Mesenchymal stem cells ( MSC s) from scleroderma patients ( SSc ) preserve their immunomodulatory properties although senescent and normally induce T regulatory cells ( T reg s ) with a functional phenotype: implications for cellular‐based therapy

Summary S ystemic 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 ( MSC s), although senescent, might preserve specific immunomodulatory abilities during SSc . MSC s were obtained from 10 SSc patients and 10 healthy controls ( HC ). Senescence was evaluated by assessing cell cycle, β‐galactosidase (β‐ G al) 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 MSC s with peripheral blood mononuclear cells ( PBMCs ) and CD 4 + cells, in order to establish both their ability to block proliferation in mixed lymphocyte reaction and in regulatory T cells ( T regs ) induction. SSc – MSC showed an increase of senescence biomarkers. Eighty per cent of MSC s were in G 0– G 1 phase, without significant differences between SSc and HC . SSc – MSC s showed an increased positive β‐ G al staining and higher p21 transcript level compared to HC cells. After doxorubicin, β‐ G al staining increased significantly in SSc – MSC s. On the contrary, doxorubicin abolished p21 activation and elicited p53 induction both in SSc – and HC – MSC s. Interleukin ( IL )‐6 and transforming growth factor ( TGF )‐β‐related transcripts and their protein levels were significantly higher in SSc – MSC s. The latter maintained their immunosuppressive effect on lymphocyte proliferation and induced a functionally regulatory phenotype on T cells, increasing surface expression of CD 69 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.