title: Mesenchymal stem cells (MSCs) from scleroderma patients (SSc) preserve their immunomodulatory properties although senescent and normally induce T regulatory cells (Tregs) with a functional phenotype: implications for cellular-based therapy.
abstract: Systemic sclerosis (SSc) is a chronic disease, with early activation of the immune system. The aim of our work was to address how SSc-mesenchymal stem cells (MSCs), although senescent, might preserve specific immunomodulatory abilities during SSc. MSCs were obtained from 10 SSc patients and 10 healthy controls (HC). Senescence was evaluated by assessing cell cycle, β-galactosidase (β-Gal) activity, p21 and p53 expression; doxorubicin was used as acute senescence stimulus to evaluate their ability to react in stressed conditions. Immunomodulatory abilities were studied co-culturing MSCs with peripheral blood mononuclear cells (PBMCs) and CD4(+) cells, in order to establish both their ability to block proliferation in mixed lymphocyte reaction and in regulatory T cells (Tregs) induction. SSc-MSC showed an increase of senescence biomarkers. Eighty per cent of MSCs were in G0-G1 phase, without significant differences between SSc and HC. SSc-MSCs showed an increased positive β-Gal staining and higher p21 transcript level compared to HC cells. After doxorubicin, β-Gal staining increased significantly in SSc-MSCs. On the contrary, doxorubicin abolished p21 activation and elicited p53 induction both in SSc- and HC-MSCs. Interleukin (IL)-6 and transforming growth factor (TGF)-β-related transcripts and their protein levels were significantly higher in SSc-MSCs. The latter maintained their immunosuppressive effect on lymphocyte proliferation and induced a functionally regulatory phenotype on T cells, increasing surface expression of CD69 and restoring the regulatory function which is impaired in SSc. Increased activation of the IL-6 pathway observed in our cells might represent an adaptive mechanism to senescence, but preserving some specific cellular functions, including immunosuppression.
authors.affiliation: Department of Biothecnological and Applied Clinical Science, Rheumatology Unit, School of Medicine, University of L'Aquila, L'Aquila,. Italy paola.cipriani@cc.univaq.it
authors.forename: P
authors.initials: P
authors.lastname: Cipriani
authors.forename: P
authors.initials: P
authors.lastname: Di Benedetto
authors.forename: V
authors.initials: V
authors.lastname: Liakouli
authors.forename: B
authors.initials: B
authors.lastname: Del Papa
authors.forename: M
authors.initials: M
authors.lastname: Di Padova
authors.forename: M
authors.initials: M
authors.lastname: Di Ianni
authors.forename: A
authors.initials: A
authors.lastname: Marrelli
authors.forename: E
authors.initials: E
authors.lastname: Alesse
authors.forename: R
authors.initials: R
authors.lastname: Giacomelli
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D056747:Immunomodulation; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004317:Doxorubicin; D015850:Interleukin-6; D037181:Lectins, C-Type; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase; D000099192:CD69 Antigens
keywords: immunomodulatory abilities; mesenchymal stem cells; senescence; systemic sclerosis