title: Persistent DNA damage-induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells.
abstract: Human mesenchymal stem cells (hMSCs) are adult multipotent stem cells located in various tissues, including the bone marrow. In contrast to terminally differentiated somatic cells, adult stem cells must persist and function throughout life to ensure tissue homeostasis and repair. For this reason, they must be equipped with DNA damage responses able to maintain genomic integrity while ensuring their lifelong persistence. Evaluation of hMSC response to genotoxic insults is of great interest considering both their therapeutic potential and their physiological functions. This study aimed to investigate the response of human bone marrow MSCs to the genotoxic agent Actinomycin D (ActD), a well-known anti-tumour drug. We report that hMSCs react by undergoing premature senescence driven by a persistent DNA damage response activation, as hallmarked by inhibition of DNA synthesis, p21 and p16 protein expression, marked Senescent Associated β-galactosidase activity and enlarged γH2AX foci co-localizing with 53BP1 protein. Senescent hMSCs overexpress several senescence-associated secretory phenotype (SASP) genes and promote motility of lung tumour and osteosarcoma cell lines in vitro. Our findings disclose a multifaceted consequence of ActD treatment on hMSCs that on the one hand helps to preserve this stem cell pool and prevents damaged cells from undergoing neoplastic transformation, and on the other hand alters their functional effects on the surrounding tissue microenvironment in a way that might worsen their tumour-promoting behaviour.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Minieri
authors.forename: Silvia
authors.initials: S
authors.lastname: Saviozzi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Gambarotta
authors.forename: Marco
authors.initials: M
authors.lastname: Lo Iacono
authors.forename: Lisa
authors.initials: L
authors.lastname: Accomasso
authors.forename: Elisa
authors.initials: E
authors.lastname: Cibrario Rocchietti
authors.forename: Clara
authors.initials: C
authors.lastname: Gallina
authors.forename: Valentina
authors.initials: V
authors.lastname: Turinetto
authors.forename: Claudia
authors.initials: C
authors.lastname: Giachino
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D003609:Dactinomycin / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D018613:Microscopy, Confocal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071857:Tumor Suppressor p53-Binding Protein 1; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; D006657:Histones; D015850:Interleukin-6; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D003609:Dactinomycin; D004247:DNA; D001616:beta-Galactosidase
keywords: DNA damage; actinomycin D; mesenchymal stem cell; senescence-associated secretory phenotype; stress-induced premature senescence