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Haematologica 2018 Volume 103(10):1730-1740
1Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; 2Department of Hematology, Fukushima Medical University, Japan; 3Medical Affairs Department, Asahi Kasei Pharma, Kanda Jinbocho, Chiyoda-ku, Tokyo, Japan and 4Department of Diagnostic Pathology, Fukushima Medical University, Japan
Ferrata Storti Foundation
Coagulation & its Disorders
Cytoprotective and pro-angiogenic functions of thrombomodulin are preserved in the C loop of the fifth epidermal growth factor-like domain
Xiangmin Wang,1,2 Bin Pan,1,2 Goichi Honda,3 Xintao Wang,2 Yuko Hashimoto,4 Hiroshi Ohkawara,2 Kailin Xu,1 Lingyu Zeng1 and Takayuki Ikezoe2
ABSTRACT
We previously found that the fifth epidermal growth factor-like domain of thrombomodulin (TME5) exerts cytoprotective and pro-angiogenic functions via G-protein coupled receptor 15 (GPR15). TME5 is comprised of three S-S bonds that divide it into three loops: A (TME5A), B (TME5B), and C (TME5C). Herein we identified the minimum structure of TME5 that produces favorable effects in vas- cular endothelial cells (ECs). We found that TME5C, composed of 19 amino acids, but not TME5A or TME5B, stimulated the proliferation of human umbilical vein endothelial cells (HUVECs) and human hepatic sinusoidal endothelial cells (HHSECs). Matrigel plug assays showed that TME5C stimulates in vivo angiogenesis. In addition, TME5C counteract- ed calcineurin inhibitor-induced apoptosis and vascular permeability in HUVECs and HHSECs. Western blot analysis indicated that exposure of either HUVECs or HHSECs to TME5C increased the levels of anti-apop- totic myeloid cell leukemia-1 protein in association with the activation of signal transduction pathways, including extracellular signal-regulated kinase, AKT, and mitogen-activated protein kinase p38. Importantly, TME5C did not affect the coagulation pathway in vitro. The cytoprotec- tive function of TME5C was mediated by cell surface-expressed GPR15, as TME5C was not able to protect vascular ECs isolated from Gpr15 knock-out (KO) mice. Strikingly, TME5C successfully ameliorated sinu- soidal obstruction syndrome in a murine model by counteracting the reduction of sinusoidal EC numbers. Taken together, the cytoprotective and pro-angiogenetic functions of TM are preserved in TME5C. The use of TME5C may be a promising treatment strategy to prevent or treat lethal complications, such as sinusoidal obstruction syndrome, whose pathogenesis is based on endothelial insults.
Introduction
Hepatic sinusoidal obstruction syndrome (SOS) is a potentially life-threaten- ing complication after hematopoietic stem cell transplantation (HSCT).1 The inci- dence of SOS ranges from 5% to 60%, depending on the conditioning regimen and transplantation type.2 The clinical manifestation of SOS includes rapid and unexplained weight gain, ascites, painful hepatomegaly, and jaundice.3 The development of SOS after HSCT is associated with injury to sinusoidal endothe- lial cells (ECs) and hepatocytes via a variety of factors, including a hepatotoxic conditioning regimen, immunosuppressive treatments with calcineurin inhibitors, and lipopolysaccharide (LPS) released by gram-negative bacteria.4,5 Due to the paucity of glutathione content in zone III of the liver, sinusoidal ECs are more vulnerable to toxic agents than hepatocytes.5 SOS is now referred to as an endothelial syndrome together with transplant-associated thrombotic microangiopathy (TA-TMA) and engraftment syndrome (ES).2,6 As a result of endothelial injury, a hypercoagulable state is caused in patients with ES.7 As of
Correspondence:
ikezoet@fmu.ac.jp or zengly2000@163.com
Received: December 18, 2017. Accepted: June 13, 2018. Pre-published: June 14, 2018.
doi:10.3324/haematol.2017.184481
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/10/1730
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