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

11573/1710161 - 2024 - Recent advances in 3D cultures
Picchio, Vittorio; Gaetani, Roberto; Chimenti, Isotta - 01m Editorial/Introduzione in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. - - issn: 1422-0067 - wos: WOS:001211235300001 (0) - scopus: 2-s2.0-85191397203 (0)

11573/1703899 - 2024 - Early impairment of paracrine and phenotypic features in resident cardiac mesenchymal stromal cells after thoracic radiotherapy
Picchio, Vittorio; Gaetani, Roberto; Pagano, Francesca; Derevyanchuk, Yuriy; Pagliarosi, Olivia; Floris, Erica; Cozzolino, Claudia; Bernava, Giacomo; Bordin, Antonella; Rocha, Filipe; Pereira, Ana Rita Simões; Ministro, Augusto; Pinto, Ana Teresa; De Falco, Elena; Serino, Gianpaolo; Massai, Diana; Tamarat, Radia; Pesce, Maurizio; Santos, Susana Constantino Rosa; Messina, Elisa; Chimenti, Isotta - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. - - issn: 1422-0067 - wos: WOS:001182770200001 (0) - scopus: 2-s2.0-85187471454 (0)

11573/1652937 - 2023 - Modified risk tobacco products and cardiovascular repair. Still very smoky
Cozzolino, Claudia; Picchio, Vittorio; Floris, Erica; Pagano, Francesca; Saade, Wael; Peruzzi, Mariangela; Frati, Giacomo; Chimenti, Isotta - 01g Articolo di rassegna (Review)
rivista: CURRENT STEM CELL RESEARCH & THERAPY (HILVERSUM, NETHERLANDS, BENTHAM SCIENCE PUBL LTD, PO BOX 1673) pp. 440-444 - issn: 1574-888X - wos: WOS:001006706900002 (0) - scopus: 2-s2.0-85159766463 (0)

11573/1666345 - 2023 - Remote adipose tissue-derived stromal cells of patients with lung adenocarcinoma generate a similar malignant microenvironment of the lung stromal counterpart
De Falco, Elena; Bordin, Antonella; Menna, Cecilia; Dhori, Xhulio; Picchio, Vittorio; Cozzolino, Claudia; De Marinis, Elisabetta; Floris, Erica; Giorgiano, Noemi Maria; Rosa, Paolo; Rendina, Erino Angelo; Ibrahim, Mohsen; Calogero, Antonella - 01a Articolo in rivista
rivista: JOURNAL OF ONCOLOGY (Cairo: Hindawi Publishing Corporation) pp. 1-15 - issn: 1687-8450 - wos: WOS:000926493000001 (1) - scopus: 2-s2.0-85147575384 (1)

11573/1688694 - 2023 - A review of therapeutic strategies against cardiac fibrosis. From classical pharmacology to novel molecular, epigenetic, and biotechnological approaches
Floris, E.; Cozzolino, C.; Marconi, S.; Tonicello, F.; Picchio, V.; Pagano, F.; Chimenti, I. - 01g Articolo di rassegna (Review)
rivista: REVIEWS IN CARDIOVASCULAR MEDICINE (Singapore: IMR Press Mercer Island WA: MedReviews LLC) pp. - - issn: 1530-6550 - wos: WOS:001106635200002 (1) - scopus: 2-s2.0-85169510704 (1)

11573/1696990 - 2023 - The role of charme in the phenotype and function of resident cardiac mesenchymal stromal cells
Floris, E; Picchio, V; Cozzolino, C; Taliani, V; Buonaiuto, G; Nicoletti, C; Ballarino, M; Chimenti, I; Pagano, F - 01h Abstract in rivista
rivista: EUROPEAN HEART JOURNAL (-London : Harcourt -Oxford : Oxford University Press) pp. - - issn: 1522-9645 - wos: (0) - scopus: (0)

