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P044 Therapeutic effects of mesenchymal stem cells induced regulatory dendritic cells on chronic colitis model in mice

Kim H.-S.*1, Jo H.1, Eom Y.W.2, Cho M.Y.3

1Yonsei University Wonju College of Medicine, Internal medicine, Wonju, South Korea 2Yonsei University Wonju College of Medicine, Cell Therapy and Tissue Engineering Center, Wonju, South Korea 3Yonsei University Wonju College of Medicine, Pathology, Wonju, South Korea

Background

Mesenchymal stem cells (MSCs), emerging cell therapeutics for inflammatory bolwel disease (IBD), have demonstrated immunomodulatory effects by interactions between T cells and dendritic cells (DCs). In this study, we investigated whether MSCs could differentiate mature DCs (mDCs) into a distinct regulatory DCs and these DCs could alleviate inflammation through a T cell modulation in DSS induced chronic colitis mouse model.

Methods

DCs were derived from mouse bone marrow and different subsets of DCs were characterized by fluorescence-activated cell sorting (FACS). Quantitative polymerase chain reaction (q-PCR) for anti-inflammatory (interleukin (IL)-10 and transforming growth factor (TGF)–β) and pro-inflammatory cytokines (interferon (IFN)-γ, tumor necrosis factor (TNF)-α and IL-6) were performed in both in vitro DC subsets and in vivo. Using splenocytes co-cultured with MSC induced DCs, q-PCRs for CD4, CD8, CD25 and Foxp3, and Western blotting for Foxp3 were performed to measure the expression of regulatory T (Treg) cell markers in vitro. In vivo dextran sulfate sodium (DSS) chronic colitis model, Expression of IL-10, TGF–β, STAT3 and Foxp3 were compared among 5 groups (control, DSS-colitis, immature DCs only, MSCs, and MSC-induced DCs).

Results

MSC-induced DCs expressed CD11c+ CD80lo CD86locell surface marker. These DCs secreted high levels of anti-inflammatory cytokines, whereas production of pro-inflammatory cytokines were diminished in vitro. Also, the levels of mRNA and protein of Foxp3+, CD4+ and CD25+ were increased in splenocytes co-cultured with MSC-induced DCs. In addition, intraperitoneal injection of MSC induced DCs significantly increased anti-inflammatory cytokines at both m-RNA and protein level and enhanced differentiation of FOXP3+ Treg cells, resulting in considerabe amelioration of chronic colitis and improvement of survival in DSS treated mice.

Conclusion

These results showed that MSCs induced DCs alliviated chronic colitis by promotin g Treg cells differentiation and the secretion of anti-inflammatory cytokines, providing potential application of MSC-induced DCs in the treatment of IBD.