Differentiation of progenitors in the liver: a matter of local choice

Abstract

The liver is a complex organ that requires multiple rounds of cell fate decision for development and homeostasis throughout the lifetime. During the earliest phases of organogenesis, the liver acquires a separate lineage from the pancreas and the intestine, and subsequently, the liver bud must appropriately differentiate to form metabolic hepatocytes and cholangiocytes for proper hepatic physiology. In addition, throughout life, the liver is bombarded with chemical and pathological insults, which require the activation and correct differentiation of adult progenitor cells. This Review seeks to provide an overview of the complex signaling relationships that allow these tightly regulated processes to occur.

Figure 1. Liver development involves multiple phases of specification and differentiation.

(A) During liver development, the liver bud is specified from the remainder of the endoderm by Wnt expression from the cardiac mesoderm. HSC, hepatic stellate cell. (B) Once specified, the endoderm matures into fetal hepatoblasts that are capable of bilineage differentiation into hepatocytes and cholangiocytes. (C) Spatial heterogeneity across the developing liver results in the specification of the ductal plate though activation of the Notch signaling pathway, in close proximity to what will ultimately become the portal tract. (D) Once specified, the ductal plate is patterned, and the side adjacent to the portal mesenchyme closely associates with laminin and expresses high levels of Sox9, whereas the side adjacent to the developing parenchyma expresses TGF-β–mediated C/EBP and contributes to zone-1 hepatocytes.

Figure 2. HPCs are involved in a complex microenvironment and are subject to multiple signals.

Regeneration in the liver can be broadly characterized into hepatocellular or biliary regeneration. In the former context, progenitor cells irradiate from the portal tracts, in which they are sheathed in laminin, which facilitates their expansion. Upon exit from the laminin niche, these cells are subject to differentiation cues, such as Wnt and HGF, which activate the pro-hepatocyte transcriptional cascade in HPCs. In biliary regeneration, HPCs emerge in a similar fashion, but they remain in the laminin ECM, in which fibroblasts are able to influence their maturation though activation of the Notch signaling pathway. This pathway influences the activation of the HNF6/HNF1β transcriptional network to correctly specify cholangiocytes.