Role of liver progenitors in liver regeneration

Abstract

During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs.

Keywords: Liver progenitor cells (LPCs); hepatic stellate cells (HSCs); liver cirrhosis; liver failure; liver regeneration; mesenchymal stem cells (MSCs); stem cells.

Figure 1

Depiction of liver progenitor cells (LPC) residing in the Canals of Herring (CoH) in the healthy liver tissue. Upon initial loss of hepatocytes liver regeneration is carried out by resident hepatocytes. If this mechanism is overwhelmed though by massive parenchymal injury in terms of confluent loss of hepatocytes or hepatocytic senescence, the LPC niche becomes activated in order to support and enhance the regenerative process. The progenitor cell mediated tissue reconstitution is orchestrated by several cytokines (e.g., IL-6, TNF-α, TGF-β, osteopontin), transcription factors [nuclear factor kappa B (NFKB) and CCAAT enhancer binding protein beta], morphogens (Hedgehog, Wnt, Notch, HIPPO), growth factors (HGF, EGF), hormones (thyroid, sympathetic, parasympathic) and adipokines (adipose tissue derived cytokines).

Figure 2

Overview of different sources of stem cells that can give rise to hepatocytes/cholangiocytes by differentiation, mediated by autocrine/paracrine signalling. Stem cells can be divided into pluripotent and multipotent cells, the latter are restricted to one lineage. Pluripotent cells can be divided into embryonic stem cells (ES) which can be extracted from blastocysts, or induced pluripotent stem cells that can be obtained from various adult human tissues (e.g., derived from skin tissue) by reprogramming with retroviral transfection of protein transcription factors. Multipotent cells are obtained from either human liver (HSCs or progenitor cells) or other tissues (mesenchymal stem cells) and differentiate towards either cholangiocytic or hepatocytic lineages.

Figure S1

Global distribution and different etiologies of clinical trials applying MSC transplantation for treatment of liver diseases and liver cirrhosis are depicted. [A search on www.clinicaltrials.gov (November 2014) with the term “mesenchymal stem cells” AND “liver failure”. The studies with status “completed”, “recruiting”, “not yet recruiting” were included, trials with the status “unknown” were excluded].