Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism

Mesenchymal stem cells (MSCs) have shown extreme clinical promise as a therapeutic regenerative system in the treatment of numerous types of diseases. A recent report, however, documented lethal pulmonary thromboembolism in a patient following the administration of adipose-derived MSCs (ADSCs). In our study, we designed experiments to examine the role of tissue factor (TF), which is highly expressed at the level of mRNA and localized to the cell surface of cultured MSCs, as a triggering factor in the procoagulative cascade activated by infused MSCs. A high mortality rate of ∼85% in mice was documented following intravenous infusion of mouse ADSCs within 24 h due to the observation of pulmonary embolism. Rotation thromboelastometry and plasma clotting assay demonstrated significant procoagulation by the cultured mouse ADSCs, and preconditioning of ADSCs with an anti-TF antibody or usage of factor VII deficient plasma in the assay successfully suppressed the procoagulant properties. These properties were also observed in human ADSCs, and could be suppressed by recombinant human thrombomodulin. In uncultured mouse adipose-derived cells (ADCs), the TF-triggered procoagulant activity was not observed and all mice infused with these uncultured ADCs survived after 24 h. This clearly demonstrated that the process of culturing cells plays a critical role in sensitizing these cells as a procoagulator through the induction of TF expression. Our results would recommend that clinical applications of MSCs to inhibit TF activity using anti-coagulant agents or genetic approaches to maximize clinical benefit to the patients.