title: Pig BMSCs Transfected with Human TFPI Combat Species Incompatibility and Regulate the Human TF Pathway in Vitro and in a Rodent Model.
abstract: BACKGROUND
  The activation of tissue factor (TF) is one of the major reasons for coagulation dysregulation after pig-to-primate xenotransplantation. Tissue factor pathway inhibitor (TFPI) is the most important inhibitor of TF. Studies have demonstrated species incompatibility between pig TFPI and human TF.
  
  
  METHODS
  A pig-to-macaque heterotopic auxiliary liver transplantation model was established to determine the origin of activated TF. Chimeric proteins of human and pig TFPI were constructed to assess the role of Kunitz domains in species incompatibility. Immortalised pig bone marrow mesenchymal stem cells transfected with human TFPI were tested for their ability to inhibit clotting in vitro.
  
  
  RESULTS
  TF from recipient was activated early after liver xenotransplantation. Pig TFPI Kunitz domain 2 bound human FXa, but Kunitz domain 1 did not effectively inhibit human TF/FVIIa. Immortalised pig bone marrow mesenchymal cells (BMSCs) transfected with human TFPI showed a prolonged recalcification time in vitro and in a rodent model.
  
  
  CONCLUSIONS
  Recipient TF is relevant to dysregulated coagulation after xenotransplantation. Kunitz domain 1 plays the most important role in species incompatibility between pig TFPI and human TF, and clotting can be inhibited by human TFPI-transfected pig BMSCs. Our study shows a possible way to resolve the incompatibility of pig TFPI.
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Hongchen
authors.initials: H
authors.lastname: Ji
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.forename: Shuqiang
authors.initials: S
authors.lastname: Yue
authors.forename: Junjie
authors.initials: J
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Zhuochao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Ben
authors.initials: B
authors.lastname: Ma
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Meng
authors.initials: M
authors.lastname: Pu
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.forename: Chong
authors.initials: C
authors.lastname: Feng
authors.forename: Desheng
authors.initials: D
authors.lastname: Wang
authors.forename: Juanli
authors.initials: J
authors.lastname: Duan
authors.forename: Dengke
authors.initials: D
authors.lastname: Pan
authors.forename: Kaishan
authors.initials: K
authors.lastname: Tao
authors.forename: Kefeng
authors.initials: K
authors.lastname: Dou
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D002478:Cells, Cultured; D006801:Humans; D066298:In Vitro Techniques; D008074:Lipoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D016031:Liver Transplantation; D008251:Macaca; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D023421:Models, Animal; D017434:Protein Structure, Tertiary; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D016042:Transplantation, Heterotopic
chemical_list: D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin