Abstract
Systemic sclerosis (SSc) is a rare and severe disease characterized by generalized fibrosis, vasculopathy and deregulation of immune cells. No curative treatment is validated to date. Mesenchymal stromal cells (MSCs) are being evaluated in clinical trials as they are effective in several preclinical models of SSc. They exert their anti-fibrotic, pro-angiogenic and immunomodulatory properties through the secretion of mediators contained in extracellular vesicles (EVs). We investigate here the role of EVs released by MSCs in their systemic effect during SSc.In a murine model of hypochlorous acid-induced SSc, we demonstrate that EVs can stop the disease course and improve histological and molecular parameters in skin and lung samples. We identify miR-29a-3p expression in both MSCs and their EVs and prove that miR-29a-3p is responsible for a large part of their therapeutic effect, targeting Dnmt3a and Pdgfr-bb, two novel targets identified in SSc.We improve the therapeutic efficacy of EVs on lung abnormalities in SSc mice by stimulating MSCs with IFNγ before EVs production whereas increasing the amount of injected EVs did not have any benefit. IFNγ modulates the expression of known immunosuppressive factors in both MSCs and EVs, potentiating their therapeutic properties.While the role of MSCs from SSc patients (SSc MSCs) in the development of the disease is debated, we show that SSc MSCs inhibit in vitro T lymphocyte proliferation and improve the myofibroblastic phenotype obtained after fibroblast stimulation using TGFβ1 which display a similar profile as fibroblasts from SSc patients in the in vitro model used here.Overall, MSC-EVs are as effective as MSCs to stop the progression of murine SSc and EVs from IFNγ-preconditioned MSCs improve their beneficial effect in the lungs. SSc MSCs maintain their anti-fibrotic and immunosuppressive properties in vitro and one of our perspectives is to evaluate their therapeutic efficacy in vivo.