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Exposure of von Willebrand factor on isolated hepatocytes promotes tethering of platelets to the cell surface

Gustafson, Elisabet, MD, PhD1; Hamad, Osama A., PhD2; Deckmyn, Hans, PhD3; Barbu, Andreea, PhD2; Ekdahl, Kristina N., PhD4; Nilsson, Bo, MD, PhD2

doi: 10.1097/TP.0000000000002707
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Background: Hepatocyte transplantation is a potentially attractive method for treatment of acute liver failure and liver-based metabolic disorders. Unfortunately, the procedure is hampered by the instant blood-mediated inflammatory reaction, (IBMIR), a thromboinflammatory response elicited by the vascular innate immune system, causing activation of the coagulation and complement systems and clearance of transplanted cells. Observations have also revealed platelets adhered to the surface of the hepatocytes. To establish hepatocyte transplantation as a clinical treatment, all factors that trigger IBMIR need to be identified and controlled. This work explores the expression of von Willebrand factor, (VWF), on isolated hepatocytes resulting in tethering of platelets.

Methods: VWF on hepatocytes was studied by flow cytometry, confocal microscopy, immunoblot and RT-PCR. Interaction between hepatocytes and platelets was studied in a Chandler loop model. Adhesion of platelets to the hepatocyte surface was demonstrated by flow cytometry and confocal microscopy.

Results: Isolated hepatocytes constitutively express VWF on their cell surface and mRNA for VWF was found in the cells. Hepatocytes and platelets, independently of coagulation formed complexes, which were shown by antibody blocking studies to be dependent on hepatocyte-associated VWF and platelet-bound glycoprotein Ibα.

Conclusion: VWF on isolated hepatocytes, causes in contact with blood, adhesion of platelets, which thereby forms an ideal surface for coagulation. This phenomenon need to be considered in hepatocyte-based reconstitution therapy and possibly even in other settings of cell transplantation.

1. Department of Women’s and Children’s Health, Division of Pediatric Surgery, Uppsala University Hospital, Sweden

2. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

3. Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium,

4. Linnæus Center of Biomaterials Chemistry, Linnæus University, Kalmar, Sweden

Disclosure: The authors declare no conflicts of interest.

Funding; This study was supported by grants from HRH the Crown Princess Louise’s Fund for Scientific Research (Sweden).

Corresponding author: Elisabet Gustafson MD PhD, ORCID: 0000-0003-3416-1841, Division of Pediatric Surgery, Department of Women's and Children's Health, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden, E-mail: elisabet.gustafson@kbh.uu.se, Tel: +46186110330, fax: +46186115905

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