Engineering Liver Tissues under the Kidney Capsule Site Provides Therapeutic Effects to Hemophilia B Mice

Abstract

Recent advances in liver tissue engineering have encouraged further investigation into the evaluation of therapeutic benefits based on animal disease models. In the present study, liver tissues were engineered in coagulation factor IX knockout (FIX-KO) mice, a mouse model of hemophilia B, to determine if the tissue engineering approach would provide therapeutic benefits. Primary hepatocytes were isolated from the liver of wild-type mice and suspended in a mixture of culture medium and extracellular matrix components. The hepatocyte suspension was injected into the space under the bilateral kidney capsules of the FIX-KO mice to engineer liver tissues. The plasma FIX activities (FIX:C) of the untreated FIX-KO mice were undetectable at any time point. In contrast, the liver tissue engineered FIX-KO mice achieved 1.5-2.5% of plasma FIX activities (FIX:C) and this elevated FIX:C level persisted throughout the 90 day experimental period. Significant FIX mRNA expression levels were found in the engineered liver tissues at levels similar to the wildtype livers. The present study demonstrates that liver tissue engineering could provide therapeutic benefits in the treatment of hemophilia B.

Genetically Modified Adipose Tissue-Derived Stem/Stromal Cells, Using Simian Immunodeficiency Virus-Based Lentiviral Vectors, in the Treatment of Hemophilia B

“…Although liver organ transplantation has cured patients with hemophilia A and B (Gordon et al, 1998), shortages of available livers have greatly limited the ability of liver transplantation to become a standard treatment. In earlier proof-of-concept studies, our laboratory has demonstrated the therapeutic value of cell-based approaches for hemophilia, including hepatocyte transplantation and liver tissue engineering (Tatsumi et al, 2008b;Ohashi et al, 2010). These successful experiments prompted us to generate FIXproducing cells from an autologous tissue origin.…”

“…Cell-based therapies have received a great deal of attention as a next-generation therapeutic approach for hemophilia (Oh et al, 2006;Follenzi et al, 2008;Kasuda et al, 2008;Tatsumi et al, 2008a,b;Ohashi et al, 2010). There has been enormous interest in the transplantation of stem cells to produce clotting factors (Chuah et al, 2004;Oh et al, 2006;Coutu et al, 2011).…”

Perioperative haemostatic management of haemophilic mice using normal mouse plasma

“…Cell-based therapy has attracted great attention as a curative therapeutic option for haemophilia [11][12][13]28,29]. Because coagulation factors are mainly produced in the liver, the liver is a reasonable target site for cell transplantation [12,28].…”

Hepatocyte Transplantation: Cell Sheet Technology for Liver Cell Transplantation

“…Therefore, as a preclinical study, our group investigated the therapeutic effect of hepatocyte-based therapy on hemophilia mice. Specifically, primary hepatocytes isolated from the liver of wild-type mice were intraportally transplanted to the liver of hemophilia B mice [ 76 ], or transplanted under the kidney capsule of hemophilia B mice as a mixture with EHS gel [ 77 , 78 ]. In both experiments, 1 to 3% increase of plasma FIX activity levels was observed in the recipient mice after the procedures, and persisted for a long-term period without development of FIX-neutralizing antibody.…”