Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Transplant Toxicities

The fifth epidermal growth factor-like region of thrombomodulin exerts cytoprotective function and prevents SOS in a murine model

Bone Marrow Transplantation volume 52, pages 73–79 (2017)Cite this article

Subjects

Abstract

The present study found that the fifth epidermal growth factor-like domain of thrombomodulin (TME5) possesses the cytoprotective function in association with an increase in levels of anti-apoptotic myeloid cell leukemia-1 protein in an activated protein C-independent manner in human umbilical vein endothelial cells (HUVECs). Importantly, TME5 counteracted calcineurin inhibitor-induced vascular permeability and successfully prevented monocrotaline-induced sinusoidal obstruction syndrome (SOS) in a murine model. Taken together, TME5 may be useful for preventing or treating lethal complications that develop after hematopoietic stem cell transplantation such as SOS and thrombotic microangiopathy in which endothelial cell damage has a role.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Suzuki K, Kusumoto H, Deyashiki Y, Nishioka J, Maruyama I, Zushi M et al. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. EMBO J 1987; 6: 1891–1897.

    Article  CAS  Google Scholar 

  2. Dittman WA, Majerus PW . Structure and function of thrombomodulin: a natural anticoagulant. Blood 1990; 75: 329–336.

    CAS  PubMed  Google Scholar 

  3. Dahlback B, Villoutreix BO . The anticoagulation protein C pathway. FEBS Lett 2005; 579: 3310–3316.

    Article  Google Scholar 

  4. Stearns DJ, Kurosawa S, Esmon CT . Microthrombomodulin. Residues 310–486 from the epidermal growth factor precursor homology domain of thrombomodulin will accelerate protein C activation. J Biol Chem 1989; 264: 3352–3356.

    CAS  PubMed  Google Scholar 

  5. Abeyama K, Stern DM, Ito Y, Kawahara K, Yoshimoto Y, Tanaka M et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel anti-inflammatory mechanism. J Clin Invest 2005; 115: 1267–1274.

    Article  CAS  Google Scholar 

  6. Conway EM, Van de Wouwer M, Pollefeyt S, Jurk K, Van Aken H, De Vriese et al. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. J Exp Med 2002; 196: 565–577.

    Article  CAS  Google Scholar 

  7. Ikezoe T, Yang J, Nishioka C, Honda G, Furihata M, Yokoyama A . Thrombomodulin protects endothelial cells from a calcineurin inhibitor-induced cytotoxicity by upregulation of extracellular signal-regulated kinase/myeloid leukemia cell-1 signaling. Arterioscler Thromb Vasc Biol 2012; 32: 2259–2270.

    Article  CAS  Google Scholar 

  8. Sakai M, Ikezoe T, Bandobashi K, Togitani K, Yokoyama A . Successful treatment of transplantation-associated thrombotic microangiopathy with recombinant human soluble thrombomodulin. Bone Marrow Transplant 2010; 45: 803–805.

    Article  CAS  Google Scholar 

  9. Ikezoe T, Togitani K, Komatsu N, Isaka M, Yokoyama A . Successful treatment of sinusoidal obstructive syndrome after hematopoietic stem cell transplantation with recombinant human soluble thrombomodulin. Bone Marrow Transplant 2010; 45: 783–785.

    Article  CAS  Google Scholar 

  10. Ikezoe T, Takeuchi A, Taniguchi A, Togitani K, Yokoyama A . Recombinant human soluble thrombomodulin counteracts capillary leakage associated with engraftment syndrome. Bone Marrow Transplant 2011; 46: 616–618.

    Article  CAS  Google Scholar 

  11. Carreras E, Diaz-Ricart M . The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant 2011; 46: 1495–1502.

    Article  CAS  Google Scholar 

  12. Ikezoe T, Takeuchi A, Chi S, Takaoka M, Anabuki K, Kim T et al. Effect of recombinant human soluble thrombomodulin on clinical outcomes of patients with coagulopathy after hematopoietic stem cell transplantation. Eur J Haematol 2013; 91: 442–447.

    Article  CAS  Google Scholar 

  13. Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007; 5: 31–41.

    Article  CAS  Google Scholar 

  14. Tsubokura M, Yamashita T, Inagaki L, Kobayashi T, Kakihana K, Wakabayashi S et al. Fatal intracranial hemorrhage following administration of recombinant thrombomodulin in a patient after cord blood transplantation. Bone Marrow Transplant 2011; 46: 1030–1031.

    Article  CAS  Google Scholar 

  15. James CM. Pichia protocols 2nd edn. Methods in Molecular Biology Vol. 389. Springer: New York, NY, 2007.

    Google Scholar 

  16. Yurimoto H, Yamane M, Kikuchi Y, Matsui H, Kato N, Sakai Y . The pro-peptide of Streptomyces mobaraensis transglutaminase functions in cis and in trans to mediate efficient secretion of active enzyme from methylotrophic yeasts. Biosci Biotechnol Biochem 2004; 68: 2058–2069.

    Article  CAS  Google Scholar 

  17. Ikezoe T, Yang Y, Heber D, Taguchi H, Koeffler HP . PC-SPES: a potent inhibitor of nuclear factor-kappa B rescues mice from lipopolysaccharide-induced septic shock. Mol Pharmacol 2003; 64: 1521–1529.

