Mesenchymal stem cells (MSCs) are used in various clinical and preclinical models for immunomodulation. However, it remains unclear how the immunomodulatory effect of MSC is communicated. MSC-induced immunomodulation is known to be mediated through both MSC-secreted cytokines and direct cell-cell interactions. Recently, it has been demonstrated that metabolically inactive, heat-inactivated MSCs (HI-MSCs) have similar anti-inflammatory capacities in LPS-induced sepsis compared with viable MSC. To further investigate the immunomodulatory effects of MSC, we introduced MSC and HI-MSC in two animal models with different immunological causes. In the first model, allogeneic hearts were transplanted from C57BL/6 mice to BALB/c recipients. MSC in combination with mycophenolate mofetil (MMF) significantly improved graft survival compared with MMF alone, whereas the application of HI-MSC had no effect on graft survival. We revealed that control MSC dose-dependently inhibited CD3+ and CD8+ T-cell proliferation in vitro, whereas HI-MSC had no effect. In the second model, sepsis was induced in mice via cecal ligation and puncture. HI-MSC treatment significantly improved the overall survival, whereas control MSCs had no effect. in vitro studies demonstrated that HI-MSCs are more effectively phagocytosed by monocytes than control MSCs and induced cell death in particular of activated CD16+ monocytes, which may explain the immune protective effect of HI-MSC in the sepsis model. The results of our study demonstrate that MSC-mediated immunomodulation in sepsis is dependent on a passive recognition of MSC by monocytes, whereas fully functional MSCs are required for inhibition of T-cell mediated allograft rejection.

HI-MSC, immunomodulation, mesenchymal stem cells, monocytes, organ transplantation, sepsis, T-cells,
Stem Cells: the international journal of cell differentiation and proliferation

Weiss, A.R.R. (Andreas R. R.), Lee, O. (Olivia), Eggenhofer, E, Geissler, E. (Elisabeth), Korevaar, S.S, Soeder, Y, … Dahlke, M.H. (2020). Differential effects of heat-inactivated, secretome-deficient MSC and metabolically active MSC in sepsis and allogenic heart transplantation. Stem Cells: the international journal of cell differentiation and proliferation. doi:10.1002/stem.3165