Abstract
Background: Systemic sclerosis (SSc) is a severe autoimmune disease for which mesenchymal stromal cells (MSCs)-based therapy was reported to reduce SSc-related symptoms in pre-clinical studies. Recently, extracellular vesicles released by MSCs (MSC-EVs) were shown to mediate most of their therapeutic effect. Here, we aimed at improving their efficacy by increasing the MSC-EV dose or by IFNγ-priming of MSCs. Methods: small size (ssEVs) and large size EVs (lsEVs) were recovered from murine MSCs that were pre-activated using 1 or 20 ng/mL of IFNγ. In the HOCl-induced model of SSc, mice were treated with EVs at day 21 and sacrificed at day 42. Lung and skin samples were collected for histological and molecular analyses. Results: increasing the dose of MSC-EVs did not add benefit to the dose previously reported to be efficient in SSc. By contrast, IFNγ pre-activation improved MSC-EVs-based treatment, essentially in the lungs. Low doses of IFNγ decreased the expression of fibrotic markers, while high doses improved remodeling and anti-inflammatory markers. IFNγ pre-activation upregulated iNos, IL1ra and Il6 in MSCs and ssEVs and the PGE2 protein in lsEVs. Conclusion: IFNγ-pre-activation improved the therapeutic effect of MSC-EVs preferentially in the lungs of SSc mice by modulating anti-inflammatory and anti-fibrotic markers.
Highlights
Systemic sclerosis (SSc) is an autoimmune disease with a severe prognosis due to generalized fibrosis and vasculopathy [1]
By comparison with the dose of 250 ng used in the previous study, a high dose of large size extracellular vesicles (EVs) (lsEVs) (1500 ng) did not stop disease progression as shown by a continuous skin thickness increase, which was similar to non-treated mice, and a higher skin thickness measured at day 42 (Figure 1A,B)
We report that IFNγ pre-activation of mesenchymal stromal cells (MSCs) improved the therapeutic effect of EVs in the lungs of SSc-induced mice with no major impact on the skin
Summary
Systemic sclerosis (SSc) is an autoimmune disease with a severe prognosis due to generalized fibrosis and vasculopathy [1]. Mesenchymal stromal cells (MSCs) have demonstrated therapeutic benefit in preclinical models of SSc thanks to their pleiotropic properties. MSCs exert their therapeutic function through the release of many soluble mediators that are secreted in the extracellular milieu and/or within extracellular vesicles (EVs). Systemic sclerosis (SSc) is a severe autoimmune disease for which mesenchymal stromal cells (MSCs)-based therapy was reported to reduce SSc-related symptoms in pre-clinical studies. Extracellular vesicles released by MSCs (MSC-EVs) were shown to mediate most of their therapeutic effect. Results: increasing the dose of MSC-EVs did not add benefit to the dose previously reported to be efficient in SSc. By contrast, IFNγ pre-activation improved MSC-EVs-based treatment, essentially in the lungs. Low doses of IFNγ decreased the expression of fibrotic markers, while high doses improved remodeling and anti-inflammatory markers
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