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

Alexandre T J Maria,Alexandre T J Maria,Alexandre T J Maria,Christian Jorgensen,Marie Maumus,Marie Maumus,Pauline Rozier,Pauline Rozier,Pauline Rozier,Philippe Guilpain,Philippe Guilpain,Philippe Guilpain,Karine Toupet,Karine Toupet,Alain Le Quellec,Danièle Noël,Danièle Noël,Danièle Noël,Marie-Catherine Vozenin

doi:10.3389/fimmu.2018.02571

Abstract

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 (HOCl) during 6 weeks, is an inducible model of the disease. Herein, we aimed at characterizing the development of skin fibrosis in HOCl-induced SSc (HOCl-SSc), and evaluating the impact of MSC infusion during the fibrogenesis process.Methods: After HOCl-SSc induction in BALB/c mice, clinical, histological and biological parameters were measured after 3 weeks (d21) and 6 weeks (d42) of HOCl challenge, and 3 weeks after HOCl discontinuation (d63). Treated-mice received infusions of 2.5 × 105 MSCs 3 weeks before sacrifice (d0, d21, d42).Results: HOCl injections induced a two-step process of fibrosis development: first, an ‘early inflammatory phase’, characterized at d21 by highly proliferative infiltrates 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 HOCl discontinuation. This phase was characterized by partial fibrosis receding, due to enhanced MMP1/TIMP1 balance. MSC treatment reduced skin thickness in the three phases of fibrogenesis, exerting more specialized mechanisms: immunosuppression, abrogation of myofibroblast activation, or further enhancing tissue remodeling, depending on the injection time-point.Conclusion: HOCl-SSc mimics three fibrotic phenotypes of scleroderma, all positively impacted by MSC therapy, demonstrating the great plasticity of MSC, a promising cure for SSc.

Highlights

Skin fibrosis is the hallmark of systemic sclerosis, a rare intractable autoimmune disorder with high morbidity and mortality due to multi-organ involvement [1]
HOCl injections induced a two-step process of fibrosis development: first, an ‘early inflammatory phase’, characterized at d21 by highly proliferative infiltrates of myofibroblasts, T-lymphocytes and macrophages
HOCl-systemic sclerosis (SSc) mimics three fibrotic phenotypes of scleroderma, all positively impacted by mesenchymal stem cells (MSCs) therapy, demonstrating the great plasticity of MSC, a promising cure for SSc

Summary

Introduction

Skin fibrosis is the hallmark of systemic sclerosis (scleroderma, SSc), a rare intractable autoimmune disorder with high morbidity and mortality due to multi-organ involvement [1]. Precise etiology for SSc remains unknown, fibrosis development in the disease may originate from a complex interplay between environmental and intrinsic triggers–including oxidative stressleading to tissue damage, immune response, endothelial cell and myofibroblast activation. The latter results in fibroblast proliferation and extracellular matrix (ECM) production [2,3,4]. Different stages of tissue fibrosis may be observed, with variable participation of immune cell activation, angiogenesis or ECM synthesis by fibroblasts. Targeting fibrosis in SSc may be challenged by the complexity of this multistage process, as well as the unpredictability of clinical evolution. Studies are still on going to help defining more precisely the clinical and biological status of SSc patients, refining therapy [5, 6]

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