11573/1693330 - 2023 - Dark chocolate intake positively modulates gut permeability in elite football athletes. A randomized controlled study
Nocella, Cristina; Cavarretta, Elena; Fossati, Chiara; Pigozzi, Fabio; Quaranta, Federico; Peruzzi, Mariangela; De Grandis, Fabrizio; Costa, Vincenzo; Sharp, Carwyn; Manara, Massimo; Nigro, Antonia; Cammisotto, Vittoria; Castellani, Valentina; Picchio, Vittorio; Sciarretta, Sebastiano; Frati, Giacomo; Bartimoccia, Simona; D'amico, Alessandra; Carnevale, Roberto - 01a Articolo in rivista
rivista: NUTRIENTS (Basel, Switzerland: Molecular Diversity Preservation International (MDPI)) pp. - - issn: 2072-6643 - wos: WOS:001085250400001 (0) - scopus: 2-s2.0-85173887529 (0)

11573/1693464 - 2023 - Effect of traditional or heat-not-burn cigarette smoking on circulating miRNAs in healthy subjects
Picchio, Vittorio; Ferrero, Giulio; Cozzolino, Claudia; Pardini, Barbara; Floris, Erica; Tarallo, Sonia; Dhori, Xhulio; Nocella, Cristina; Loffredo, Lorenzo; Biondi-Zoccai, Giuseppe; Carnevale, Roberto; Frati, Giacomo; Chimenti, Isotta; Pagano, Francesca - 01a Articolo in rivista
rivista: EUROPEAN JOURNAL OF CLINICAL INVESTIGATION (Blackwell Science Limited:PO Box 88, Oxford OX2 0NE United Kingdom:011 44 1865 776868, 011 44 1865 206038, EMAIL:, INTERNET:, Fax: 011 44 1865 721205) pp. - - issn: 0014-2972 - wos: WOS:001123347400001 (1) - scopus: 2-s2.0-85178878885 (1)

11573/1652010 - 2022 - Human platelet lysate‐derived extracellular vesicles enhance angiogenesis through miR‐126
Bordin, Antonella; Chirivì, Maila; Pagano, Francesca; Milan, Marika; Iuliano, Marco; Scaccia, Eleonora; Fortunato, Orazio; Mangino, Giorgio; Dhori, Xhulio; De Marinis, Elisabetta; D'amico, Alessandra; Miglietta, Selenia; Picchio, Vittorio; Rizzi, Roberto; Romeo, Giovanna; Pulcinelli, Fabio; Chimenti, Isotta; Frati, Giacomo; De Falco, Elena - 01a Articolo in rivista
rivista: CELL PROLIFERATION ([Oxford]: [Blackwell Science].) pp. 1-19 - issn: 1365-2184 - wos: WOS:000840138700001 (12) - scopus: 2-s2.0-85135740211 (11)

11573/1615940 - 2022 - 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 - 01a Articolo in rivista
rivista: CELL DEATH DISCOVERY ([London]: Nature Publishing Group, 2015-) pp. - - issn: 2058-7716 - wos: WOS:000777182100004 (3) - scopus: 2-s2.0-85127502865 (3)

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
Pagano, Francesca; Picchio, Vittorio; Bordin, Antonella; Cavarretta, Elena; Nocella, Cristina; Cozzolino, Claudia; Floris, Erica; Angelini, Francesco; Sordano, Alessia; Peruzzi, Mariangela; Miraldi, Fabio; Biondi-Zoccai, Giuseppe; De Falco, Elena; Carnevale, Roberto; Sciarretta, Sebastiano; Frati, Giacomo; Chimenti, Isotta - 01a Articolo in rivista
rivista: JOURNAL OF PATHOLOGY (John Wiley & Sons Limited:1 Oldlands Way, Bognor Regis, P022 9SA United Kingdom:011 44 1243 779777, EMAIL:, INTERNET:, Fax: 011 44 1243 843232) pp. 136-148 - issn: 0022-3417 - wos: WOS:000832612100001 (5) - scopus: 2-s2.0-85135115453 (5)

11573/1613913 - 2022 - The dynamic facets of the cardiac stroma. Fom classical markers to omics and translational perspectives
Picchio, Vittorio; Bordin, Antonella; Floris, Erica; Cozzolino, Claudia; Dhori, Xhulio; Peruzzi, Mariangela; Frati, Giacomo; De Falco, Elena; Pagano, Francesca; Chimenti, Isotta - 01g Articolo di rassegna (Review)
rivista: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH () pp. 1172-1187 - issn: 1943-8141 - wos: WOS:000803985100028 (4) - scopus: (0)

