Liver Regeneration and Cell Transplantation for End-Stage Liver Disease

Liver transplantation is the only curative option for end-stage liver disease; however, the limitations of liver transplantation require further research into other alternatives. Considering that liver regeneration is prevalent in liver injury settings, regenerative medicine is suggested as a promising therapeutic strategy for end-stage liver disease. Upon the source of regenerating hepatocytes, liver regeneration could be divided into two categories: hepatocyte-driven liver regeneration (typical regeneration) and liver progenitor cell-driven liver regeneration (alternative regeneration). Due to the massive loss of hepatocytes, the alternative regeneration plays a vital role in end-stage liver disease. Advances in knowledge of liver regeneration and tissue engineering have accelerated the progress of regenerative medicine strategies for end-stage liver disease. In this article, we generally reviewed the recent findings and current knowledge of liver regeneration, mainly regarding aspects of the histological basis of regeneration, histogenesis and mechanisms of hepatocytes’ regeneration. In addition, this review provides an update on the regenerative medicine strategies for end-stage liver disease. We conclude that regenerative medicine is a promising therapeutic strategy for end-stage liver disease. However, further studies are still required.

Maraviroc Prevents HCC Development by Suppressing Macrophages and the Liver Progenitor Cell Response in a Murine Chronic Liver Disease Model

Maraviroc (MVC), a CCR5 antagonist, reduces liver fibrosis, injury and tumour burden in mice fed a hepatocarcinogenic diet, suggesting it has potential as a cancer therapeutic. We investigated the effect of MVC on liver progenitor cells (LPCs) and macrophages as both have a role in hepatocarcinogenesis. Mice were fed the hepatocarcinogenic choline-deficient, ethionine-supplemented diet (CDE) ± MVC, and immunohistochemistry, RNA and protein expression were used to determine LPC and macrophage abundance, migration and related molecular mechanisms. MVC reduced LPC numbers in CDE mice by 54%, with a smaller reduction seen in macrophages. Transcript and protein abundance of LPC-associated markers correlated with this reduction. The CDE diet activated phosphorylation of AKT and STAT3 and was inhibited by MVC. LPCs did not express Ccr5 in our model; in contrast, macrophages expressed high levels of this receptor, suggesting the effect of MVC is mediated by targeting macrophages. MVC reduced CD45+ cells and macrophage migration in liver and blocked the CDE-induced transition of liver macrophages from an M1- to M2-tumour-associated macrophage (TAM) phenotype. These findings suggest MVC has potential as a re-purposed therapeutic agent for treating chronic liver diseases where M2-TAM and LPC numbers are increased, and the incidence of HCC is enhanced.

Microtissue geometry and cell-generated forces drive patterning of liver progenitor cell differentiation in 3D

Investigating the role of mechanical signaling on stem and progenitor cell differentiation in three-dimensional (3D) microenvironments is key to fully understanding these processes. Towards this, we implemented a hydrogel microwell based method to produce arrays of multicellular microtissues in constrained geometries, which cause distinct profiles of mechanical signals in 3D. We applied this platform to a model liver development system to investigate the impact of tissue geometry and mechanical stress on liver progenitor cell bipotential differentiation into hepatocyte-like and biliary-like cells. We fabricated 3D liver progenitor cell microtissues of varied geometries, including cylinder and toroid, and used image segmentation on confocal images to track individual single cell phenotype within defined spatial coordinates. These studies demonstrated patterning of hepatocytic differentiation to the outer shell of the cylinder and toroid microtissues, except at the inner diameter surface of the toroid tissues. Biliary differentiation was distributed throughout the microtissue interior regions and was additionally increased in toroid tissues compared to cylinder tissues. We used finite element modeling to predict stress distributions in these microtissues which demonstrated that cell-cell tension correlated with hepatocytic fate, while compression correlated with decreased hepatocytic differentiation and increased biliary differentiation. Overall, this combined approach that integrates microscale fabrication, imaging and analysis, and mechanical modeling serve as a demonstration of how microtissue geometry can drive patterning of mechanical stresses that regulate cell differentiation trajectories. It also can serve as a platform for the further investigation of tissue morphogenetic signaling mechanisms in the liver as well as other stem cell differentiation contexts.

Liver progenitor cell-driven liver regeneration

The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver diseases. Hepatocyte-driven liver regeneration that involves the proliferation of preexisting hepatocytes is a primary regeneration mode. On the other hand, liver progenitor cell (LPC)-driven liver regeneration that involves dedifferentiation of biliary epithelial cells or hepatocytes into LPCs, LPC proliferation, and subsequent differentiation of LPCs into hepatocytes is a secondary mode. This secondary mode plays a significant role in liver regeneration when the primary mode does not effectively work, as observed in severe liver injury settings. Thus, promoting LPC-driven liver regeneration may be clinically beneficial to patients with severe liver diseases. In this review, we describe the current understanding of LPC-driven liver regeneration by exploring current knowledge on the activation, origin, and roles of LPCs during regeneration. We also describe animal models used to study LPC-driven liver regeneration, given their potential to further deepen our understanding of the regeneration process. This understanding will eventually contribute to developing strategies to promote LPC-driven liver regeneration in patients with severe liver diseases.