Effects of Pro-inflammatory Cytokine Pretreatment on MSC Potency, Survival, and Migration

Authors

• SJ Kim
• B Milo
• JA Frank

Abstract

Mesenchymal stem cell (MSC) therapy shows great promise in many inflammatory diseases and GVHD by modulating host inflammatory immune reactions. However, the therapeutic potency of MSC in relation to survival and homing of the cells need to be elucidated to improve cell therapy. Recently, pro-inflammatory activation of MSC with interferon(IFN)-ϒ, tumor necrosis factor(TNF)-α, and/or interleukin(IL)-1β was reported to improve the efficacy of MSC therapy in various inflammatory disease models. Also, prediction of the MSC potency in vivo by measuring TNF-specific gene(TSG)-6 levels of the therapeutic cells was reported. We used these recent studies to correlate changes in physical parameters and surface markers to cell homing, and to identify pretreatment regimen for optimal potency and survival of MSC in cell therapy. MSC were pretreated with IFN-ϒ, TNF-α, IL-1β, and combination of IFN-ϒ + TNF-α for 24h. IFN-ϒ + TNF-α combination group resulted in a cell size increase, upregulated cell adhesion surface markers (CD49e, CD49f, CD162, CD11a, CD54) and chemotaxis receptors (cMet, CXCR4), and increased HLA-DR. The combination group showed the greatest immune suppression and potency with upregulation in IDO, CD274, and TSG-6 compared to IFN-ϒ or TNF-α alone. However, pretreatment with TNF-α resulted in the greatest expression of matrix metalloprotein . Migration of cells in wound-healing assay showed the same trend in TNF-α , but not in the combination group. Finally, effects of pro-inflammatory cytokine pretreatment in cell proliferation, xeno/allo-graft blood compatibility, and survival under oxidative stress condition were investigated to identify pretreatment group to maximize therapeutic effect.

Scientific Focus Area: Stem Cell Biology

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