11573/1656264 - 2022 - Multicellular 3D models for the study of cardiac fibrosis
Picchio, Vittorio; Floris, Erica; Yuriy, Derevyanchuk; Cozzolino, Claudia; Messina, Elisa; Francesca, Pagano; Chimenti, I; Gaetani, Roberto - 01g Articolo di rassegna (Review)
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. 1-14 - issn: 1422-0067 - wos: WOS:000867724000001 (7) - scopus: 2-s2.0-85139906081 (8)

11573/1605118 - 2022 - Cardiac stromal cells on stage. From dull filler to specialized actors
Picchio, Vittorio; Pagano, Francesca; Chimenti, Isotta - 01g Articolo di rassegna (Review)
rivista: BIOCELL (Center Region Invest Cientif Tecn:Casilla de Correo 131, 5500 Mendoza Argentina:011 54 61 205020, EMAIL:, Fax: 011 54 61 380232) pp. - - issn: 0327-9545 - wos: WOS:000762216300001 (1) - scopus: 2-s2.0-85126588830 (1)

11573/1667523 - 2022 - Sex-related differences in oxidative, platelet, and vascular function in chronic users of heat-not-burn vs. traditional combustion cigarettes
Schirone, Leonardo; Loffredo, Lorenzo; Carnevale, Roberto; Battaglia, Simona; Marti, Roberta; 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 - 01a Articolo in rivista
rivista: ANTIOXIDANTS (Basel: MDPI) pp. - - issn: 2076-3921 - wos: WOS:000831491800001 (1) - scopus: 2-s2.0-85132429244 (1)

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
Belviso, Immacolata; Angelini, Francesco; Di Meglio, Franca; Picchio, Vittorio; Sacco, Anna Maria; Nocella, Cristina; Romano, Veronica; Nurzynska, Daria; Frati, Giacomo; Maiello, Ciro; Messina, Elisa; Montagnani, Stefania; Pagano, Francesca; Castaldo, Clotilde; Chimenti, Isotta - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. 1-18 - issn: 1422-0067 - wos: WOS:000589005400001 (19) - scopus: 2-s2.0-85094593088 (19)

11573/1472641 - 2020 - Inhibition of miR-155 attenuates detrimental vascular effects of tobacco cigarette smoking
Frati, Giacomo; Forte, Maurizio; Di Nonno, Flavio; Bordin, Antonella; Chimenti, Isotta; Picchio, Vittorio; Cavarretta, Elena; Stanzione, Rosita; Bianchi, Franca; Carnevale, Roberto; Nocella, Cristina; Schiavon, Sonia; Vecchio, Daniele; Marchitti, Simona; De Falco, Elena; Rubattu, Speranza; Paneni, Francesco; Biondi-Zoccai, Giuseppe; Versaci, Francesco; Volpe, Massimo; Pagano, Francesca; Sciarretta, Sebastiano - 01a Articolo in rivista
rivista: JOURNAL OF THE AMERICAN HEART ASSOCIATION. CARDIOVASCULAR AND CEREBROVASCULAR DISEASE (Oxford: Wiley-Blackwell) pp. 1-18 - issn: 2047-9980 - wos: WOS:000599866300003 (10) - scopus: 2-s2.0-85098476086 (10)

11573/1358169 - 2020 - The Noncoding side of cardiac differentiation and regeneration
Pagano, Francesca; Calicchio, Alessandro; Picchio, Vittorio; Ballarino, Monica - 01g Articolo di rassegna (Review)
rivista: CURRENT STEM CELL RESEARCH & THERAPY (HILVERSUM, NETHERLANDS, BENTHAM SCIENCE PUBL LTD, PO BOX 1673) pp. 723-738 - issn: 1574-888X - wos: WOS:000590335800007 (6) - scopus: 2-s2.0-85090917343 (5)

