Proliferating Cholangiocytes: A Neuroendocrine Compartment in the Diseased Liver

Alvaro, Domenico; Mancino, Maria Grazia; Glaser, Shannon; Gaudio, Eugenio; Marzioni, Marco; Francis, Heather; Alpini, Gianfranco

doi:10.1053/j.gastro.2006.07.023

Cited by 260 publications

(316 citation statements)

References 161 publications

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“…Consistent with the concept that decreased cholangiocyte proliferation is associated with reduced cAMP levels (a key regulator of cholangiocyte proliferation), [1][2][3]5 in vivo treatment of BDL rats with RAMH significantly (Po0.05) decreased intracellular cAMP levels (82.9775.50 fmol/1 Â 10 5 cells, n ¼ 7) of purified cholangiocytes compared to cholangiocyte cAMP levels from NaCl-treated BDL rats (111.1078.57 fmol/1 Â 10 5 cells, n ¼ 7). Administration of RAMH to normal rats did not alter cAMP levels of cholangiocytes compared to cholangiocytes from normal rats treated with NaCl (not shown).…”

Section: Histamine Regulation Of Cholangiocyte Growth H Francis Et Alsupporting

confidence: 59%

“…45 A major event to be considered is the impairment of the proliferative response of cholangiocytes, which involves apoptotic cell death. 1,45,46 Apoptosis of cholangiocytes in the course of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (the two most common of the cholangiopathies) 1,45 has been associated with the local release of mediators by cells of the immune system. [47][48][49] Indeed, some of those mediators like nitric oxide and cytokines have been shown to affect cholangiocyte biology.…”

Section: Discussionmentioning

confidence: 99%

“…Following incubation at 371C for 1 h, intracellular cAMP levels (a key player in the regulation of cholangiocyte hyperplasia) [1][2][3]5 were determined in cells treated at room temperature for 5 min 38,39 with (i) 0.2% BSA or (ii) RAMH (10 mM) in the absence or presence of pertussis toxin (PTX) (1 mM). 40 To determine that RAMH has no effect on the Ga o activated signaling pathway (phospholipase C/IP 3 /Ca 2 þ / PKCa-dependent pathway), 41,42 we measured intracellular IP 3 levels in cholangiocytes stimulated at room temperature for 10 min 43 with (i) 0.2% BSA or (ii) RAMH (10 mM).…”

Section: In Vitro Studiesmentioning

confidence: 99%

“…22 The rationale for studying the role of H3R in the regulation of cholangiocyte growth in BDL rats is first based on the fact that H3R exerts their effects by coupling to Ga i/o proteins with inhibition of adenylyl cyclase, 21,22 a key factor in the regulation of cholangiocyte growth. [1][2][3]5 The aims of our study were to: (i) evaluate the presence of H3R protein in bile ducts from normal and BDL rat liver sections; (ii) study the expression of H3R mRNA in purified cholangiocytes from normal and BDL rats; (iii) determine the in vivo effect of (a) the H3R agonist, (R)-(a)-(À)-methylhistamine dihydrobromide (RAMH), 23,24 (b) the H3 HR antagonist, thioperamide maleate 25,26 and (c) histamine, in the absence or presence of thioperamide maleate, on cholangiocyte proliferation in BDL rats; and (iv) to elucidate, in purified BDL cholangiocytes, the transduction mechanisms by which RAMH regulates the proliferation of these cells.…”

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confidence: 99%

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H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway

