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.

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

“…Notably, module 39 contains Krt19, a marker for bile duct epithelial cells. 29,30 Thus, for a given avgAbsEG, higher expression of module 39 genes predicts BDH indicating a mechanism involving extracellular matrix remodeling (Table 1). Further, multiple modules can be combined within classifiers for predicting 29-day study outcomes (adverse versus non-adverse) using compound-induced expression changes at 1 or 4 days, improving Utilizing modules to enable marker gene identification via a two-step approach Molecular markers for toxicity (and other) phenotypes are usually defined at the gene level.…”

“…29 BDH (expansion of bile duct epithelia), a common sequela of cholestasis, may occur with or without cooccurring fibrosis (stellate cell activation), oval cell hyperplasia (expansion of hepatic precursor cells), and inflammation due to Kupffer cell activation and/or invading lymphocytes. 30,36,37 Characterizing BDH as adverse or non-adverse may depend on the severity of hyperplasia, the morphology of the biliary epithelium, occurrence of inflammation, and other factors. 38 We conducted a rat bile duct ligation study, a common model for cholestatic liver injury and BDH, 39,40 and monitored injury and expression changes from 3 h through 14 days.…”

Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment

“…Accordingly, regeneration following most types of injury or after partial hepatectomy is achieved from the hepatocyte pool without major contribution of progenitor cells (3,8). However, when liver injury is chronic and when the ability of mature hepatocytes to proliferate is blocked, a reserve cell compartment located within the biliary compartment -often termed oval cells or liver progenitor cells (LPCs) -expands in patients and in experimental injury models and may contribute to the formation of hepatocytes (3,7,(9)(10)(11)(12)(13). However, several recent fate-tracing studies have challenged a major role for the LPC/ biliary compartment in the formation of hepatocytes, showing either no or only very little contribution to the hepatocyte pool (8,(14)(15)(16)(17)(18).…”

Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling

“…However, regeneration of a diseased liver relies on activation of resident stem cells to replace the irreversibly damaged hepatocytes and biliary cells, which lose the capacity to proliferate ; Thorgeirsson and Grisham 2003;Duncan et al 2009;Boulter et al 2013). Hepatic stem cells are thought to reside within the terminal bile ductules, also referred to as Hering canals (Alison et al 1996;Theise et al 1999).…”