Hepatic Progenitor Cells/Oval Cells Mediate Pro-inflammatory Responses upon Liver Injuries

Introduction:

Hepatocellular carcinoma (HCC) preferentially develops in the context of chronic liver damage and inflammation. Chronic liver injury results in impaired hepatocyte regeneration and activation of hepatic progenitor cells/oval cells (OCs), leading to inflammation-associated tumor formation.

The receptor for advanced glycation end products (RAGE) signaling axis is often associated with inflammatory responses in various tissues1and contributes to steatosis, fibrosis and HCC formation. During liver pathogenesis, it functions as a key regulator in OC activation mediated by damage-associated molecular pattern (DAMP) molecules that are released by immune cells and necrotic cells. Our previous study demonstrated that ablation of Rage in an inflammation-driven HCC mouse model (Mdr2-/-) delays onset of liver fibrosis, diminishes OCs expansion capacity and impairs HCC formation2.

Results:

An acute liver injury mouse model (induced by choline-deficient ethionine-supplemented (CDE) diet) was utilized to investigate OC activation in response to hepatic damages. We demonstrated that mRNA expressions of Rage, stem cell markers (EpCAM, CD44, CD133) and OC markers (Ck7, Ck19, Sox9) were found to be abundantly expressed in OCs from CDE-treated mice when compared to normal hepatocytes. Histologically, OCs were highly activated and migrated towards inflamed regions of the liver in mice fed with CDE diet.

Liver injuries induce abundant cell death in the form of necrosis, mainly of hepatocytes, and thus activate different types of liver resident cells, such as OCs, stellate cells and immune cells. Accordingly, treatment of OCs with necrotic medium (NM) prepared from hepatocytes potently activate ERK and NF-kB signaling pathways. Moreover, qPCR analyses showed that ERK and NF-kB downstream target genes, including c-fos, tnf-α, IL-6 and cxcl2, were upregulated upon NM treatment.

Summary and future perspectives:

Our previous study and recent results imply that Rage is essential for OC activation in the context of chronic liver damage and inflammation. Necrotic cells induce critical survival and pro-inflammatory pathways and genetic programs in OCs, which in turn, induce pro-tumorigenic molecules supporting tumor cell growth and survival. To delineate the underlying mechanistic and functional role of Rage in OCs during inflammation-associated hepatocarcinogenesis, we will employ OC-specific Rage knockout models to address four potential roles of Rage in OCs, including (1) OC activation, (2) OC-modulated tissue microenvironment, (3) liver inflammation and (4) HCC formation both in vitro and in vivo.

References:

1. Riehl, A., Németh, J., Angel, P. & Hess, J. The receptor RAGE: Bridging inflammation and cancer. Cell Commun. Signal.7,12 (2009).

2. Pusterla, T., Nemeth, J., Stein, I., Wiechert, L., Knigin, D., Marhenke, S., Longerich, T., Kumar, V., Arnold, B., Vogel, A., Bierhaus, A., Pikarsky, E., Hess, J., and Angel, P. Receptor for advanced glycation endproducts (RAGE) is a key regulator of oval cell activation and inflammation-associated liver carcinogenesis in mice. Hepatology.58,363 – 73 (2013).