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Cholangiocyte primary cilia in liver health and disease

Mayo Clinic College of Medicine, Department of Internal Medicine, Rochester, Minnesota 55905, USA.
Developmental Dynamics (Impact Factor: 2.67). 08/2008; 237(8):2007-12. DOI: 10.1002/dvdy.21530
Source: PubMed

ABSTRACT The epithelial cells lining intrahepatic bile ducts (i.e., cholangiocytes), like many cell types in the body, have primary cilia extending from the apical plasma membrane into the bile ductal lumen. Cholangiocyte cilia express proteins such as polycystin-1, polycystin-2, fibrocystin, TRPV4, P2Y12, AC6, that account for ciliary mechano-, osmo-, and chemo-sensory functions; when these processes are disturbed by mutations in genes encoding ciliary-associated proteins, liver diseases (i.e., cholangiociliopathies) result. The cholangiociliopathies include but are not limited to cystic and fibrotic liver diseases associated with mutations in genes encoding polycystin-1, polycystin-2, and fibrocystin. In this review, we discuss the functions of cholangiocyte primary cilia, their role in the cholangiociliopathies, and potential therapeutic approaches.

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    • "Monocilia, or primary cilia, are a normal feature of bile ducts as they have been previously documented in freshly isolated normal rat liver bile duct cells (Ishii et al. 1989) and in the ultrastructural analysis of intact human (Enzan et al. 1974) and porcine (Singh and Shahidi 1986) liver. Because the primary cilium is essential in the normal functioning of bile ducts, this is an important feature of our pig hepatocyte/cholangiocyte culture system (Gradilone et al. 2007; Masyuk et al. 2008; Keitel et al. 2010). Monocilia have also been identified by transmission electron microscopy in collagen gel cultures of hyperplastic rat bile duct cells, where cystic multicellular structures formed in a 3-D collagen matrix that was provided (Sirica and Gainey 1997). "
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    ABSTRACT: A serum-free, feeder cell-dependent, selective culture system for the long-term culture of porcine hepatocytes or cholangiocytes was developed. Liver cells were isolated from 1-wk-old pigs or young adult pigs (25 and 63 kg live weight) and were placed in primary culture on feeder cell layers of mitotically blocked mouse fibroblasts. In serum-free medium containing 1% DMSO and 1 μM dexamethasone, confluent monolayers of hepatocytes formed and could be maintained for several wk. Light and electron microscopic analysis showed hepatocytes with in vivo-like morphology, and many hepatocytes were sandwiched between the feeder cells. When isolated liver cells were cultured in medium without dexamethasone but with 0.5% DMSO, monolayers of cholangioctyes formed that subsequently self-organized into networks of multicellular ductal structures, and whose cells had monocilia projecting into the lumen of the duct. Gamma-glutamyl transpeptidase (GGT) was expressed by the cholangiocytes at their apical membranes, i.e., at the inner surface of the ducts. Cellular GGT activity increased concomitantly with the development of ductal structures. Cytochrome P-450 was determined in microsomes following addition of metyrapone to the cultures. In vivo-like levels of P-450s were found in hepatocyte monolayers while levels of P-450 were markedly reduced in cholangiocyte monolayers. Serum protein secretion in conditioned media was analyzed by Western blot and indicated that albumin, transferrin, and haptoglobin levels were maintained in hepatocytes while albumin and haptoglobin declined over time in cholangiocytes. Quantitative RT-PCR analysis showed that serum protein mRNA levels were significantly elevated in the hepatocytes monolayers in comparison to the bile ductule-containing monolayers. Further, mRNAs specific to cholangiocyte differentiation and function were significantly elevated in bile ductule monolayers in comparison to hepatocyte monolayers. The results demonstrate an in vitro model for the study of either porcine hepatocytes or cholangiocytes with in vivo-like morphology and function.
    In Vitro Cellular & Developmental Biology - Animal 02/2011; 47(3):218-33. DOI:10.1007/s11626-010-9382-3 · 1.00 Impact Factor
