Role of hepatic progenitor cells in nonalcoholic fatty liver disease development: cellular cross-talks and molecular networks

Abstract

Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases ranging from simple fatty liver to nonalcoholic steatohepatitis, (NASH) which may progress to cirrhosis and hepatocellular carcinoma. NASH has been independently correlated with atherosclerosis progression and cardiovascular risk. NASH development is characterized by intricate interactions between resident and recruited cells that enable liver damage progression. The increasing general agreement is that the cross-talk between hepatocytes, hepatic stellate cells (HSCs) and macrophages in NAFLD has a main role in the derangement of lipid homeostasis, insulin resistance, danger recognition, immune tolerance response and fibrogenesis. Moreover, several evidences have suggested that hepatic stem/progenitor cell (HPCs) activation is a component of the adaptive response of the liver to oxidative stress in NAFLD. HPC activation determines the appearance of a ductular reaction. In NASH, ductular reaction is independently correlated with progressive portal fibrosis raising the possibility of a periportal fibrogenetic pathway for fibrogenesis that is parallel to the deposition of subsinusoidal collagen in zone 3 by HSCs. Recent evidences indicated that adipokines, a class of circulating factors, have a key role in the cross-talk among HSCs, HPCs and liver macrophages. This review will be focused on cellular cross-talk and the relative molecular networks which are at the base of NASH progression and fibrosis.

Figure 1

(A) Immunohistochemistry for α-smooth muscle actin (α-SMA) in non-alcoholic fatty liver disease (NAFLD). In NAFLD, pericentral fibrogenesis is due to activation of hepatic stellate cells (HSCs) which acquire α-SMA positivity. Original Magnification: 20×; (B) Immunohistochemistry for α-smooth muscle actin (α-SMA) and Cytokeratin (CK)-7 in NAFLD. In advanced stages of NAFLD, periportal fibrogenesis is present. In this case, α-SMA positive myofibroblasts surround CK7+ reactive ductules at the periphery of portal spaces. Original Magnification: 20×; (C) Immunohistochemistry for CD68 in NAFLD. CD68 is specifically expressed by Kupffer cells and macrophages which are distributed throughout entire liver lobule both at pericentral and periportal position. Macrophage foam cells are clearly recognized in left image. Original Magnification: 20× (right) and 40× (left).

Figure 2

Cartoon indicating possible cellular cross-talks among hepatic stellate cells (HSCs), hepatic progenitor cells (HPCs) and Kupffer cells/macrophage (KC/MΦ) in NAFLD progression. Two distinct fibrogenic pathways are present in NAFLD. Pericentral fibrogenesis is due to activation of HSCs by damaged hepatocytes. On the other hand, hepatocyte damaging could stimulate HPC proliferation, thus resulting in the appearance of ductular reaction (DR); in turn, DR activates portal myofibroblasts (MF) which are responsible of periportal fibrogenesis. Finally, KC/MΦ polarization toward M1 phenotype could be involved in both pathways since M1-MΦs are able to stimulate HSCs and HPCs. PV = portal vein; CV = central vein; HA = hepatic artery.

Figure 3

Cartoon indicating possible molecular cross-talks involving hepatic stellate cells (HSCs), hepatic progenitor cells (HPCs) and liver macrophages. In NAFLD, HPCs highly proliferate determining the appearance of ductular reaction (DR). HPC proliferation is determined by the up-regulation of both Wnt and Notch pathways. DR can produce several fibrogenetic factors such as TGF-β and PDGF which, in turn, activate portal myofibroblasts and HSCs to produce type 1 collagen. In parallel, the HPCs could differentiate towards hepatocytes; this process is characterized by a down-regulation of Notch signal and could be driven by macrophage Wnt3a secretion. PV = portal vein; BD = bile duct.