Abstract
Bone marrow mesenchymal stem cells (MSCs) have demonstrated therapeutic effects for colitis through immunomodulation and anti-inflammation. However, whether MSC-derived exosomes possessed the similar function remains unclear. In present study, exosomes were isolated from control and IFN-γ-primed MSCs and was verified by transmission electron microscope (TEM) and immunofluorescence staining. Administration of exosomes to mice significantly improved the disease activity index and histological score of colitis, and decreased the ratio of Th17 cells with elevated Treg cells ratio in mice colitis model. Exosomes from IFN-γ-primed MSCs showed superior therapeutic effects to colitis. Exosomes treatment inhibited Th17 differentiation in vitro, and exosomes from IFN-γ-primed MSCs showed higher inhibition efficacy. Mechanistically, exosomes treatment significantly decreased the expression of Stat3 and p-Stat3 to inhibit Th17 cells differentiation. IFN-γ pretreatment increased the level of miR-125a and miR-125b of exosomes, which directly targeted on Stat3, to repress Th17 cell differentiation. Moreover, combination of miR-125a and miR-125b agmior infusion also showed therapeutic effects for colitis, accompanied by decreased Th17 cell ratio. Collectively, this study demonstrates that IFN-γ treatment promoted exosomes from MSCs to attenuate colitis through increasing the level of miR-125a and miR-125b, which binding on 3′-UTR of Stat3 to repress Th17 cell differentiation. This study provides a new approach of exocytosis on the treatment of colitis.
Highlights
Mesenchymal stem cells (MSCs) have displayed tremendous therapeutic effects for variety of diseases due to their multilineage differentiation and strong immunomodulatory ability[1,2,3,4]
Two hundred micrograms of exosomes derived from control or IFN-γprimed MSCs were systemically infused to mice on day 3 and sacrifice the mice on day 10 for further evaluations (Fig. 2a)
These results indicated that exosomes derived from MSCs showed therapeutic effects for experimental colitis in mice, and the therapeutic effects of exosomes could be enhanced by IFN-γ pretreatment
Summary
Mesenchymal stem cells (MSCs) have displayed tremendous therapeutic effects for variety of diseases due to their multilineage differentiation and strong immunomodulatory ability[1,2,3,4]. The results demonstrated that IFN-γ treatment could enhance the capacity of exosomes derived from MSCs to attenuate mice colitis phenotype via upregulating the level of miR-125a and miR-125b, which directly targeting on the 3′-UTR of Stat[3] to repress Th17 cells and the inflammation. To compare the therapeutic effects of exosomes from control and IFN-γ-primed MSCs, we induced experimental colitis by administrating 3% DSS in drink water for 10 days using C57BL/6J mice.
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