Cotransplantation of preactivated mesenchymal stem cells improves intraportal engraftment of islets by inhibiting liver natural killer cells in mice

The activation of natural killer (NK) cells in the liver inhibits engraftment of intraportally transplanted islets. We attempted to modulate the activity of NK cells by cotransplanting mesenchymal stem cells (MSCs) with islets in mice. We first investigated the ability of MSCs to secrete prostaglandin E2 , a predominant inhibitor of NK cell function, in various combinations of inflammatory cytokines. Notably, we found that prostaglandin E2 production was partially delayed in MSCs activated by inflammatory cytokines in vitro, whereas liver NK cells were activated early after islet transplant in vivo. Accordingly, preactivated MSCs, but not naive MSCs, substantially suppressed the expression of activation markers in liver NK cells after cotransplant with islets. Similarly, cotransplant with preactivated MSCs, but not naive MSCs, markedly improved the survival of islet grafts. These results highlight MSC cotransplant as an effective and clinically feasible method for enhancing engraftment efficiency. The authors show that in a syngeneic intraportal islet transplantation mouse model, high prostaglandin E2 production from mesenchymal stem cells preactivated by pro‐inflammatory cytokines suppresses NK cells after cotransplantation with islets, and subsequently improves islet graft survival.