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Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

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Functional Heterogeneity of the Intrahepatic Biliary Epithelium

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Summary

In this book chapter, we discuss the latest findings related to the concept that the bile duct system is heterogeneous regarding: (i) morphological characteristics; (ii) physiological response to gastrointestinal hormones/peptides; (iii) apoptotic and proliferative activity in response to liver injury/toxins. We will first review the anatomy and morphological features of the bile duct system. Following a brief overview on cholangiocyte functions, we will describe the in vivo models and in vitro experimental tools allowing us to define that small and large cholangiocytes (which line small and large bile ducts) are functionally heterogeneous. Following an overview on the receptors/transporters/channels that are differentially expressed by cholangiocytes, we will discuss the different sized ducts that differentially respond to hepatic injury/toxins.

Overview of Biliary Anatomy and Morphology

In the liver, there are two types of epithelia parenchymal and biliary.1,2 The predominant epithelial cell type, hepatocytes, is responsible for the initiation of bile secretion by the active transport of bile acids into the bile canaliculus.3 Intrahepatic bile duct cells (i.e., cholangiocytes) are organized in a simple epithelium, which line a three dimensional network of interconnecting ducts of different sizes.2,4 This three-dimensional web of interconnecting ducts extends from the canals of Hering to the extrahepatic ducts.5 The function of hepatocytes is to secrete bile at the bile canaliculus,3 whereas cholangiocytes modify bile of canalicular origin by a series of spontaneous and hormone regulated reabsorptive and secretory events before it reaches the duodenum.2,5,6

In humans, the intrahepatic biliary epithelium has been divided based upon the size of the ducts: small bile ductules (<15 μm in diameter), interlobular ducts (15-100 μm in diameter), septal ducts (100-300 μm in diameter), area ducts (300-400 μm in diameter), segmental ducts (400-800 μm in diameter) and hepatic ducts (> 800 μm in diameter)5,7 (Table 1). The intrahepatic biliary epithelium is formed by ducts of different sizes ranging from 5-100 μm in external diameter and cholangiocytes of different cell area (8 to 80-100 μm2).8 The rat intrahepatic biliary epithelium has been classified based upon heterogeneity in function of small (< 15 μm in diameter) and large (> 15 μm in diameter) ducts.5,9 A significant relationship exists between cholangiocyte area and external bile duct diameter.8 For example, in situ and in vitro studies have shown that small ducts are lined by small cholangiocytes (approximately 8 μm in diameter) whereas large ducts are lined by large cholangiocytes (≥15 μm in diameter).8-11 This finding is of particular importance since it allows for the assignment of functions of isolated small and large cholangiocytes to the different sized portions of the intrahepatic biliary tree in situ. The anatomical relationship between the human and rat liver is undefined.5 However, small bile ducts in rats are thought to correspond to bile ductules in humans and large bile ducts in rats may correspond to human interlobular bile ducts (Table 1).5

Table 1. Terminology and relationship between human and rat intraheptic bile ducts.

Table 1

Terminology and relationship between human and rat intraheptic bile ducts.

Transmission electron microscopic analysis of rat liver sections and isolated rat intrahepatic bile duct units (IBDU) reveal that large bile ducts are lined by 8-15 cholangiocytes whereas small ducts are lined by 4-5 cells.9,12 Both small and large cholangiocytes have multilobulated nucleus, numerous vesicles at the subapical region, tight junctions, high density of microvilli, lysosomes and a few mitochondria.9,12 Large cholangiocytes have a columnar shape whereas small cholangiocytes have a “roughly cubic” shape.12 The Golgi apparatus is abundant and it is located between the apical pole and the nucleus.12 Large cholangiocytes have a small nucleus and conspicuous cytoplasm, whereas small cholangiocytes possess a high nucleus/cytoplasm ratio.12 The different nucleus/cytoplasm ratio seen between small and large cholangiocytes12 may be an important explanation for the functional heterogeneity of small and large cholangiocytes. We suggest that the presence of a larger nucleus (where messenger RNA synthesis occurs) and smaller cytoplasm in small cholangiocytes suggests that small cholangiocytes may be primordial “stem” cells, whereas large cholangiocytes (with a larger cytoplasm area, where RNA translation occurs) represent more sophisticated, differentiated cells; thus able to synthesize membrane receptors and transporters and react responsively to agonists (e.g., secretin, somatostatin and endothelin-1).2,8-11,13

