Human Liver Regeneration: An Etiology Dependent Process

Abstract

Regeneration of the liver has been an interesting and well-investigated topic for many decades. This etiology and time-dependent mechanism has proven to be extremely challenging to investigate, certainly in human diseases. A reason for this challenge is found in the numerous interactions of different cell components, of which some are even only temporarily present (e.g., inflammatory cells). To orchestrate regeneration of the epithelial cells, their interaction with the non-epithelial components is of utmost importance. Hepatocytes, cholangiocytes, liver progenitor cells, and peribiliary glands have proven to be compartments of regeneration. The ductular reaction is a common denominator in virtually all liver diseases; however, it is predominantly found in late-stage hepatic and biliary diseases. Ductular reaction is an intriguing example of interplay between epithelial and non-epithelial cells and encompasses bipotential liver progenitor cells which are able to compensate for the loss of the exhausted hepatocytes and cholangiocytes in biliary and hepatocytic liver diseases. In this manuscript, we focus on the etiology-specific damage that is observed in different human diseases and how the liver regulates the regenerative response in an acute and chronic setting. Furthermore, we describe the importance of morphological keynotes in different etiologies and how spatial information is of relevance for every basic and translational research of liver regeneration.

Keywords: acute liver damage; chronic liver damage; ductular reaction; human liver diseases; liver carcinogenesis; liver progenitor cell; liver regeneration.

Figure 1

Overview of liver regeneration in chronic hepatic diseases. Activation of progenitor cells is induced by senescence or exhaustion of cholangiocytes or hepatocytes. After longstanding hepatocellular damage, macrophages stimulate the proliferation of liver progenitor cells (LPCs) via the Wnt and TWEAK pathway. In chronic cholangiocytic damage, myofibroblasts influence LPCs via the Notch and YAP pathway. In addition, HSC, myofibroblasts, and macrophages regulate the extracellular matrix (ECM) through deposition of collagens and secretion of matrix metalloproteases (MMPs). Abbreviations: yes-associated protein 1 (YAP), TNF-related weak inducer of apoptosis (TWEAK), hepatic C virus (HCV), hepatocyte nuclear factor 4 alfa (HNF4α), macrophage receptor with collagenous structure (MARCO), insulin-like growth factor 2 (IGF2), platelet-derived growth factor receptor A (PDGFRA), primary sclerosing cholangitis (PSC), fibronectin (FN1), laminin subunit gamma-2 (LAMC2), C-X-C motif chemokine ligand 5 and 6 (CXCL5/6), chemokine (C-C motif) ligand 28 (CCL28), forkhead box protein J1 (FOXJ1), and jun proto-oncogene (JUN).

Figure 2

Needle biopsy of a patient with acetaminophen intoxication in the early phase. Characterized by typical centrilobular necrosis, swollen hepatocytes, and an inflammatory infiltrate (asterisk) (A). Explanted liver after acute acetaminophen overdose with some islands of remaining hepatocytes (arrowheads), surrounded by a fulminant inflammatory infiltrate. No ductular reaction present yet (B). Explanted liver after acute and chronic acetaminophen abuse with no remaining hepatocytes left. Complete collapse of the supporting framework. A prominent ductular reaction (arrows) tries to compensate for the loss of hepatocytes as a result of severe intoxication (C). Keratin-19 staining of the ductular reaction in a fulminant necrotizing toxic hepatitis (D). Original magnification ×20. Scale bar: 50 µm.

Figure 3

Needle biopsy of a patient with early non-alcoholic fatty liver disease (NAFLD) is characterized by macrovesicular steatosis and lobular inflammation (asterisk) in the centrilobular area (A). Sirius Red staining, highlighting the fibrosis in an explanted liver of a NAFLD patient, illustrates the cirrhotic end-stage of the disease by the presence of regenerative nodules of hepatocytes surrounded by bridging fibrosis (arrowheads) (B). Keratin-19 staining in a cirrhotic liver highlights the ductular reaction at the border of a nodule (arrow) (C). Keratin-7 staining in a cirrhotic liver illustrates the presence of intermediate hepatocytes and mature hepatocytes by gradual expression of CK7 (D). Original magnification ×20, scale bar 50 µm (A and C); ×10 original magnification, scale bar 200 µm (B) and ×40 original magnification, scale bar 20 µm (D).

Figure 4

Needle biopsy of a patient with early-stage primary biliary cholangitis. This is pathologically characterized by a prominent dominant lymphocytic infiltrate and interlobular bile duct damage (asterisk) (A). Sirius Red staining, highlighting the fibrosis in an explanted liver of a primary sclerosing cholangitis patient. Note the distinct fibrotic “jigsaw puzzle pattern” (arrowheads) compared to hepatocytic diseases (B). Keratin-19 staining in a cirrhotic liver highlights the ductular reaction at the border of a nodule and in the stromal component where new biliary ducts are formed (arrows) (C). Neural cell adhesion molecule (NCAM) staining of the reactive bile ducts (arrowhead) and a patchy infiltrate in the mature bile ducts (D). Adapted from [88] with permission. Original magnification ×20, scale bar 50 µm (A and C); ×10 original magnification, scale bar 200 µm (B) and ×40 original magnification, scale bar 20 µm (D).

Figure 5

The spectrum of primary liver cancer. Firstly, the typical hepatocellular carcinoma (HCC) is observed, which is characterized by a hepatocellular morphology (trabecular growth pattern) and Keratin-19 (K19) negativity (A). Secondly, a carcinoma with a hepatocellular morphology and immunohistochemical expression of progenitor cell markers (e.g., K19) is noted (B). In the middle of the spectrum is the combined hepatocellular-cholangiocarcinoma (cHCC-CCA). This carcinoma is represented by a dual morphology and immunohistochemical expression. This tumor has a morphology that still is in accordance with hepatocellular characteristics (C); it also has a component with a clear cholangiocytic (glandular) growth pattern (D). The glandular cholangiocytic derived structures are strongly expressing K19 (D). At the end of the spectrum, a typical intrahepatic cholangiocarcinoma (ICC) is noted (E). Original magnification ×20. Scale bar: 50 µm. Abbreviation: HE, hematoxylin and eosin.