Liver cell therapy: is this the end of the beginning?

Abstract

The prevalence of liver diseases is increasing globally. Orthotopic liver transplantation is widely used to treat liver disease upon organ failure. The complexity of this procedure and finite numbers of healthy organ donors have prompted research into alternative therapeutic options to treat liver disease. This includes the transplantation of liver cells to promote regeneration. While successful, the routine supply of good quality human liver cells is limited. Therefore, renewable and scalable sources of these cells are sought. Liver progenitor and pluripotent stem cells offer potential cell sources that could be used clinically. This review discusses recent approaches in liver cell transplantation and requirements to improve the process, with the ultimate goal being efficient organ regeneration. We also discuss the potential off-target effects of cell-based therapies, and the advantages and drawbacks of current pre-clinical animal models used to study organ senescence, repopulation and regeneration.

Keywords: Biomaterials; Cell sheet; Cell tracking; Co-culture; Differentiation; Engraftment; Extracellular matrix; Hepatic progenitor cells; Hepatocyte-like cells (HLCs); Mesenchymal stem cells (MSCs).

Fig. 1

Directed differentiation of pluripotent stem cells (PSCs) and their potential applications. PSCs were maintained on laminin extracellular matrix (ECM) and differentiated toward hepatic tissue using a four-stage process employing Activin A (ACTA), Wnt3a, and using differentiation medium (80% knockout DMEM (KO-DMEM), 20% knockout serum replacement (KSR), GlutaMAX, non-essential amino acids, β-mercaptoethanol, 1% Dimethyl sulfoxide (DMSO), and penicillin/streptomycin), and HepatoZYME maturation medium supplemented with Oncostatin M (OSM) and human hepatocyte growth factor (HGF). Following differentiation and tissue engineering, monolayer, co-culture, sphere and organoids could be applied in the future to model human biology, generate artificial liver devices, and used as cell-based therapies in vivo. The liver is shown in brown, the spleen in reddish-brown, and the liver bandage as a patch on the liver. Arrows (red) point to the site of cell delivery