Activation of stem cells in hepatic diseases

Abstract

The liver has enormous regenerative capacity. Following acute liver injury, hepatocyte division regenerates the parenchyma but, if this capacity is overwhelmed during massive or chronic liver injury, the intrinsic hepatic progenitor cells (HPCs) termed oval cells are activated. These HPCs are bipotential and can regenerate both biliary epithelia and hepatocytes. Multiple signalling pathways contribute to the complex mechanism controlling the behaviour of the HPCs. These signals are delivered primarily by the surrounding microenvironment. During liver disease, stem cells extrinsic to the liver are activated and bone-marrow-derived cells play a role in the generation of fibrosis during liver injury and its resolution. Here, we review our current understanding of the role of stem cells during liver disease and their mechanisms of activation.

Fig. 1

Injury of the healthy liver (a) may be repaired in two ways. Either regeneration from the fully differentiated hepatocyte compartment (brown) is maintained (b) or it is impaired (e). In the case of maintained hepatocyte proliferation, replacement of damaged hepatocytes is quickly and efficiently achieved by division of pre-existing hepatocytes (c) resulting in the restoration of hepatocyte number (d) without expansion of HPCs. If hepatocyte injury occurs in the context of impaired hepatocyte proliferation (e), then stem cells (grey) located in the terminal biliary tree (green) are activated leading to the generation of a transit amplifying compartment (black, f), which spreads into the liver parenchyma (g). These cells are able to replace damaged hepatocytes, often forming regenerative nodules (h)

Fig. 2

Human ductular reaction in a patient with recurrent hepatitis C infection following cadaveric liver transplantation. a Pre-perfusion biopsy of donor liver prior to both implantation and hepatitis C infection; note the CK7⁺ cells in the bile ducts (arrows). b, c Biopsies from the same liver 1 and 6 months, respectively, after transplantation and hepatitis C infection. These sections show CK7⁺ HPCs (arrowheads) extending from the periportal regions into the parenchyma.

Fig. 3

A variety of influence HPC behaviour by modulating mitosis, differentiation and migration (abbreviations are explained in Table 1 and in the Abbreviations list)

Fig. 4

Overview of HPC activation during liver injury. During hepatic injury, regeneration of hepatocytes may occur from hepatocytes or by expansion and differentiation of HPCs. Bone marrow stem cells (BMSC) are also activated forming macrophages, myofibroblasts and endothelial cells. Macrophages may fuse with hepatocytes. Macrophages and myofibroblasts also play key roles in both the production and resolution of fibrosis in the liver