Hepatocyte Transplantation: Quo Vadis?

Abstract

Orthotopic liver transplantation (OLT) has been effective in managing end-stage liver disease since the advent of cyclosporine immunosuppression therapy in 1980. The major limitations of OLT are organ supply, monetary cost, and the burden of lifelong immunosuppression. Hepatocyte transplantation, as a substitute for OLT, has been an exciting topic of investigation for several decades. HT is potentially minimally invasive and can serve as a vehicle for delivery of personalized medicine through autologous cell transplant after modification ex vivo. However, 3 major hurdles have prevented large-scale clinical application: (1) availability of transplantable cells; (2) safe and efficient ex vivo gene therapy methods; and (3) engraftment and repopulation efficiency. This review will discuss new sources for transplantable liver cells obtained by lineage reprogramming, clinically acceptable methods of genetic manipulation, and the development of hepatic irradiation-based preparative regimens for enhancing engraftment and repopulation of transplanted hepatocytes. We will also review the results of the first 3 patients with genetic liver disorders who underwent preparative hepatic irradiation before hepatocyte transplantation.

Figure 1.

Summary of mechanisms associated with preparative hepatic irradiation. (1) Increases LSEC apoptosis and sloughing, which increases porosity of sinusoids and increases migration of transplanted cells into liver parenchyma. (2) Enhancement of hepatocyte engraftment and integration in liver cords. (3) Reduction of Kupffer cell activity, which reduces phagocytic clearance of transplanted cells

In-text box 1:

Summary of mechanisms by which preparative hepatic irradiation improves cell engraftment and repopulation

Figure 2.

The process of correction of a metabolic disease through ex-vivo gene therapy of autologous somatic cells such as fibroblasts. Fibroblasts are corrected ex-vivo and then reprogrammed and differentiated to hepatocyte-like-cells (HLCs). After transplantation, these hepatocytes integrate in the patient liver, where they produce deficient factors or enzymes.