Cholangiocyte Functions

The secretory activity of cholangiocytes is regulated by a number of gastrointestinal hormones (e.g., secretin, gastrin, somatostatin, bombesin and vasoactive intestinal peptide),2,5,6,8-11,14-18 peptides (i.e., endothelin-1),13 enzymes,19 bile acids20,21 and nerves.22,23 Secretin has been shown to be an important component in the regulation of ductal secretion.2,6,8-11,17,23 Secretin is a 27-amino acid neuroendocrine peptide synthesized by S cells localized mainly in the mucosal of the duodenum and proximal jejunum.24,25 The secretin receptor is expressed in a number of organs including the pancreas and heart.26 In rat liver, secretin receptor is expressed only by cholangiocytes,27 which makes this receptor a unique tool for evaluating the functional heterogeneity of cholangiocytes.8-11 When secretin interacts with its receptor,8-11,27 there is an induction of intracellular cAMP levels8-11,17,23 and increased cAMP dependent protein kinase (PKA) activity.28 PKA phosphorylates the cystic fibrosis transmembrane regulator (CFTR) generating an efflux of chloride,11,29 thereby leading to the activation of the Cl-/HCO3- exchanger8,30 resulting in the secretion of bicarbonate in bile.6,14,17 Somatostatin, another gastrointestinal hormone of importance, has been shown to inhibit secretin-stimulated cAMP levels and Cl-/HCO3- exchanger activity through interaction with SSTR2 receptors, leading to a decrease in ductal bicarbonate secretion.10,14

Cholangiocytes are mitotically dormant under normal physiological conditions.10,31 However, cholangiocytes respond to pathological perturbations leading to cholangiocyte proliferation (hyperplasia)6,10,32 or loss (ductopenia).33,34 In animal models, cholangiocytes proliferatein response to bile duct ligation (BDL),6,10,32 partial hepatectomy,31 chronic feeding of bile acids (i.e., taurocholate and taurolithocholate)21,35 or alpha-napthylisothiocyanate (ANIT).34 Ductopenia has been observed in large ducts following acute administration of CCl4 to normal or BDL rats.36,37

In Vivo and in Vitro Experimental Models

The recent development of in vivo models and in vitro techniques have led to an explosion in the knowledge related to the concept that the intrahepatic biliary epithelium is morphologically and functionally heterogeneous.2,8-11 The in vivo models (e.g., BDL, CCl4 administration, partial hepatectomy and feeding of ANIT or bile salts) are pathophysiologically important since this has allowed us to evaluate the apoptotic, proliferative and secretory responses of specific duct sized to liver injury/toxins (see section on proliferative heterogeneity and apoptotic susceptibility of small and large cholangiocytes in response to injury and toxins).2,8-11,20,23,35-39 A major advancement came from the development of distinct subpopulations of small (<8 μm in size) and large (>15 μm in diameter) cholangiocytes or small (<15 μm in diameter) and large (>15 μm in diameter) IBDU from specific portions of the intrahepatic biliary ductal system, which allowed us to begin to define the heterogeneous functions of specific sized ducts of the intrahepatic biliary tree.2,8-11,20,23,35-39 The detailed isolation, phenotypic and functional characterization of small and large cholangiocytes or IBDU is described in detail elsewhere.8-11,34,36,37

Functional Heterogeneity Found in Other Epithelia

The functional heterogeneity of cholangiocytes is similar to other epithelial cells, which line several tissues and organs, such as renal tubular cells in the kidney40-42 and enterocytes in the intestine.43,44 In the kidney, transepithelial water movement is regulated in the proximal tubule and the descending limb of Henle's loop by aquaporin water channels.42 In the small and large intestine, enterocytes heterogeneously express the membrane transporters involved in the absorptive and secretory processes along the length of the crypt-villus axis.43,44

Heterogeneity of Cholangiocytes

Small Cholangiocytes

Small murine bile ducts express annexin-V.45 Since annexin-V is involved in the regulation of cell apoptosis,46 this finding45 raises the possibility that small ducts may be more resistant than large ducts to hepatic injury/toxins. In support of this notion, recent studies have shown that bcl-2 (an anti-apoptotic protein)47 is expressed by ductules and small bile ducts in normal human liver and human liver with cirrhosis and focal nodular hyperplasia.48

