Bioengineering liver tissue by repopulation of decellularised scaffolds

Abstract

Liver transplantation is the only curative therapy for end stage liver disease, but is limited by the organ shortage, and is associated with the adverse consequences of immunosuppression. Repopulation of decellularised whole organ scaffolds with appropriate cells of recipient origin offers a theoretically attractive solution, allowing reliable and timely organ sourcing without the need for immunosuppression. Decellularisation methodologies vary widely but seek to address the conflicting objectives of removing the cellular component of tissues whilst keeping the 3D structure of the extra-cellular matrix intact, as well as retaining the instructive cell fate determining biochemicals contained therein. Liver scaffold recellularisation has progressed from small rodent in vitro studies to large animal in vivo perfusion models, using a wide range of cell types including primary cells, cell lines, foetal stem cells, and induced pluripotent stem cells. Within these models, a limited but measurable degree of physiologically significant hepatocyte function has been reported with demonstrable ammonia metabolism in vivo. Biliary repopulation and function have been restricted by challenges relating to the culture and propagations of cholangiocytes, though advances in organoid culture may help address this. Hepatic vasculature repopulation has enabled sustainable blood perfusion in vivo, but with cell types that would limit clinical applications, and which have not been shown to have the specific functions of liver sinusoidal endothelial cells. Minority cell groups such as Kupffer cells and stellate cells have not been repopulated. Bioengineering by repopulation of decellularised scaffolds has significantly progressed, but there remain significant experimental challenges to be addressed before therapeutic applications may be envisaged.

Keywords: Regenerative; Bioengineering; Scaffolds; Liver; Decellularisation; Recellularisation

Core Tip: Given the limited resource of livers for transplantation, repopulation of decellularised scaffolds with recipient cells offers a theoretically attractive organ source without the need for immunosuppression. Bioengineered livers have progressed from small rodent to large animal blood perfusion models. Although some hepatocyte function has been achieved, challenges remain in cholangiocyte repopulation, reconstitution of the vasculature, and other minority cell groups. The cell types used in experimental models to date have yielded advances but may need to be altered if the currently distant prospect of clinical application is to be envisaged.