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Abstract Number: 1726

Therapeutic Efficacy of Mesenchymal Stem Cells in Diffuse Murine Hypochlorite-Induced Systemic Sclerosis

Alexandre Maria1, Claire Bony2, Karine Toupet2, Christian Jorgensen3, Philippe Guilpain4 and Daniele Noel5, 1U844, Inserm, Montpellier, France, 2Inserm, Montpellier, France, 3Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, CHU Lapeyronie., Montpellier, France, 4Department of Internal Medicine, Montpellier, France, 5Inserm U844, UM1, Montpellier, France

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Cell therapy, fibrosis, mesenchymal stem cells and systemic sclerosis

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Session Information

Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose

Systemic sclerosis (SSc) is a rare intractable disease with unmet medical need and fibrosis-related mortality. Absence of efficient treatments has prompted to develop novel therapeutic strategies among which mesenchymal stem cells (MSCs) appear one of the most attractive options. Herein we provide the first preclinical study using MSCs in the relevant hypochlorite (HOCl)-induced murine model of diffuse SSc, recapitulating the main features of the disease: multivisceral fibrosis, vasculopathy, and autoimmunity.

Methods

Balb/c mice underwent six weeks of daily intradermal injections of HOCl leading to SSc-HOCl phenotype. Different doses of syngenic bone marrow-derived MSCs (2.5×105; 5×105 or 106cells) were infused in the tail vein of the mice, either the day before disease induction, or at day 21. Skin thickness was measured weekly, and samples of skin and lung were taken at euthanasia (d42) to assess by RT-qPCR the expression of collagens I and III, TGF-β1, alpha-smooth actin muscle (α-SMA), MMP-1 and -9, Tissue Inhibitor of MMP (TIMP1), Hepatocyte Growth Factor (HGF), VEGFA, IL-1β, TNF-α, IL-6, IL-10, Superoxide Dismutase (SOD2), and Heme Oxygenase (HMOX1). Anti-scl70 antibodies levels were measured in sera by ELISA.

Results

We first compared the effects of different doses of MSCs (2.5×105; 5×105 and 106) infused the day before disease induction, on clinical and biological parameters. When considering skin thickness in time, we observed a slower progression in MSC-treated mice, with the best results obtained with the lowest dose of 2.5×105 MSCs. At euthanasia, a lower expression of fibrotic markers (collagens I and III, TGF-β1, α-SMA) was observed in both skin and lung of treated mice, consistent with histological improvement and inversely proportional to the injected dose. Importantly, sera from treated mice exhibited lower levels of anti-scl70 autoantibodies and enhanced antioxidant capacity, confirming the systemic effect of MSCs. Of interest, MSC administration was also efficient when infused at d21 while disease is known to be established. We further provide evidence at a molecular level that in skin and lung tissues, MSCs exerted an anti-fibrotic role by normalizing extracellular matrix remodeling parameters (MMP-1 and -9, TIMP-1, HGF, VEGFA), as well as reducing pro-inflammatory cytokines (IL1β, TNF-α, IL-6, IL-10) and increasing antioxidant defenses (SOD2, HMOX1).

Conclusion

In conclusion, this preclinical study is the first to demonstrate the therapeutic efficacy of MSCs in SSc, acting through the modulation of inflammation, tissue remodeling and antioxidant defenses. The benefits observed in a curative approach are particularly promising in sight of clinical perspectives.


Disclosure:

A. Maria,
None;

C. Bony,
None;

K. Toupet,
None;

C. Jorgensen,
None;

P. Guilpain,
None;

D. Noel,
None.

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