Recent work by our group has suggested that small cholangiocytes may be primordial, undifferentiated cells that line a tube structure responsible for carrying bile from the bile canaliculus to the large bile ducts where the bile is modified by hormone responsive large cholangiocytes.8- 11 In contrast to large cholangiocytes, 8-11 small cholangiocytes do not express secretin or somatostatin SSTR2 receptor; nor do they respond to secretin or somatostatin in normal physiological conditions. Small cholangiocytes are also considered to be mitotically dormant.8-11 However, in certain animal models (e.g., after acute CCl4 administration or chronic ANIT feeding)34,36,37 when there is damage of large cholangiocytes associated with a loss of proliferative and secretory capacity,34,36,37 small cholangiocytes transiently compensate for this loss by de novo activation of secretory activity (including expression of secretin receptor) and proliferative capacity.34,36,37

Small cholangiocytes have been shown to de novo express the apical bile acid transporter (ABAT) and to proliferate (Fig. 1) during chronic feeding of taurocholate and taurolithocholate.35 Small cholangiocytes have also been shown to express the receptors for endothelin (ETA and ETB). Endothelin signals through the activation of intracellular Ca2+.13 Also, preliminary data from our laboratory (Glaser and Alpini, unpublished observations, 2002) has demonstrated that small cholangiocytes express the receptors for M3 acetylcholine, alpha 1 adrenergic and D2 dopaminergic agonists and insulin, which also signal through activation of intracellular Ca2+.22,49-54 Currently, work is in progress in our laboratory to determine if small ducts participate in ductal bile flow by secreting water and electrolytes through a Ca2+-dependent pathway independent from the cAMP-dependent pathway observed in large cholangiocytes. A schematic representation of the possible intracellular signaling mechanism for secretion in small cholangiocytes is shown in (Fig. 2A).

Figure 1. Proliferative capacity of small and large cholangiocytes purified from TC-, TLC, or control-fed rats was assessed by measurement of PCNA protein expression by western blot analysis.

Figure 1

Proliferative capacity of small and large cholangiocytes purified from TC-, TLC, or control-fed rats was assessed by measurement of PCNA protein expression by western blot analysis. Both taurocholate and taurolithocholate feeding increases proliferative (more...)

Figure 2A. Schematic cartoon related to the possible role of small cholangiocytes on ductal secretion.

Figure 2A

Schematic cartoon related to the possible role of small cholangiocytes on ductal secretion. The above cartoon shows that small cholangiocytes (that do not express the receptor for secretin and somatostatin and are unresponsive to these two hormones) express (more...)

Large Cholangiocytes

The blood group sialylated Lewisa antigens are expressed by human large septal bile ducts.55 In normal human liver and in those from patients with extrahepatic bile duct obstruction, the hepatic, segmental, area, and septal bile ducts, and peribiliary glands express pancreatic enzymes (i.e., pancreatic lipase, pancreatic α-amylase, and trypsin).56,57 Large cholangiocytes are the major contributors to hormone- and bile acid-regulated bile flow in the biliary tree.8-11,20,21,30,36,37 Previous studies have shown that large cholangiocytes, in contrast to small cholangiocytes, are well-differentiated cells capable of absorption, secretion and transport of water and electrolytes.8-11,20,21,36,37 In rat liver, only large cholangiocytes express the basolateral receptors for secretin and somatostatin and respond to these two hormones with changes in ductal secretion.8-11 Large cholangiocytes also express CFTR and other chloride channels and the Cl-/HCO3- exchanger, which are the primary routes for large cholangiocytes to add chloride, bicarbonate and other electrolytes into bile.8-11 Studies in human liver also report the presence of the Cl-/HCO3- exchanger only in large bile ducts.58 Recent studies by our group and others have demonstrated20,59 that bile ducts express the apical Na+-dependent bile acid transporter (ABAT) by which bile salts enter cholangiocytes, thus modifying ductal functions.20,59 Furthermore, we have shown that certain bile salts such as taurocholate and taurolithocholate enter large cholangiocytes through ABAT20 and stimulate secretin-stimulated ductal bile flow only in large cholangiocytes.20,38 Figure 2B illustrates the intracellular mechanisms of secretion in large cholangiocytes. These data have been obtained from in vivo, in situ and in vitro studies of the bile duct system of rats.

Figure 2B. Large cholangiocytes express the basolateral receptors for secretin and somatostatin and respond to these two hormones with changes in ductal secretion.

