Therapeutic Effects of Hepatocyte Transplantation on Hemophilia B

Abstract

Hepatocyte transplantation offers an alternative therapeutic approach in the treatment of liver-related diseases. Hemophilia B is a bleeding disorder lacking factor IX (FIX) production in the liver, and achieving more than 1% coagulation activity results in significant improvement in the quality of life of the patients. The aim of this study was to investigate the efficacy of hepatocyte transplantation in the mouse model of hemophilia B. We transplanted isolated normal mouse hepatocytes into the liver of FIX knock-out mice. In some recipient mice, additional hepatocyte transplantations were performed 15 days after the first transplant. The recipient plasma FIX activities increased at 1% to 2% and persisted throughout the experimental period. An additional increase was achieved by the repeated transplantation. Close correlation between FIX messenger RNA levels of the liver and plasma FIX activity levels was observed. These results demonstrate that hepatocyte transplantation can provide therapeutic benefits in the treatment of hemophilia B.

The therapeutic effect of bone marrow–derived liver cells in the phenotypic correction of murine hemophilia A

“…16 Recently, a therapeutic effect of hepatocytes in hemophilia B mice has been documented. 35 The transplantation of BMCs into HA mice restored plasma FVIII activity well above the therapeutic correction level, which could eliminate spontaneous bleeding. Moreover, we did not observe the formation of FVIII inhibitors during this 18-month investigation.…”

“…32 Clinical studies show that approximately 20% of HA patients develop inhibitors to treatment 33 and that these patients are difficult to treat. 34 Cell-based therapies using isolated primary hepatocytes 16,35 or LSECs 17,18 are suggested to treat clotting disorders. In the past few years, a novel and exciting option to regenerate damaged liver from BM-derived cells has been proposed by many investigators.…”

Effects on coagulation factor production following primaryhepatomitogen-induced direct hyperplasia

“…Since FⅨ is a critical protein for mediating blood coagulation [11,12] , further investigation needs to be addressed for the elucidation of the mechanism producing the biologically active FⅨ during the regeneration phase.…”

“…Liver regeneration appears to adversely affect the production of other liver-specific proteins not directly involved in the regenerative process, including albumin and ornithine transcarbamylase. In terms of hemostasis, the production and secretion of the coagulation factors, anti-coagulant factors, and fibrinolytic factors are highly dependent on the hepatocytes in the liver [9][10][11][12] . There is evidence that some of the liver-specific proteins have temporal suppression in their production during compensatory liver regeneration [5,13,14] .…”

Improving the Techniques for Human Hepatocyte Transplantation: Report from a Consensus Meeting in London

“…Other sites (e.g., subrenal, subcutaneous, or intramuscular spaces) are tation that, at least initially, the need for immunosuppression would probably be low. The consensus of the being explored (46,47,58,60). The therapeutic potential of ectopic hepatocyte transplantation has been demonmeeting was to produce more preclinical data in the pigto-primate model as a necessary step to further considerstrated in animal models, including hemophilia and ascorbic acid deficiency (46,60).…”