FALCO, ELENA; PERUZZI, MARIANGELA; MIRALDI, FABIO; CAVARRETTA, ELENA; BIONDI ZOCCAI, GIUSEPPE; SCIARRETTA, SEBASTIANO; FRATI, GIACOMO; MARULLO, ANTONINO
  • 11573/1688694 - 2023 - A review of therapeutic strategies against cardiac fibrosis. From classical pharmacology to novel molecular, epigenetic, and biotechnological approaches (01g Articolo di rassegna (Review))
    FLORIS, ERICA; COZZOLINO, CLAUDIA; PICCHIO, VITTORIO; CHIMENTI, ISOTTA
  • 11573/1358169 - 2020 - The Noncoding side of cardiac differentiation and regeneration (01g Articolo di rassegna (Review))
    PAGANO, FRANCESCA; CALICCHIO, ALESSANDRO; PICCHIO, VITTORIO; BALLARINO, MONICA
  • 11573/1442349 - 2020 - Building an artificial cardiac microenvironment. A focus on the extracellular matrix (01g Articolo di rassegna (Review))
    PAGLIAROSI, OLIVIA; PICCHIO, VITTORIO; CHIMENTI, ISOTTA; MESSINA, ELISA; GAETANI, ROBERTO
  • 11573/1461918 - 2020 - The microenvironment of decellularized extracellular matrix from heart failure myocardium alters the balance between angiogenic and fibrotic signals from stromal primitive cells (01a Articolo in rivista)
    ANGELINI, FRANCESCO; PICCHIO, VITTORIO; NOCELLA, CRISTINA; FRATI, GIACOMO; MESSINA, ELISA; CASTALDO, CLOTILDE; CHIMENTI, ISOTTA
  • 11573/1472641 - 2020 - Inhibition of miR-155 attenuates detrimental vascular effects of tobacco cigarette smoking (01a Articolo in rivista)
    FRATI, GIACOMO; BORDIN, ANTONELLA; CHIMENTI, ISOTTA; PICCHIO, VITTORIO; CAVARRETTA, ELENA; STANZIONE, ROSITA; CARNEVALE, ROBERTO; NOCELLA, CRISTINA; SCHIAVON, SONIA; VECCHIO, DANIELE; MARCHITTI, SIMONA; DE FALCO, ELENA; RUBATTU, SPERANZA DONATELLA; PANENI, FRANCESCO; BIONDI ZOCCAI, GIUSEPPE; VOLPE, MASSIMO; SCIARRETTA, SEBASTIANO
  • 11573/1605118 - 2022 - Cardiac stromal cells on stage. From dull filler to specialized actors (01g Articolo di rassegna (Review))
    PICCHIO, VITTORIO; CHIMENTI, ISOTTA
  • 11573/1615940 - 2022 - The impact of autophagy modulation on phenotype and survival of cardiac stromal cells under metabolic stress (01a Articolo in rivista)
    CHIMENTI, ISOTTA; PICCHIO, VITTORIO; SCHIRONE, LEONARDO; SCHIAVON, SONIA; D'AMBROSIO, LUCA; RUBATTU, SPERANZA DONATELLA; PERUZZI, MARIANGELA; GRECO, ERNESTO; CALOGERO, ANTONELLA; DE FALCO, ELENA; FRATI, GIACOMO; SCIARRETTA, SEBASTIANO
  • 11573/1613913 - 2022 - The dynamic facets of the cardiac stroma. Fom classical markers to omics and translational perspectives (01g Articolo di rassegna (Review))
    PICCHIO, VITTORIO; BORDIN, ANTONELLA; FLORIS, ERICA; COZZOLINO, CLAUDIA; PERUZZI, MARIANGELA; FRATI, GIACOMO; DE FALCO, ELENA; CHIMENTI, ISOTTA
  • 11573/1652010 - 2022 - Human platelet lysate‐derived extracellular vesicles enhance angiogenesis through miR‐126 (01a Articolo in rivista)
    BORDIN, ANTONELLA; CHIRIVI', MAILA; PAGANO, FRANCESCA; MILAN, MARIKA; IULIANO, MARCO; MANGINO, GIORGIO; DE MARINIS, ELISABETTA; D'AMICO, ALESSANDRA; MIGLIETTA, SELENIA; PICCHIO, VITTORIO; RIZZI, ROBERTO; ROMEO, GIOVANNA; PULCINELLI, FABIO MARIA; CHIMENTI, ISOTTA; FRATI, GIACOMO; DE FALCO, ELENA
  • 11573/1656264 - 2022 - Multicellular 3D models for the study of cardiac fibrosis (01g Articolo di rassegna (Review))
    PICCHIO, VITTORIO; FLORIS, ERICA; COZZOLINO, CLAUDIA; MESSINA, ELISA; CHIMENTI, ISOTTA; GAETANI, ROBERTO
  • 11573/1649645 - 2022 - Progressive stages of dysmetabolism are associated with impaired biological features of human cardiac stromal cells mediated by the oxidative state and autophagy (01a Articolo in rivista)
    PICCHIO, VITTORIO; BORDIN, ANTONELLA; CAVARRETTA, ELENA; NOCELLA, CRISTINA; COZZOLINO, CLAUDIA; FLORIS, ERICA; ANGELINI, FRANCESCO; PERUZZI, MARIANGELA; MIRALDI, FABIO; BIONDI ZOCCAI, GIUSEPPE; DE FALCO, ELENA; CARNEVALE, ROBERTO; SCIARRETTA, SEBASTIANO; FRATI, GIACOMO; CHIMENTI, ISOTTA
  • 11573/1666345 - 2023 - Remote adipose tissue-derived stromal cells of patients with lung adenocarcinoma generate a similar malignant microenvironment of the lung stromal counterpart (01a Articolo in rivista)
    DE FALCO, ELENA; BORDIN, ANTONELLA; MENNA, CECILIA; PICCHIO, VITTORIO; COZZOLINO, CLAUDIA; DE MARINIS, ELISABETTA; FLORIS, ERICA; GIORGIANO, NOEMI MARIA; ROSA, PAOLO; RENDINA, ERINO ANGELO; IBRAHIM, MOHSEN; CALOGERO, ANTONELLA
  • 11573/1652937 - 2023 - Modified risk tobacco products and cardiovascular repair. Still very smoky (01g Articolo di rassegna (Review))
    COZZOLINO, CLAUDIA; PICCHIO, VITTORIO; FLORIS, ERICA; SAADE, WAEL; PERUZZI, MARIANGELA; FRATI, GIACOMO; CHIMENTI, ISOTTA
  • 11573/1472636 - 2020 - Innovative in vitro models for the study of lung diseases (02a Capitolo o Articolo)
    PICCHIO, VITTORIO; CAMMISOTTO, VITTORIA; CARNEVALE, ROBERTO; CHIMENTI, ISOTTA

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