Mesenchymal stem cells maintain immunomodulatory capacity after cell death

F. Luk, S.F.H. de Witte, M. Franquesa, S.S. Korevaar, T. Strini, F.J.M.F. Dor, M.G.H. Betjes, C.C. Baan, M.J. Hoogduijn

Wednesday 9 march 2016

12:45 - 12:55h at Theaterzaal

Categories: Plenaire sessie

Parallel session: Plenaire sessie II - Nieuwe uitdagingen in de transplantatiegeneeskunde

Mesenchymal stem cells (MSC) are widely studied as cell therapeutic agent after solid organ transplantation. However, MSC therapy comes with safety concerns and in vitro expansion of MSC is labor intensive and time consuming. Moreover, full elucidation of mechanisms of action of MSC therapy is lacking. Identification of key cellular or soluble components that are responsible for the effects of MSC will result in a better understanding of MSC therapeutic activity and might give the opportunity to generate these components as an alternative to the use of live cells. MSC were isolated and expanded from adipose tissue of healthy kidney donors. In order to discriminate between immunomodulation via cell-cell interaction or via secreted factors MSC were inactivated by heating for 30 minutes at 50 °C. Heat inactivated (HI)-MSC preserved their immunophenotype, but lost the ability to secrete soluble factors. 3x10^5 HI- and viable MSC were used to treat lipopolysaccharide (LPS) induced sepsis mice. The immunomodulatory interaction between MSC and different immune cell types was evaluated by co-culturing MSC with peripheral blood mononuclear cells and MACS purified B cells and monocytes. Cell proliferation and cell phenotype was determined by flow cytometry. Cytokine levels were measured with ELISA. MSC and HI-MSC drastically reduced circulating levels of pro-inflammatory IFN-γ and increased anti-inflammatory IL-10 after LPS induced sepsis. In vitro, living MSC reduced T cell proliferation in a dose dependent manner whereas HI-MSC had no effect. both HI- and living MSC inhibited B cell memory formation but only viable MSC were capable to induce IL-10 producing regulatory B cells. However, both living and HI-MSC significantly suppressed TNF-α production by LPS stimulated monocytes in vitro. This indicates that monocytes respond in a similar fashion to dead MSC and living MSC and partly explains how MSC exert their immunosuppressive effect after infusion. These results demonstrate that MSC modulate immune responses via two mechanisms. One is mediated by active interactions between viable MSC and immune cells. The other depends on modulation of monocyte function, which requires the presence but not viability of MSC. Both mechanism may contribute to the potential of MSC for immunotherapy in solid organ transplantation.