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, b-galactosidase (b-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 b-Gal staining and higher p21 transcript. level compared to HC cells. After doxorubicin, b-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)-b-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.