Liver bioengineering: current status and future perspectives

Abstract

The present review aims to illustrate the strategies that are being implemented to regenerate or bioengineer livers for clinical purposes. There are two general pathways to liver bioengineering and regeneration. The first consists of creating a supporting scaffold, either synthetically or by decellularization of human or animal organs, and seeding cells on the scaffold, where they will mature either in bioreactors or in vivo. This strategy seems to offer the quickest route to clinical translation, as demonstrated by the development of liver organoids from rodent livers which were repopulated with organ specific cells of animal and/or human origin. Liver bioengineering has potential for transplantation and for toxicity testing during preclinical drug development. The second possibility is to induce liver regeneration of dead or resected tissue by manipulating cell pathways. In fact, it is well known that the liver has peculiar regenerative potential which allows hepatocyte hyperplasia after amputation of liver volume. Infusion of autologous bone marrow cells, which aids in liver regeneration, into patients was shown to be safe and to improve their clinical condition, but the specific cells responsible for liver regeneration have not yet been determined and the underlying mechanisms remain largely unknown. A complete understanding of the cell pathways and dynamics and of the functioning of liver stem cell niche is necessary for the clinical translation of regenerative medicine strategies. As well, it will be crucial to elucidate the mechanisms through which cells interact with the extracellular matrix, and how this latter supports and drives cell fate.

Keywords: Extracellular matrix; Liver; Regenerative medicine; Scaffold; Stem cells; Tissue engineering.

Figure 1

Gross and microscopic anatomy of acellular ferret livers. Upper row: The liver on the left is almost entirely decellularized, however it remains a segment still cellular (interrupted line); on the left, instead, the liver is fully acellular as expression of successful decellularization; Middle row: Scanning electronic microscopic ruling out the presence of any cell remnant and showing the triad completely acellular (arrow); Lower row: Hematoxylin and eosin confirms the lack of cellular element within the remaining liver extracellular matrix (arrow).

Figure 2

Movat-Pentachrome staining of acellular liver sections shows yellow staining for collagen and dark staining for elastin surrounding the vascular structures.