11573/1442349 - 2020 - Building an artificial cardiac microenvironment. A focus on the extracellular matrix
Pagliarosi, O.; Picchio, V.; Chimenti, I.; Messina, E.; Gaetani, R. - 01g Articolo di rassegna (Review)
rivista: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (Lausanne : Frontiers Media S.A., 2013-) pp. - - issn: 2296-634X - wos: WOS:000573948900001 (18) - scopus: 2-s2.0-85091252277 (20)

11573/1472636 - 2020 - Innovative in vitro models for the study of lung diseases
Picchio, Vittorio; Cammisotto, Vittoria; Pagano, Francesca; Carnevale, Roberto; Chimenti, Isotta - 02a Capitolo o Articolo
libro: Cell Interaction - Regulation of Immune Responses, Disease Development and Management Strategies - (978-1-83968-417-3)

11573/1336408 - 2019 - On the road to regeneration. “Tools” and “Routes” towards efficient cardiac cell therapy for ischemic cardiomyopathy
Pagano, F.; Picchio, V.; Chimenti, I.; Sordano, A.; De Falco, E.; Peruzzi, M.; Miraldi, F.; Cavarretta, E.; Zoccai, G. B.; Sciarretta, S.; Frati, G.; Marullo, A. G. M. - 01g Articolo di rassegna (Review)
rivista: CURRENT CARDIOLOGY REPORTS (Philadelphia, PA : Current Science, c1999-) pp. - - issn: 1523-3782 - wos: WOS:000494454900004 (12) - scopus: 2-s2.0-85074293338 (12)

11573/1173053 - 2018 - The biological mechanisms of action of cardiac progenitor cell therapy
Pagano, F; Picchio, V; Angelini, F; Iaccarino, A; Peruzzi, M; Cavarretta, E; Biondi-Zoccai, G; Sciarretta, S; De Falco, E; Chimenti, I; Frati, G - 01g Articolo di rassegna (Review)
rivista: CURRENT CARDIOLOGY REPORTS (Philadelphia, PA : Current Science, c1999-) pp. - - issn: 1523-3782 - wos: WOS:000441673500002 (17) - scopus: 2-s2.0-85051622792 (17)

11573/1222231 - 2018 - CPCs and ECM. A good mix for cardiac regeneration
Picchio, Vittorio; Di Raimo, Tania; Angelini, Francesco - 01g Articolo di rassegna (Review)
rivista: MED ONE (London : Qingres Limited) pp. - - issn: 2397-9119 - wos: (0) - scopus: (0)

11573/1016476 - 2017 - Getting old through the blood. Circulating molecules in aging and senescence of cardiovascular regenerative cells
Angelini, Francesco; Pagano, Francesca; Bordin, Antonella; Picchio, Vittorio; De Falco, Elena; Chimenti, Isotta - 01g Articolo di rassegna (Review)
rivista: FRONTIERS IN CARDIOVASCULAR MEDICINE (Lausanne: Frontiers Media S.A., 2014-) pp. - - issn: 2297-055X - wos: WOS:000426119600001 (16) - scopus: 2-s2.0-85060999849 (16)

11573/952552 - 2017 - Human lung spheroids as In vitro niches of lung progenitor cells with distinctive paracrine and plasticity properties
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 - 01a Articolo in rivista
rivista: STEM CELLS TRANSLATIONAL MEDICINE (New York: AlphaMed Press) pp. 767-777 - issn: 2157-6564 - wos: WOS:000398204600009 (22) - scopus: 2-s2.0-85017537015 (26)

11573/1000116 - 2017 - Normal versus pathological cardiac fibroblast-derived extracellular matrix differentially modulates cardiosphere-derived cell paracrine properties and commitment
Pagano, Francesca; Angelini, Francesco; Castaldo, Clotilde; Picchio, Vittorio; Messina, Elisa; Sciarretta, Sebastiano; Maiello, Ciro; Biondi Zoccai, Giuseppe; Frati, Giacomo; Meglio, Franca Di; Nurzynska, Daria; Chimenti, Isotta - 01a Articolo in rivista
rivista: STEM CELLS INTERNATIONAL (SAGE-Hindawi) pp. 1-9 - issn: 1687-9678 - wos: WOS:000404220500001 (20) - scopus: 2-s2.0-85027055380 (19)

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