Thrombomodulin expression on Langerhans' islet: can endogenous ‘anticoagulant on demand’ overcome detrimental thrombotic complications in clinical islet transplantation?

Recent studies have revealed that tissue factor (TF) was expressed on islet, which might play a critical role in mediating the harmful thrombotic complications in pancreatic islet transplantation [1]. TF initiates activation of extrinsic coagulation cascade leading to thrombin generation, and results in the triggering of inflammatory response, which might have a role for the transplanted graft loss and portal thrombosis [1]. The evidences are thus implying that graft TF regulation might be a therapeutic target to achieve successful clinical islet transplantation (including not only islet tissue but also stem-cell-based transplantation) for the treatment of type I diabetes. However, systemic anticoagulant treatment before islet transplantation is unlikely to be applicable because of hemostatic conditions. Furthermore, systemic TF inhibition after transplantation seems ineffective as the TF-mediated coagulant activation is limited to within 15 min following the procedure [2]. In this context, we could find significance in our observations that natural anticoagulant thrombomodulin (TM) was also abundantly expressed by islet endocrine cells, as well as by the enriched vascular endothelial cells in human islet tissue. As shown in Fig. 1, immunostaining of normal pancreas sections showed that TM was present on the surface of islet cells as well as vascular endothelial cells (observed as factor VIII-positive cells; data not shown), whereas no TM was found in the components of exocrine pancreas such as acinar or duct cells. The evidence was further confirmed by biochemical analysis (i.e., Western blot and RT-PCR) using mouse islet line, MIN6 cells (data not shown). The non-covalent binding of thrombin to TM blocks procoagulant properties of thrombin and redirects substrate specificity towards activation of plasma protein C (PC) [3,4], which exerts additional anticoagulant effects (i.e., inactivating coagulant factors Va and VIIIa.) [4]. TM protein thus acts as an anticoagulant on demand , inhibiting coagulation cascade at the site and/or incidence of thrombin generation. Consistent with the evidence, soluble TM successfully inhibits thrombin activities without significant hemorrhagic or hemostatic complications [5]. Furthermore, TM/PC pathway attenuates inflammatory responses such as endotoxin-induced tissue damage, TF expression and cytokine production [6]. Physiologically, endogenous islet TM might play an important role for the maintenance of microcirculatory homeostasis in pancreatic endocrine system. Thus, the regulatory cross-talk between coagulant system and inflammation, mediated by TF/TM regulation by islet components, may determine the fate of graft tissues in islet transplantation. Especially in recipient diabetic individuals, the implanted islet tissues tend to be exposed to inflammatory milieu, which may induce increased TF and decreased TM expression by islet components. Hence, ex vivo TM overexpression in donor islet cells by adenoviral gene transduction, or by the treatment with TM-increasing agents (i.e., cyclic AMP, PDE inhibitors, and retinoic acid) may be candidate strategies to prevent detrimental thrombotic complications in islet transplantation.