TWEAK induces liver progenitor cell proliferation

Abstract

Progenitor ("oval") cell expansion accompanies many forms of liver injury, including alcohol toxicity and submassive parenchymal necrosis as well as experimental injury models featuring blocked hepatocyte replication. Oval cells can potentially become either hepatocytes or biliary epithelial cells and may be critical to liver regeneration, particularly when hepatocyte replication is impaired. The regulation of oval cell proliferation is incompletely understood. Herein we present evidence that a TNF family member called TWEAK (TNF-like weak inducer of apoptosis) stimulates oval cell proliferation in mouse liver through its receptor Fn14. TWEAK has no effect on mature hepatocytes and thus appears to be selective for oval cells. Transgenic mice overexpressing TWEAK in hepatocytes exhibit periportal oval cell hyperplasia. A similar phenotype was obtained in adult wild-type mice, but not Fn14-null mice, by administering TWEAK-expressing adenovirus. Oval cell expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was significantly reduced in Fn14-null mice as well as in adult wild-type mice with a blocking anti-TWEAK mAb. Importantly, TWEAK stimulated the proliferation of an oval cell culture model. Finally, we show increased Fn14 expression in chronic hepatitis C and other human liver diseases relative to its expression in normal liver, which suggests a role for the TWEAK/Fn14 pathway in human liver injury. We conclude that TWEAK has a selective mitogenic effect for liver oval cells that distinguishes it from other previously described growth factors.

Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins

“…OV6/CK19/Rab3b + hepatic progenitors may be more susceptible to the microenvironment, rendering growth of these cells in culture more fastidious. A recent study has demonstrated that a TNF family member called TWEAK (TNF-like weak inducer of apoptosis) specifically stimulated endogenous hepatic oval cell proliferation both in vivo and in vitro [53]. This selective mitogen may provide a valuable tool to discriminate between endogenous and HSCs-derived hepatic progenitor cells as well as potentially permitting expansion of the former in culture.…”

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…Oval cells are derived from the canal of Hering, and in rodents this canal barely extends beyond the limiting plate ( Figures 4, 5); in contrast, in human liver the organization of the biliary tree is different, with the canal of Hering extending to the proximate third of the lobule [68] and so apparently requiring a name change from oval cells to 'hepatic progenitor cells' (HPCs) [69]. An enormous range of markers has been used to identify ovals cells (Table 2) [70][71][72][73][74][75][76][77][78][79][80][81][82][83] and some, such as Dlk, may signal imminent hepatocyte differentiation [71]. A popular experimental procedure to elicit an oval cell response in rats is to pre-treat the animals with 2-acetylaminofluorene (2-AAF) before performing a two-thirds PH (the 2-AAF/PH protocol).…”

“…Hedgehog (Hh) signalling acting through the receptor Patched (PTC) on oval cells/HPCs is required for their survival [76]. Perhaps most significantly, inflammatory cells produce a range of cytokines and chemokines that initiate the response [82,83]; SDF-1 attracts CXCR4 + T cells, and these cells express TNF-like weak inducer of apoptosis (TWEAK), which stimulates oval cell proliferation by engaging its receptor Fn14 [80]. Other elements of the inflammatory response that may stimulate oval cells include lymphotoxin-β, IFNγ , TNFα and even histamine [81].…”

Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells

“…In this respect, the 2005 report by Jakubowski and coworkers 8 was a milestone publication; it proposed a TNF family member, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), as a direct LPC mitogen. Like most TNF superfamily ligands, TWEAK [also known as tumor necrosis factor (ligand) superfamily member 12, CD255, or previously APO3 ligand] is initially synthesized as a type II transmembrane protein that can be cleaved into a soluble cytokine.…”

“…This hypothesized relationship between LPCs and Fn14 signaling was strengthened by experiments described by Jakubowski and coworkers. 8 In their study, it was demonstrated that hepatic TWEAK overexpression, after transgenic or adenoviral delivery, induces an LPC response; knockout (KO) of TWEAK/Fn14 inhibits the appearance of LPCs in an experimental model of oval cell proliferation. Furthermore, TWEAK directly induces proliferation of a biliary epithelial cell line with progenitor-like characteristics.…”