Erythropoietin improves effects of mesenchymal stem cells in an experimental model of sepsis

In last years several studies have shown that mesenchymal stem cells (MSCs) are able to reduce the systemic inflammatory response and mortality in experimental models of sepsis. As recently found, the surface of MSCs have receptors for erythropoietin (EPO). So we hypothesized that the introduction of EPO together with MSCs may enhance their effect and improve the results of sepsis treatment. Aim: To evaluate morphologic and immunologic effects of combined treatment with EPO and MSC in an experimental LPS sepsis model in rats. Methods: 50 Wistar rats were randomized into 5 groups: Group 1 - the healthy controls, Groups 2-5 were intraperitoneally introduced bacterial LPS 20 mg/kg. Two hours after LPS injection animals received the following intravenous treatments: Group 3 - 4×105 allogeneic MSCs, Group 4 - 8.5 μg of recombinant EPO_beta, Group 5 - MSCs and EPO in the same doses. Surviving animals were euthanased on the 4th day. The morphological study of the liver, spleen, thymus, lungs, kidney tissues was performed. We analyzed the tissue changes, white blood cells count and serum level of IL-1β, IL-2, IL-6, TNF-α. Results: Mortality in LPS groups did not differ. The highest white blood cells count was found in the group of combined treatment EPO+MSCs (8.15×106 cells/ml) compared with controls (2,15×106 cells/ml) and LPS controls (6,52×106 cells/ml). There were no differences in levels of TNF-α, IL-2 and IL-6 between the groups, but serum IL-1β level in groups 2 and 4 was significantly higher than in treated with MSCs and MSCc + EPO animals. Histologically in the group 5 we observed significantly less leukocyte lung interalveolar septal infiltration and kidney tubular dystrophy. The most significant differences in group LPS + EPO were found in the lymphoid tissue - considerable hyperplasia of spleen white pulp and thymus cortex, whereas in the other groups different degrees of atrophy of the corresponding zones were noted. Conclusions: Combined treatment with EPO and MSCs can reduce acute lung injury and kidney damage, cause hyperplasia of lymphoid tissue and enhance the immune response more than separate treatment in an experimental model of sepsis in rats.