Structural and functional hepatocyte polarity and liver disease

Abstract

SummaryHepatocytes form a crucially important cell layer that separates sinusoidal blood from the canalicular bile. They have a uniquely organized polarity with a basal membrane facing liver sinusoidal endothelial cells, while one or more apical poles can contribute to several bile canaliculi jointly with the directly opposing hepatocytes. Establishment and maintenance of hepatocyte polarity is essential for many functions of hepatocytes and requires carefully orchestrated cooperation between cell adhesion molecules, cell junctions, cytoskeleton, extracellular matrix and intracellular trafficking machinery. The process of hepatocyte polarization requires energy and, if abnormal, may result in severe liver disease.A number of inherited disorders affecting tight junction and intracellular trafficking proteins have been described and demonstrate clinical and pathophysiological features overlapping those of the genetic cholestatic liver diseases caused by defects in canalicular ABC transporters. Thus both structural and functional components contribute to the final hepatocyte polarity phenotype. Many acquired liver diseases target factors that determine hepatocyte polarity, such as junctional proteins. Hepatocyte depolarization frequently occurs but is rarely recognized because hematoxylin-eosin staining does not identify the bile canaliculus. However, the molecular mechanisms underlying these defects are not well understood. Here we aim to provide an update on the key factors determining hepatocyte polarity and how it is affected in inherited and acquired diseases.

Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis

“…There was, however, liver-specific enrichment for hallmark gene sets representing regulation of Kras signalling, epithelial and mesenchyme transition, angiogenesis, notch signalling and apical junction and apical surface. The latter are likely to reflect underlying changes in hepatocytes, which although not grossly abnormal in structure in H&E sections, may nevertheless have an important role in liver pathophysiology during disease 51 .…”

Characterization of hepatocyte-based in vitro systems for reliable toxicity testing

“…Immunocytochemistry analysis may be used concomitantly for in situ staining of polarity indicators at the sinusoidal/basolateral pole, like the asialoglycoprotein receptor, the sodium-potassium adenosine 5′-triphosphatase and the sodium-taurocholate cotransporter, as well as at the apical pole, including dipeptidyl peptidase IV, gamma glutamyltranspeptidase and the bile salt export pump. Furthermore, immunohistochemistry analysis of markers of mature hepatocyte cyto-architecture, such as the intermediate filament cytokeratin 18, can be performed (Gissen and Arias 2015;Treyer and Müsch 2013). Clearly, the most convincing evidence relates to functional polarity (Deharde et al 2016).…”

Take a deep breath and digest the material: organoids and biomaterials of the respiratory and digestive systems

“…[82][83][84]88] When hepatocytes fail to function, the onset of liver disease occurs and in extreme cases requires organ transplantation. [86,88,89] Cultured hepatocyte cells could be used as a source to restore normal liver function in patients with liver disease. [85,88] Although two-dimensional cultures of hepatocytes have been used for drug discovery and cell transplantation, these systems lack some hepatocyte function, cellular and structural organization, and interactions with the surrounding nonhepatocyte tissues such as the ducts, stroma, and vasculature.…”

“…Moreover, hepatocyte function varies, and depends if the hepatocyte is near a central vein or bile duct. [89,90] Therefore, the presence of vasculature or ducts is essential to fully recapitulate the function of the hepatocytes. Current liver organoid models have incorporated the vasculature by either co-culturing with vasculature cells and/or transplantation using the host vasculature.…”