Fibrosis Development in HOCI-Induced Systemic Sclerosis: A Multistage Process Hampered by Mesenchymal Stem Cells

Objectives: Skin fibrosis is the hallmark of systemic sclerosis (SSc) a rare intractable disease with unmet medical need. We previously reported the anti-fibrotic potential of mesenchymal stem cells (MSCs) in a murine model of SSc. This model, based on daily intra-dermal injections of hypochlorite (HOCI) during 6 weeks, is an inducible model of the disease. Herein, we aimed at characterizing the development of skin fibrosis in HOCI-induced SSc (HOCl-SSc), and evaluating the impact of MSC infusion during the fibrogenesis process. Methods: After HOCI-SSc induction in BALB/c mice, clinical, histological and biological parameters were measured after 3 weeks (d21) and 6 weeks (d42) of HOCI challenge, and 3 weeks after HOCI discontinuation (d63). Treated-mice received infusions of 2.5 x 10(5) MSCs 3 weeks before sacrifice (d0, d21, d42). Results: HOCI injections induced a two-step process of fi brosis development: first, an 'early inflammatory phase', characterized at d21 by highly proliferative in filtrates of myofibroblasts, T-lymphocytes and macrophages. Second, a phase of 'established matrix fibrosis', characterized at d42 by less inflammation, but strong collagen deposition and followed by a third phase of 'spontaneous tissue remodeling ' after HOCI discontinuation. This phase was characterized by partial fi brosis receding, due to enhanced MMP1/TIMP1 balance. MSC treatment reduced skin thickness in the three phases of fi brogenesis, exerting more specialized mechanisms: immunosuppression, abrogation of myofibroblast activation, or further enhancing tissue remodeling, depending on the injection time-point. Conclusion: HOCI-SSc mimics three fibrotic phenotypes of scleroderma, all positively impacted by MSC therapy, demonstrating the great plasticity of MSC, a promising cure for SSc.