IRMB, University of Montpellier, INSERM, 34295 Montpellier, France.
Department of Internal Medicine, Multi-Organic Diseases, CHU, 34295 Montpellier, France.
Cells. 2021 Oct 13;10(10):2727. doi: 10.3390/cells10102727.
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.
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.
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 , and in MSCs and ssEVs and the PGE2 protein in lsEVs.
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.
系统性硬化症（SSc）是一种严重的自身免疫性疾病，临床前研究表明间充质基质细胞（MSCs）为基础的治疗方法可以减轻 SSc 相关症状。最近，MSCs 释放的细胞外囊泡（MSC-EVs）被证明可以介导其大部分治疗效果。在这里，我们旨在通过增加 MSC-EV 剂量或 IFNγ 预处理 MSC 来提高其疗效。
从小鼠 MSCs 中回收小尺寸（ssEVs）和大尺寸 EVs（lsEVs），这些 MSC 先前使用 1 或 20ng/ml IFNγ 进行预激活。在 HOCl 诱导的 SSc 模型中，在第 21 天用 EVs 治疗小鼠，并在第 42 天处死。收集肺和皮肤样本进行组织学和分子分析。
增加 MSC-EV 剂量并不能增加以前报道的在 SSc 中有效的剂量的疗效。相比之下，IFNγ 预处理改善了基于 MSC-EVs 的治疗，主要是在肺部。低剂量 IFNγ 降低了纤维化标志物的表达，而高剂量则改善了重塑和抗炎标志物。IFNγ 预处理上调了 MSC 和 ssEVs 中的 和 以及 lsEVs 中的 PGE2 蛋白。
IFNγ 预处理通过调节抗炎和抗纤维化标志物，优先改善 SSc 小鼠 MSC-EVs 的治疗效果。