Figure 2B

Large cholangiocytes express the basolateral receptors for secretin and somatostatin and respond to these two hormones with changes in ductal secretion. Large cholangiocytes also express CFTR and other chloride channels and the Cl-/HCO3- exchanger, which (more...)

Proliferative Heterogeneity and Apoptotic Susceptibility of Small and Large Cholangiocytes in Response to Injury and Toxins

Cholangiocytes have been shown to heterogeneously respond to injury and toxins.10,34-37,39 In rat models, small and large ducts have been shown to differentially respond to injuries (e.g., BDL or partial hepatectomy),10,39 dietary treatments (bile acid feeding)21 and hepatic toxins (ANIT and CCl4).34,36,37 The injury model BDL induces specific proliferation of only large cholangiocytes whereas the small cholangiocytes remain mitotically dormant.10 However, following partial hepatectomy both small and large cholangiocytes participate in the regrowth of the intrahepatic biliary tree.39 Neither BDL23 nor partial hepatectomy31 induce apoptosis of cholangiocytes. The hepatic toxin CCl4 has been shown to induce damage by apoptosis of large secretin-responsive ducts, which is associated with loss of proliferative and secretory activities.36,37 However, it has been demonstrated that small cholangiocytes are more resistant to CCl4 damage and de novo proliferate and secrete in an effort to compensate for the loss of large cholangiocyte functions.36,37 The differential response may be linked to the presence of cytochrome P450 2E1 only in large cholangiocytes.37 Chronic feeding of ANIT induces apoptosis of both small and large cholangiocytes, which is associated with increased proliferation of large ducts, and de novo proliferation of small ducts.34 Chronic feeding of bile acids such as taurocholate and taurolithocholate to normal rats induces proliferation of both small and large cholangiocytes without activation of apoptosis.35 The heterogeneous responses of cholangiocytes to liver injury/toxins are summarized in (Table 2)

Table 2. Effects of liver injury/toxins and dietary regimens on apoptotic and proliferative response of small and large bile ducts from rats.

Table 2

Effects of liver injury/toxins and dietary regimens on apoptotic and proliferative response of small and large bile ducts from rats.

Summary

In this book chapter, we have discussed the findings related to the heterogeneity of bile ducts regarding: (i) morphology8,9,12 and secretory response to gastrointestinal hormones/peptides2,8- 11,36,37 and bile salts;2,21,35,38 and (ii) apoptotic and proliferative activity in response to liver injury/toxins.10,33,34,36,37 Bile ducts are morphologically heterogeneous with small ducts lined by small cholangiocytes whereas larger cholangiocytes line larger ducts.8,9,12 While large intrahepatic bile ducts express the receptor for secretin and somatostatin, CFTR and Cl-/HCO3- and respond to these two hormones with changes in ductal secretion, small ducts do not express the receptor for secretin and somatostatin, CFTR and Cl-/HCO3- and do not respond to these two hormones.2,8-11 Small and large ducts also differ regarding the proliferative and apoptotic responses to liver injury/toxins.2,10,34,36,37 The physiology of small cholangiocytes (which are mitotically dormant and de novo proliferate in conditions associated with damage of large cAMP-responsive ducts) is undefined.

Future Perspectives

The concept that intrahepatic cholangiocytes are functionally heterogeneous is pathologically important since cholangiocyte proliferation/loss is an event restricted to specific duct size.2 Additional studies are warranted for understanding the physiology of small cholangiocytes (that de novo respond to secretin and begin to proliferate only in conditions associated with damage of large hormone-responsive ducts)34,36,37 in the overall contribution of cholangiocyte secretory activity. Further studies are necessary to evaluate the role of cholinergic, adrenergic, dopaminergic and serotoninergic innervation in the regulation of the heterogeneous responses of bile ducts to gastrointestinal hormones, injury/toxins and viruses. Since microvascular proliferation is observed only in large proliferating ducts from BDL rats,60 we suggest studies aimed to evaluate the role of blood supply and circulating factors (e.g., vascular endothelial growth factor) in the regulation of the heterogeneous response of cholangiocytes to liver injury/toxins.

Acknowledgments

The work included in this book chapter was supported by a grant award to Dr. LeSage and Dr. Alpini from Scott & White Hospital and Texas A&M University, by an NIH grant DK54208 to Dr. LaSage, by VA Merit Award to Dr. Alpini, and a NIH grant DK58411 to Dr. Alpini.

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