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    • "Primary cilia host critical signal transduction pathways that involve Hedgehog, Wnt, PDGFR-alpha, and integrin signaling. They also sense chemical, osmotic, and mechanical stimuli such as luminal fluid flow, and regulate important cellular functions including proliferation and maintenance of planar cell polarity and mitotic spindle orientation to ensure normal epithelial function and normal diameter of tubular structures such as renal and biliary ducts [Masyuk et al., 2008; Rodat- Despoix and Delmas, 2009]. HRFCDs belong to the larger group of disorders collectively referred to as " ciliopathies " [Veland et al., 2009]. "
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    ABSTRACT: Hepatorenal fibrocystic diseases (HRFCDs) are among the most common inherited human disorders. The discovery that proteins defective in the autosomal dominant and recessive polycystic kidney diseases (ADPKD and ARPKD) localize to the primary cilia and the recognition of the role these organelles play in the pathogenesis of HRFCDs led to the term "ciliopathies." While ADPKD and ARPKD are the most common ciliopathies associated with both liver and kidney disease, variable degrees of renal and/or hepatic involvement occur in many other ciliopathies, including Joubert, Bardet-Biedl, Meckel-Gruber, and oral-facial-digital syndromes. The ductal plate malformation (DPM), a developmental abnormality of the portobiliary system, is the basis of the liver disease in ciliopathies that manifest congenital hepatic fibrosis (CHF), Caroli syndrome (CS), and polycystic liver disease (PLD). Hepatocellular function remains relatively preserved in ciliopathy-associated liver diseases. The major morbidity associated with CHF is portal hypertension (PH), often leading to esophageal varices and hypersplenism. In addition, CD predisposes to recurrent cholangitis. PLD is not typically associated with PH, but may result in complications due to mass effects. The kidney pathology in ciliopathies ranges from non-functional cystic dysplastic kidneys to an isolated urinary concentration defect; the disorders contributing to this pathology, in addition to ADPKD and ARPKD, include nephronophithisis (NPHP), glomerulocystic kidney disease and medullary sponge kidneys. Decreased urinary concentration ability, resulting in polyuria and polydypsia, is the first and most common renal symptom in ciliopathies. While the majority of ADPKD, ARPKD, and NPHP patients require renal transplantation, the frequency and rate of progression to renal failure varies considerably in other ciliopathies. This review focuses on the kidney and liver disease found in the different ciliopathies.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 11/2009; 151C(4):296-306. DOI:10.1002/ajmg.c.30225 · 3.54 Impact Factor
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    ABSTRACT: Within many mechanosensitive tissues and organs such as vascular endothelium, renal and liver epithelium, and bone, the cells residing within them are exposed to fluid flow. The process by which flow-induced mechanical loads are sensed by these cells and transduced into a biochemical signal is mostly unknown. The primary cilium is a rod-like, microtubule-based structure that projects from the cell surface into the extracellular environment. By possessing (1) mechanical characteristics that allow it to deflect under fluid flow, and (2) a number of receptors, channels, and signaling molecules, the primary cilium is uniquely suited to function as a cellular “flow sensor”. In our review of the primary cilium and its role in sensing of fluid flow, we consider ciliary mechanobiology from both biological and mechanical perspectives. The first part of this chapter focuses on comparing and contrasting ciliary flow sensing mechanisms in kidney epithelial cells, cardiovascular endothelial cells, bile duct epithelial cells, nodal cells, and bone cells. We demonstrate that ciliary sensation of fluid flow can involve molecular mechanisms that are shared across diverse cell types, yet can also uniquely differ between cell types as well. The second part of this chapter focuses on ciliary mechanics. In particular, we review the contribution of various ciliary components to the mechanical behavior of the cilium, and efforts to mechanically model cilium deflection under flow.
    01/1970: pages 99-124;
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