Reduction of Graft-versus-Host-Disease in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice by co-transplantation of syngeneic human umbilical cord-derived mesenchymal stromal cells (UC-MSCs).

Abstract Background Graft-versus-Host Disease (GvHD) is one of the major complications following hematopoietic stem cell transplantation (HSCT), which remains the only curative therapy for many malignant diseases of the hematopoietic system. The immunomodulatory potential of mesenchymal stromal cells (MSCs) to treat GvHD is currently being tested in various preclinical and clinical trials. Objectives As the results of the preclinical and clinical trials on the use of MSCs to treat GvHD have not been consistent, we analyzed the potential beneficial effects of syngeneic versus allogenic treatment setting, culture expansion of the MSC and various MSC cell doses and time points of MSC transplantation in a murine GvHD model. Study Design We established a murine GvHD model based on the transplantation of umbilical cord blood-derived HSCs (UC-HSCs) and used this model to assess the therapeutic potential of umbilical cord-derived mesenchymal stromal cells (UC-MSCs). The use of HSC and MSC populations derived from the same donor allowed us to exclude third party cells and test the UC-HSCs and UC-MSCs in a matched setting. Moreover, we were able to compare various doses, transplantation time points, and the influence of culture expansion of the MSCs on the impact of treatment. This resulted in 16 different treatment groups. Results The most efficient setting for the treatment of the UC-HSC-induced GvHD reaction was based on the simultaneous administration of 1  ×  106 culture-expanded, syngeneically matched UC-MSCs. This therapy effectively reduced the number of CD8+ T cells in the blood, protected the mice from weight loss and prolonged their survival until the end of observation period. Conclusion Taken together, our data show beneficial effects of (1) syngeneic over allogeneic UC-HSCs and UC-MSCs; (2) culture-expanded cells over freshly isolated primary cells; (3) simultaneous over sequential administration and (4) high doses of UC-MSCs. The animal model of GvHD established here is now available for more detailed studies, including a comparative analysis of the efficacy of MSCs derived from alternative sources, such as adipose tissue or bone marrow.