title: Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism.
abstract: 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.
authors: Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors: Kohei
authors: K
authors: Tatsumi
authors: Kazuo
authors: K
authors: Ohashi
authors: Yoshinori
authors: Y
authors: Matsubara
authors: Ayako
authors: A
authors: Kohori
authors: Takahiro
authors: T
authors: Ohno
authors: Hiroshi
authors: H
authors: Kakidachi
authors: Akihiro
authors: A
authors: Horii
authors: Kazuko
authors: K
authors: Kanegae
authors: Rie
authors: R
authors: Utoh
authors: Takanori
authors: T
authors: Iwata
authors: Teruo
authors: T
authors: Okano
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D001777:Blood Coagulation; D002478:Cells, Cultured; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011655:Pulmonary Embolism / Q000209:etiology* / Q000378:metabolism; D018180:Thrombomodulin; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: D018180:Thrombomodulin; D013925:Thromboplastin