Lung Fibrosis Is Improved by Extracellular Vesicles from IFNγ-Primed Mesenchymal Stromal Cells in Murine Systemic Sclerosis

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.

Recent advances to enhance the immunomodulatory potential of mesenchymal stem cells

“…The administration of IFN-g-pre-activated MSCs in rats with ischemia-reperfusion injury of kidneys induced by the renal artery ligation showed significantly decreased infiltration of proinflammatory immune cells to the site of injury reducing renal fibrosis (70). Interestingly, even the extracellular vesicles derived from IFN-g-primed MSCs improved the fibrosis of the lung in mice with systemic sclerosis (71). Such an effect can be linked to the increased production of PGE2 by primed MSCs that expand the number of CD163+/CD206+ immunosuppressive macrophages in the site of injury resulting in reducing inflammation (70).…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles as Idiopathic Pulmonary Fibrosis Microenvironment Targeted Delivery

“…In fact, the clinical transition to MSC-EVs is still in its infancy and needs to face many challenges. Here, we summarize the studies of MSC-EVs administration in pulmonary fibrosis in vivo in Table 2 [ 20 , 108 , 117 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 ] and an overview of therapeutic modalities of MSC-EVs for IPF in Figure 3 .…”

The Emerging Role of Extracellular Vesicles from Mesenchymal Stem Cells and Macrophages in Pulmonary Fibrosis: Insights into miRNA Delivery

“…The process was iterated until no more publications were obtained. A total of 17 studies were uncovered on this topic, from China, USA, Brazil, Australia, France, and Korea, performed between 2014 and 2022 [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. More information is summarized in Table 1 .…”

“…Bone marrow is one of the most extensively investigated sources of MSCs, nine of these studies having assessed the therapeutic effect of bone marrow MSC-derived EVs on pulmonary fibrosis [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 52 ]. For example, bleomycin has been used as a primary strategy to induce a pulmonary fibrosis model, and this approach has been well characterized.…”

“…In addition to their effects on silica- and bleomycin-induced pulmonary fibrosis, human bone marrow MSC-derived EVs can inhibit the progression of LPS-induced lung injury and fibrosis by repressing NF-κB and Hedgehog pathways [ 38 ]. Of note, mouse bone marrow MSC EVs have a similar effect to human EVs, since mouse EVs appeared in the lungs of systemic sclerosis mice with promotion of anti-inflammatory and antifibrotic markers, while IFNγ pre-activation accelerated the therapeutic effect [ 43 ].…”