Sheets of healthy rat liver cells (above) were used as transplant material in animal models of end-stage liver disease as an alternative to whole organ transplantation. [Kenneith Dunn - Indiana University School of Medicine]
Sheets of healthy rat liver cells (above) were used as transplant material in animal models of end-stage liver disease as an alternative to whole organ transplantation. [Kenneith Dunn – Indiana University School of Medicine]

End-stage liver failure offers few treatment options for patients—with transplantation currently being the only established management regimen. Unfortunately, this course of treatment is limited by the shortage of donors and suitability of available organs. Over the past several years, interest and research into transplantation of donor hepatocytes (liver cells) has begun to increase; however, this method has some drawbacks. The rate of survival for primary hepatocytes is limited, and these cells can often cause severe complications.

Yet, researchers from the Nagasaki University Graduate School of Biomedical Sciences in Japan have begun to test the therapeutic efficacy and feasibility of transplanting multilayered sheets of hepatocytes and fibroblasts into the subcutaneous cavity of laboratory rats modeled with end-stage liver failure. The investigators believe their efforts will help find potential therapeutic alternatives to whole liver transplants and improve the outcomes of current hepatocyte transplantation procedures.    

“Until now, no studies have successfully investigated the use of hepatocyte sheet engineering therapy for treating liver disease,” explained senior author Susumu Eguchi, M.D., Ph.D., professor at Nagasaki University. “Our study demonstrated that multilayered hepatocyte sheets generated from primary hepatocytes and primary skin fibroblasts were able to proliferate after transplantation and support the host liver function while improving the serum albumin level up to the normal range within two months.”

The findings from this study were published online recently in Cell Transplantation through an article entitled “Efficacy of multi-layered hepatocyte sheet transplantation for radiation-induced liver damage and partial hepatectomy in a rat model.”

Dr. Eguchi and his colleagues were able to demonstrate that cells in the multilayered sheets survived better than cells transplanted using traditional methods. Moreover, the hepatocyte sheet cells proliferated normally and were able to maintain liver function for at least two months within test animals.

The researchers concluded that poor oxygenation of transplanted tissue is one of the primary reasons traditional hepatocyte transplantation efficacy is low. In contrast, the scientists observed that after just the first week of transplantation with the hepatocyte sheets, the tissue had become permeated with multiple capillary vessels. 

“Hypoxia is a major cause of poor hepatocyte survival,” noted the researchers. “Therefore, immediately after transplantation, all transplanted cells are supplied with oxygen only from surface diffusion because of the lack of capillary vessels when other methods of transplantation are used.”

The scientists went on to explain that since the hepatocytes were so close to the blood vessels after the transplantation procedure, this was a confirmation that vascularization is paramount toward their survival and function. 

“Tissue engineering has become an attractive target for regenerative medicine, and we believe that hepatocyte sheet transplantation technology offers a great therapeutic opportunity both for the treatment of metabolic liver diseases and providing support for liver function in patients with end-stage liver failure,” the researchers concluded.

Dr. Eguchi and his team were excited by their findings and are continuing their research to find ways to improve the transplantation efficacy and cell survival rates for postoperative patients. 

“Stratifying hepatocytes on nonparenchymal cells has been shown to contribute to hepatocyte survival and functional integrity” said Stephen Strom, Ph.D., professor in the Department of Laboratory Medicine at the Karolinska Institutet, who was not directly connected with the current study. “The observed benefits may likely be attributed to the nonparenchymal cells, fibroblasts, in this case, conferring essential cytokines and extracellular matrix components to the hepatocytes. The present study contributes to the current dialogue about this technique by elucidating some of the physiological mechanisms underpinning its effectiveness. Future studies should be aimed at further assessing the clinical potential of this method.”