Rearrangement of hepatocellular F-actin precedes the formation of rosette-like structures in parenchyma of cholestatic rat liver

Abstract

The involvement of hepatocytes in proliferation of bile ductule-like structures during cholestasis remains controversial. The present study was an attempt to address the issue of whether hepatocytes transform into ductular epithelial cells in response to cholestasis and, if so, which mechanisms are involved. Cholestasis was induced by common bile duct-ligation (CBDL) in rat liver for 2, 7, and 14 days. Immunofluorescence microscopy of cytokeratin 19 (CK19) was performed to assess the proliferation of bile ductules. Hepatocellular filamentous actin (F-actin) was studied using fluorescence microscopy of 7-nitrobenzene-2-oxa-1,3-diazole phallacidin and electron microscopy. Double labeling of F-actin and laminin was performed to reveal the relationship between rearrangement of F-actin and deposition of the extracellular matrix protein. The results showed that the localization of F-actin in hepatocytes underwent considerable changes after CBDL, from an even distribution at the entire plasma membrane in control liver to a more concentrated localization at one domain of the plasma membrane. This was followed by formation of rosette-like structures in pericentral and midzonal areas of the parenchyma. CK19 was expressed, as in the control liver, in the epithelial cells of proliferated bile ductules in enlarged portal tracts but not in rosette-like structures of CBDL livers. Furthermore, CBDL induced increasing amounts of laminin in the basal lamina of bile ducts and in connective tissue of portal tracts. In parenchyma, the newly deposited laminin was in close association with the rosette-like structures. It is concluded that the rearrangement of hepatocellular F-actin after CBDL precedes the formation of rosette-like structures. It is speculated that the altered F-actin contracts at one side of hepatocytes leading to tubular structures. Laminin may play an important role in this transformation process.(HEPATOLOGY 1998;27:765-771.)

Intrahepatic cholangiocyte regeneration from an Fgf‐dependent extrahepatic progenitor niche in a zebrafish model of Alagille Syndrome

“…These observations suggest severe cholestasis in jag1b/2b mutants (Figure 1B–D). [ 17‐19 ] Nearly all double mutants die by 9 dpf, without any detectable IHD cells (Figure 1A–E).…”

“…These lipid droplets are located at the foci of rosette structures formed by hepatocytes surrounding a densely packed group of Mdr1 + canaliculi (Figure 1B). [17][18][19] Further, senescence-associated beta-galactosidase (SA β-gal) staining reveals cellular senescence throughout much of the liver of jag1b/2b mutants (Figure 1B), suggesting extensive liver damage. These observations suggest severe cholestasis in jag1b/2b mutants (Figure 1B-D).…”

Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease

“…These structures are in stark contrast to the normal bile canaliculi formed by two juxtaposed hepatocytes, and rather resemble the bile duct morphology (Fig 2C). Morphologically similar histopathological alterations were described in primary biliary cholangitis (PBC) (Nagore et al, 1989), focal nodular hyperplasia (Butron Vila et al, 1984) and chronic bile duct ligation in rats (Song et al, 1998). They were termed cholestatic liver cell rosettes to differentiate them from hepatitis liver cell rosettes (Nagore et al, 1989).…”

Actomyosin contractility drives bile regurgitation as an early response during obstructive cholestasis

“…[7] Several pathological changes that are effected consequent to increased biliary pressure have been identified, including changes in transporter expression which reduce the uptake and increase the basolateral export of bile acids, [6] and the accumulation of actin along the canalicular membrane. [8,9] Indeed, the thickening of the PAC observed in common bile duct ligation rodent models has also been observed in patients with biliary atresia. [10] However, these reports have largely been correlative; little is known about the exact sequence of events that is triggered to effect homeostatic regulation of abnormal elevations in biliary pressure.…”