Adipose-derived mesenchymal stem cells overexpressing thrombomodulin reduce thrombogenic risk and enhance therapeutic efficacy

Adipose-derived mesenchymal stem cells (ASCs) are expected to be a new therapy to prevent progression of renal fibrosis; however, they were reported to have procoagulant activity, raising concerns about thrombogenic risk. Thrombomodulin (TM) acts as an anticoagulant factor by binding to thrombin, leading to the hypothesis that ASCs overexpressing TM (TM-ASCs) could be safely used for cell therapy by reducing the risk of thromboembolism. Overexpression of TM using adeno-associated virus (AAV) reduced rat deaths related to renal infarction and pulmonary embolism induced by ASCs. Interestingly, TM-ASCs alleviated renal inflammation and fibrosis potently in ischemia-reperfusion injury (IRI) rats. The therapeutic mechanism of TM-ASCs involved increased prostaglandin E2 (PGE2) secretion, a shift in the macrophage phenotype to immunosuppressive M2 in vitro, and potent M2 macrophage polarization in the damaged areas in vivo. We produced ASCs with enhanced TM expression by pretreatment with a selective inhibitory kappa-B kinase-β (IKKβ) inhibitor. These ASCs also improved thrombotic mortality and markedly attenuated renal fibrosis induced by IRI, similar to TM-ASCs generated by AAV. ASCs with enhanced TM expression by IKKβ also increased PGE2 secretion, leading to a more pronounced polarization of M2 macrophages. Taken together, ASCs with enhanced TM expression eliminated the risk of thrombosis and reinforced therapeutic efficacy. These ASCs might become a standard cellular therapy for renal fibrosis via the intravascular injection of mesenchymal stem cells in the future.