Immunoregulatory Property Of Human Adult Adipose-derived Flk-1+mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are multipotent nonhematopietic progenitor cells possessing self-renewal capacity, multilineage differentiation potential, extensive proliferation ability, and low immunogenecity characteristic. These properties make MSCs useful for lots of potential clinical applications. Numerous investigations have showed that MSCs may modulate the immune system, but the exact mechanisms underlying are still not fully understood yet.In addition, several clinical studies performed to date confirm safety of infusion of MSCs, lacking adverse effects.Cyclosporine A (CsA), known as a very effective immunosuppressive reagent, is widely used in clinical fields. However, therapeutical dose of CsA is close to its toxic dose and the numerous severe adverse effects of longterm and large dose for usage of CsA are increasingly recognized. It provids intense motivation for seeking new strategies, and drug regimens based on the combination of low-dose CsA with other drugs have been recommended. In this study, we investigated the effect of CsA, human adult Flk-1+AMSCs (adipose-derived Flk-1+mesenchymal stem cells) alone or their combination on proliferation of human T cells stimulated by phytohemagglutinin (PHA) and explored the molecule mechanisms that maybe involved.The purpose of the first part of this paper was to investigate possible molecule mechanisms of the immunomodulatory property of Flk-1+AMSCs.Our results showed that Flk-1+AMSCs constitutively expressed high level of the Notch ligand Jagged-1 and could induce the activation of Notch signaling in T cells, resulting in suppression of nuclear translocation and DNA binding activity of nuclear factorκB (NF-κB), and thus hampered the transcription and production of cytokine such as interleukin-2 and interferon-γwhich finanally impaired the activation and proliferation of PHA-actived T cells. These data indicate that Jagged-1/Notch ligation is closely related to immunomodulatory effect of Flk-1+AMSCs which may provide an effective mechanism to the immunosuppressive property of Flk-1+AMSCs by direct cell-cell contact.In the second part of this paper, study was designed to investigate the immuno-modulatory effect of CsA, Flk-1+AMSCs alone or their combination on proliferation of human T cells stimulated by PHA and to explore the molecule mechanisms that maybe involved. Combination of moderate-dose Flk-1+AMSCs and low-dose CsA was significantly more powerful than moderate-dose Flk-1+AMSCs or large-dose CsA alone in suppressing transcription and production of IL-2 and IFN-y, hampering activation of NF-κB, and blocking proliferation of PHA-actived T cells. Flk-1+AMSCs facilitate the immunosuppressive effect of CsA on T cells through Jagged-1/Notch related inhibition of NF-κB signaling. The combintion of moderate-dose Flk-1+AMSCs and low-dose CsA represents a rationale therapeutic approach aimed to prevent adverse effects of both reagents while maintaining adequate immunosuppression.