    Article  CAS  Google Scholar 

  18. Ikezoe T, Tanosaki S, Krug U, Liu B, Cohen P, Taguchi H et al. Insulin-like growth factor binding protein-3 antagonizes the effects of retinoids in myeloid leukemia cells. Blood 2004; 104: 237–242.

    Article  CAS  Google Scholar 

  19. Niimi S, Oshizawa T, Naotsuka M, Ohba S, Yokozawa A, Murata T et al. Establishment of a standard assay method for human thrombomodulin and determination of the activity of the Japanese reference standard. Biologicals 2002; 30: 69–76.

    Article  CAS  Google Scholar 

  20. Nakamura K, Hatano E, Miyagawa-Hayashino A, Okuno M, Koyama Y, Narita M et al. Soluble thrombomodulin attenuates sinusoidal obstruction syndrome in rat through suppression of high mobility group box 1. Liver Int 2014; 34: 1473–1487.

    Article  CAS  Google Scholar 

  21. Shi CS, Shi GY, Chang YS, Han HS, Kuo CH, Liu C et al. Evidence of human thrombomodulin domain as a novel angiogenic factor. Circulation 2005; 111: 1627–1636.

    Article  CAS  Google Scholar 

  22. Cutler C, Kim HT, Ayanian S, Bradwin G, Revta C, Aldridge J et al. Prediction of veno-occlusive disease using biomarkers of endothelial injury. Biol Blood Marrow Transplant 2010; 16: 1180–1185.

    Article  CAS  Google Scholar 

  23. Qiao J, Fu J, Fang T, Huang Y, Mi H, Yang N et al. Evaluation of the effects of preconditioning regimens on hepatic veno-occlusive disease in mice after hematopoietic stem cell transplantation. Exp Mol Pathol 2015; 98: 73–78.

    Article  CAS  Google Scholar 

  24. Rio B, Andreu G, Nicod A, Arrago JP, Dutrillaux F, Samama M et al. Thrombocytopenia in venocclusive disease after bone marrow transplantation or chemotherapy. Blood 1986; 67: 1773–1776.

    CAS  PubMed  Google Scholar 

  25. Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 2000; 192: 565–570.

    Article  CAS  Google Scholar 

  26. Huttunen HJ, Fages C, Rauvala H . Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem 1999; 274: 19919–19924.

    Article  CAS  Google Scholar 

  27. Geiger H, Pawar SA, Kerschen EJ, Nattamai KJ, Hernandez I, Liang HP et al. Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat Med 2012; 18: 1123–1129.

    Article  CAS  Google Scholar 

  28. Kuo CH, Sung MC, Chen PK, Chang BI, Lee FT, Cho CF et al. FGFR1 mediates recombinant thrombomodulin domain-induced angiogenesis. Cardiovasc Res 2015; 105: 107–117.

    Article  CAS  Google Scholar 

  29. Moll S, Lindley C, Pescatore S, Morrison D, Tsuruta K, Mohri M et al. Phase I study of a novel recombinant human soluble thrombomodulin, ART-123. J Thromb Haemost 2004; 2: 1745–1751.

    Article  CAS  Google Scholar 

  30. Nomura S, Ishii K, Maeda Y, Katayama Y, Yagi H, Fujishima N et al. The preventative effects of recombinant thrombomodulin on transplantation-associated coagulopathy after allogeneic hematopoietic stem cell transplantation. J Stem Cell Res Therapy 2014; 4: 247.

    Article  Google Scholar 

  31. Ikezoe T, Yang J, Nishioka C, Yokoyama A . Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen. Bone Marrow Transplant 2015; 50: 113–120.

    Article  CAS  Google Scholar 

  32. Ferrara JL, Levine JE, Reddy P, Holler E . Graft-versus-host disease. Lancet 2009; 373: 1550–1561.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Adaptable and Seamless Technology Transfer Program through target-driven R&D, JST, SENSHIN Medical Research Foundation and KAKENHI (26461406).

Author information

Author notes

  1. J Yang

    Present address: J Yang, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.,

Authors and Affiliations

  1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

    T Ikezoe, J Yang, C Nishioka, B Pan & A Yokoyama

  2. Department of Hematology, Fukushima Medical University, Fukushima City, Fukushima, Japan

    T Ikezoe

  3. Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, China

    B Pan & K Xu

  4. Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

    M Furihata

  5. Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan

    K Nakamura, H Yurimoto & Y Sakai

  6. Medial Affairs Department, Asahi Kasei Pharma, Kanda Jinbocho, Chiyoda-ku, Tokyo, Japan

    G Honda

Authors
  1. T Ikezoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Nishioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Furihata
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H Yurimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Y Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A Yokoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Ikezoe.

Ethics declarations

Competing interests

GH is an employee of Asahi Kasei Pharma. The remaining authors declare no competing financial interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ikezoe, T., Yang, J., Nishioka, C. et al. The fifth epidermal growth factor-like region of thrombomodulin exerts cytoprotective function and prevents SOS in a murine model. Bone Marrow Transplant 52, 73–79 (2017). https://doi.org/10.1038/bmt.2016.195

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2016.195

This article is cited by

Search

Advanced search

Quick links