Francis

Franchitto

Ueno

et al. 2007

Laboratory Investigation

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152

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Histamine regulates many functions by binding to four histamine G-coupled receptor proteins (H1R, H2R, H3R and H4R). As H3R exerts their effects by coupling to Ga i/o proteins reducing adenosine 3 0 , 5 0 -monophosphate (cAMP) levels (a key player in the modulation of cholangiocyte hyperplasia/damage), we evaluated the role of H3R in the regulation of biliary growth. We posed the following questions: (1) Do cholangiocytes express H3R? (2) Does in vivo administration of (R)-(a)-(À)-methylhistamine dihydrobromide (RAMH) (H3R agonist), thioperamide maleate (H3R antagonist) or histamine, in the absence/presence of thioperamide maleate, to bile duct ligated (BDL) rats regulate cholangiocyte proliferation? and (3) Does RAMH inhibit cholangiocyte proliferation by downregulation of cAMP-dependent phosphorylation of protein kinase A (PKA)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ets-like gene-1 (Elk-1)? The expression of H3R was evaluated in liver sections by immunohistochemistry and immunofluorescence, and by real-time PCR in cholangiocyte RNA from normal and BDL rats. BDL rats (immediately after BDL) were treated daily with RAMH, thioperamide maleate or histamine in the absence/presence of thioperamide maleate for 1 week. Following in vivo treatment of BDL rats with RAMH for 1 week, and in vitro stimulation of BDL cholangiocytes with RAMH, we evaluated cholangiocyte proliferation, cAMP levels and PKA, ERK1/2 and Elk-1 phosphorylation. Cholangiocytes from normal and BDL rats express H3R. The expression of H3R mRNA increased in BDL compared to normal cholangiocytes. Histamine decreased cholangiocyte growth of BDL rats to a lower extent than that observed in BDL RAMH-treated rats; histamine-induced inhibition of cholangiocyte growth was partly blocked by thioperamide maleate. In BDL rats treated with thioperamide maleate, cholangiocyte hyperplasia was slightly higher than that of BDL rats. In vitro, RAMH inhibited the proliferation of BDL cholangiocytes. RAMH inhibition of cholangiocyte growth was associated with decreased cAMP levels and PKA/ERK1/2/Elk-1 phosphorylation. Downregulation of cAMP-dependent PKA/ERK1/2/Elk-1 phosphorylation (by activation of H3R) is important in the inhibition of cholangiocyte growth in liver diseases.

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Section: Histamine Regulation Of Cholangiocyte Growth H Francis Et Alsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: In Vitro Studiesmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway

Francis

Franchitto

Ueno

et al. 2007

Laboratory Investigation

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152

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“…1,2 This process is called the atypical ductular reaction, and it has been interpreted as a regenerative proliferation of so-called hepatic progenitor cells, which are believed to be present in the vicinity of the portal tract. 3,4 However, this reaction might also be due to the ductular metaplasia of hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Sone

Nishikawa

Nagahama

et al. 2012

The American Journal of Pathology

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We previously demonstrated that mature rat hepatocytes transdifferentiate to bile ductular cells when cultured in a three-dimensional collagen-rich matrix. Here, we show that the phenotype of transdifferentiated hepatocytes can be reversed by modulating culture conditions. Spheroidal aggregates of hepatocytes were cultured within a collagen gel matrix in the presence of serum and tumor necrosis factor-α. Spheroids transformed into ductular structures composed of small cuboidal cells, lost the expression of hepatocytic markers, while aberrantly expressed bile ductular markers. The transdifferentiated cells were then retrieved from the gels, plated on Matrigel-coated surfaces, and cultured in serum-free media. Cells spontaneously formed spheroidal aggregates and recovered hepatocytic phenotype. While Dexamethasone (Dex), which suppressed the phosphorylation of ERK and Jun N-terminal kinase, facilitated the recovery, the combination with interleukin-6 or oncostatin M resulted in the recovery of HNF-4α protein expression and the typical hepatocytic morphology and a decrease in the expression of bile ductular markers. A cDNA microarray analysis revealed that the hepatocyte-specific mRNA expression profile was recovered in these cells. Our results demonstrate that hepatocytes are able to recover their phenotypes following bile ductular transdifferentiation, suggesting that hepatocytic and bile ductular phenotypes may be mutually reversible.4

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Cholangiocyte Functions in Health and Disease: The Ciliary Connection

Masyuk

LaRusso

2009

The Liver

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Proliferating Cholangiocytes: A Neuroendocrine Compartment in the Diseased Liver

Cited by 260 publications

References 161 publications

H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway

H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Cholangiocyte Functions in Health and Disease: The Ciliary Connection

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