Fibrosis Development in HOCl-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 (...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02571/full |
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| author | Alexandre T. J. Maria Alexandre T. J. Maria Karine Toupet Marie Maumus Pauline Rozier Pauline Rozier Marie-Catherine Vozenin Alain Le Quellec Christian Jorgensen Christian Jorgensen Danièle Noël Danièle Noël Philippe Guilpain Philippe Guilpain |
| author_facet | Alexandre T. J. Maria Alexandre T. J. Maria Karine Toupet Marie Maumus Pauline Rozier Pauline Rozier Marie-Catherine Vozenin Alain Le Quellec Christian Jorgensen Christian Jorgensen Danièle Noël Danièle Noël Philippe Guilpain Philippe Guilpain |
| author_sort | Alexandre T. J. Maria |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T20:35:13Z |
| format | Article |
| id | doaj.art-900a903b50394298a0b8640fa3e1c936 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T20:35:13Z |
| publishDate | 2018-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-900a903b50394298a0b8640fa3e1c9362022-12-22T00:12:56ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-11-01910.3389/fimmu.2018.02571411926Fibrosis Development in HOCl-Induced Systemic Sclerosis: A Multistage Process Hampered by Mesenchymal Stem CellsAlexandre T. J. Maria0Alexandre T. J. Maria1Karine Toupet2Marie Maumus3Pauline Rozier4Pauline Rozier5Marie-Catherine Vozenin6Alain Le Quellec7Christian Jorgensen8Christian Jorgensen9Danièle Noël10Danièle Noël11Philippe Guilpain12Philippe Guilpain13IRMB, Montpellier University, INSERM, CHU Montpellier, Montpellier, FranceDepartment of Internal Medicine–Multi-Organic Diseases, Saint-Eloi Hospital, Montpellier, FranceIRMB, Montpellier University, INSERM, CHU Montpellier, Montpellier, FranceIRMB, Montpellier University, INSERM, CHU Montpellier, Montpellier, FranceIRMB, Montpellier University, INSERM, CHU Montpellier, Montpellier, FranceDepartment of Internal Medicine–Multi-Organic Diseases, Saint-Eloi Hospital, Montpellier, FranceLaboratory of Radiation Oncology Department, University Hospital of Lausanne (CHUV), Lausanne, SwitzerlandDepartment of Internal Medicine–Multi-Organic Diseases, Saint-Eloi Hospital, Montpellier, FranceIRMB, Montpellier University, INSERM, CHU Montpellier, Montpellier, FranceClinical Immunology and Osteoarticular Diseases Therapeutic Unit, Lapeyronie Hospital, Montpellier, FranceIRMB, Montpellier University, INSERM, CHU Montpellier, Montpellier, FranceClinical Immunology and Osteoarticular Diseases Therapeutic Unit, Lapeyronie Hospital, Montpellier, FranceIRMB, Montpellier University, INSERM, CHU Montpellier, Montpellier, FranceDepartment of Internal Medicine–Multi-Organic Diseases, Saint-Eloi Hospital, Montpellier, FranceObjectives: 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.https://www.frontiersin.org/article/10.3389/fimmu.2018.02571/fullmesenchymal stem cellssystemic sclerosisfibrosishypochloriteoxidative stressscleroderma |
| spellingShingle | Alexandre T. J. Maria Alexandre T. J. Maria Karine Toupet Marie Maumus Pauline Rozier Pauline Rozier Marie-Catherine Vozenin Alain Le Quellec Christian Jorgensen Christian Jorgensen Danièle Noël Danièle Noël Philippe Guilpain Philippe Guilpain Fibrosis Development in HOCl-Induced Systemic Sclerosis: A Multistage Process Hampered by Mesenchymal Stem Cells Frontiers in Immunology mesenchymal stem cells systemic sclerosis fibrosis hypochlorite oxidative stress scleroderma |
| title | Fibrosis Development in HOCl-Induced Systemic Sclerosis: A Multistage Process Hampered by Mesenchymal Stem Cells |
| title_full | Fibrosis Development in HOCl-Induced Systemic Sclerosis: A Multistage Process Hampered by Mesenchymal Stem Cells |
| title_fullStr | Fibrosis Development in HOCl-Induced Systemic Sclerosis: A Multistage Process Hampered by Mesenchymal Stem Cells |
| title_full_unstemmed | Fibrosis Development in HOCl-Induced Systemic Sclerosis: A Multistage Process Hampered by Mesenchymal Stem Cells |
| title_short | Fibrosis Development in HOCl-Induced Systemic Sclerosis: A Multistage Process Hampered by Mesenchymal Stem Cells |
| title_sort | fibrosis development in hocl induced systemic sclerosis a multistage process hampered by mesenchymal stem cells |
| topic | mesenchymal stem cells systemic sclerosis fibrosis hypochlorite oxidative stress scleroderma |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.02571/full |
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