What is Your Cellf Identity? Depends on Who is Standing Next to You

Proliferation of bile duct like structures, referred to as ductular reaction, is prevalent in chronic liver diseases in humans and mice. In many cases the proliferating cholangiocyte-like cells are derived from mature hepatocytes, thus representing hepatocyte to cholangiocyte metaplasia (HCM). Metaplasia is the replacement of one histological identity by another. It follows chronic tissue damage, and considered a predisposition to cancer. In the liver, HCM is a potential precursor to intrahepatic cholangiocarcinoma (iCCA). Here we show that IKKβ(EE)Hep PtenΔHep mice produces massive numbers of metaplastic cells of hepatocytic origin as a result of HCM, providing a unique opportunity to examine the phenomenon in high resolution. We performed transcriptome analysis along the course of the HCM timeline. Our bioinformatic analysis suggested that retinoic acid (RA) and hepatic stellate cells (HSC) are potential early causative regulators of HCM. Immunostaining for α-smooth muscle actin (α-SMA), an HSC activation marker, revealed that HSC activation had 100% spatial correlation with HCM appearance in both IKKβ(EE)Hep PtenΔHep mice and non-transgenic liver damage models. Treating IKKβ(EE)Hep PtenΔHep mice with a pharmacologic retinoic acid receptor inhibitor abolished all characterized HCM traits, and the preceding HSC activation. Treating primary hepatocyte spheroids with RA in vitro significantly elevated metaplastic markers. Thus, our results suggest that HSC play a role in the formation of HCM via secretion of RA. Delineating the course of HCM development may shed light on its role in neoplastic and regenerative processes in the liver, and provide new opportunities for liver cancer prevention and treatment.