title: SIRT1 inhibition affects angiogenic properties of human MSCs.
abstract: Human mesenchymal stem cells (hMSCs) are attractive for clinical and experimental purposes due to their capability of self-renewal and of differentiating into several cell types. Autologous hMSCs transplantation has been proven to induce therapeutic angiogenesis in ischemic disorders. However, the molecular mechanisms underlying these effects remain unclear. A recent report has connected MSCs multipotency to sirtuin families, showing that SIRT1 can regulate MSCs function. Furthermore, SIRT1 is a critical modulator of endothelial angiogenic functions. Here, we described the generation of an immortalized human mesenchymal bone marrow-derived cell line and we investigated the angiogenic phenotype of our cellular model by inhibiting SIRT1 by both the genetic and pharmacological level. We first assessed the expression of SIRT1 in hMSCs under basal and hypoxic conditions at both RNA and protein level. Inhibition of SIRT1 by sirtinol, a cell-permeable inhibitor, or by specific sh-RNA resulted in an increase of premature-senescence phenotype, a reduction of proliferation rate with increased apoptosis. Furthermore, we observed a consistent reduction of tubule-like formation and migration and we found that SIRT1 inhibition reduced the hypoxia induced accumulation of HIF-1α protein and its transcriptional activity in hMSCs. Our findings identify SIRT1 as regulator of hypoxia-induced response in hMSCs and may contribute to the development of new therapeutic strategies to improve regenerative properties of mesenchymal stem cells in ischemic disorders through SIRT1 modulation.
authors.forename: Chiara
authors.initials: C
authors.lastname: Botti
authors.affiliation: Istituto Nazionale Tumori, Struttura Complessa Oncologia Medica Melanoma Immunoterapia Oncologica e Terapia Innovativa, Via Mariano Semmola 80131 Napoli, Italy. chiara_botti@yahoo.it
authors.forename: Botti
authors.initials: B
authors.lastname: Chiara
authors.forename: Ilaria
authors.initials: I
authors.lastname: Caiafa
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Napoli, Via L. De Crecchio 7, 80138 Napoli, Italy.
authors.forename: Caiafa
authors.initials: C
authors.lastname: Ilaria
authors.forename: Antonietta
authors.initials: A
authors.lastname: Coppola
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Napoli, Via L. De Crecchio 7, 80138 Napoli, Italy.
authors.forename: Coppola
authors.initials: C
authors.lastname: Antonietta
authors.forename: Francesca
authors.initials: F
authors.lastname: Cuomo
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Napoli, Via L. De Crecchio 7, 80138 Napoli, Italy.
authors.forename: Cuomo
authors.initials: C
authors.lastname: Francesca
authors.forename: Marco
authors.initials: M
authors.lastname: Miceli
authors.affiliation: Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, Via P. Castellino 111, 80131 Napoli, Italy.
authors.forename: Miceli
authors.initials: M
authors.lastname: Marco
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Napoli, Via L. De Crecchio 7, 80138 Napoli, Italy ; Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, Via P. Castellino 111, 80131 Napoli, Italy.
authors.forename: Altucci
authors.initials: A
authors.lastname: Lucia
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Napoli, Via L. De Crecchio 7, 80138 Napoli, Italy ; Istituto Nazionale Tumori, Struttura Complessa Oncologia Medica Melanoma Immunoterapia Oncologica e Terapia Innovativa, Via Mariano Semmola, 80131 Napoli, Italy.
authors.forename: Gilda
authors.initials: G
authors.lastname: Cobellis
authors.forename: Cobellis
authors.initials: C
authors.lastname: Gilda
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D002468:Cell Physiological Phenomena / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D000860:Hypoxia; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D009284:Naphthols / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D009284:Naphthols; C439060:sirtinol; C447939:SIRT1 protein, human; D056564:Sirtuin 1