Development of a pretreatment strategy to enhance the efficiency of hepatocyte transplantation in mice

Hepatocyte transplantation (HTx) is a promising approach for the treatment of genetic liver diseases. However, the poor engrafted efficiency of 0.03‐0.5% of transplanted cells in the recipient livers usually limits the clinical applications. In previous study, we observed an enhanced engraftment of intrasplenically injected cancer cells into the liver of a specific mouse strain due to its narrowed sinusoid, and therefore suspected that narrow sinusoids may enhance the efficiency of HTx. To validate this hypothesis, we transplanted primary hepatocytes by intrasplenic injection into WT C57BL/6 and mice treated with an antibody (Ab) that is known to cause narrow sinusoids of the liver. We found the amount of injected donor cells was nearly 2 times more in the Ab‐treated mice than those in the WT livers at all the time points followed. To confirm the possibility of clinical application of this Ab‐treatment strategy, we tested its therapeutic effect using the hemophilia B disease model. We compared the therapeutic effect between untreated and Ab‐pretreatment strategy on hemophilia B receiving functional hepatocytes for control of bleeding. Transplanted mice were followed for one month, and their sera were analyzed periodically for the activity and antigen levels of coagulant factor IX. We found that mice receiving Ab‐pretreatment strategy had higher FIX antigen and clotting activity than those of untreated groups. Our results showed the Ab that is effective in narrowing the hepatic sinusoids may be useful for improving cell/stem cell therapy for liver diseases in the near future.