Optimization of the therapeutic efficacy of human umbilical cord blood-mesenchymal stromal cells in an NSG mouse xenograft model of graft-versus-host disease.

Abstract

Although in vitro studies have demonstrated the immunosuppressive capacity of mesenchymal stromal cells (MSCs), most in vivo studies on graft-versus-host disease (GVHD) have focused on prevention, and the therapeutic effect of MSCs is controversial. Moreover, optimal time intervals for infusing MSCs have not been established. We attempted to evaluate whether human umbilical cord blood-MSCs (hUCB-MSCs) could either prevent or treat GVHD in an NSG mouse xenograft model by injection of MSCs before or after in vivo clearance. Mice were infused with either a single dose or multiple doses of 5 × 10(5) hUCB-MSCs (3- or 7-day intervals) before or after GVHD onset. Before onset, hUCB-MSCs significantly improved the survival rate only when repeatedly injected at 3-day intervals. In contrast, single or repeated injections after GVHD onset significantly increased the survival rate and effectively attenuated tissue damage and inflammation. Furthermore, the levels of prostaglandin E2 and transforming growth factor-β1 increased significantly, whereas the level of interferon-γ decreased significantly in all MSC treatment groups. These data establish the optimal time intervals for preventing GVHD and show that hUCB-MSCs effectively attenuated symptoms and improved survival rate when administered after the onset of GVDH.