Advances in the generation of bioengineered bile ducts

Justin, Alexander W.; Saeb‐Parsy, Kourosh; Markaki, Athina E.; Vallier, Ludovic; Sampaziotis, Fotios

doi:10.1016/j.bbadis.2017.10.034

Cited by 20 publications

(18 citation statements)

References 72 publications

(110 reference statements)

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“…With the availability of eBD biopsies collected during liver transplantation, we embarked on characterizing organoids from the extrahepatic biliary epithelium (eBD) and compared them to paired organoids initiated from iBD of the same donor. The non-canonical Wnt-stimulated extrahepatic cholangiocyte organoids as described by Sampaziotis 16 , isolated from eBD are potent cells for regenerative medicine applications 26 , 27 . However, these cholangiocyte organoids are assumedly derived from mature primary cholangiocytes (not stem/progenitor cells) and are not dependent on canonical Wnt signaling like the LGR5-positive ICO 14 and ECO.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, an earlier study on TROP2 in eBD reported that though TROP2 is non expressed in peribiliary glands, upon damage of the bile ducts TROP2 is clearly upregulated in these glands epithelial cells 31 . Although novel culture techniques provide evidence for long-term expansion of primary hepatocytes 32 , 33 and primary cholangiocytes 26 , 27 , both cell types remain challenging to maintain in culture while keeping their mature functions 13 , 14 , 28 . Expansion of ECO could provide in this shortcoming.…”

Section: Discussionmentioning

confidence: 99%

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Human extrahepatic and intrahepatic cholangiocyte organoids show region-specific differentiation potential and model cystic fibrosis-related bile duct disease

Verstegen

Roos

Burka

et al. 2020

Sci Rep

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The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor cells. This study aimed to characterize human extrahepatic cholangiocyte organoids (ECO) using canonical Wnt-stimulated culture medium previously developed for intrahepatic cholangiocyte organoids (ICO). Paired ECO and ICO were derived from common bile duct and liver tissue, respectively. Characterization showed both organoid types were highly similar, though some differences in size and gene expression were observed. Both ECO and ICO have cholangiocyte fate differentiation capacity. However, unlike ICO, ECO lack the potential for differentiation towards a hepatocyte-like fate. Importantly, ECO derived from a cystic fibrosis patient showed no CFTR channel activity but normal chloride channel and MDR1 transporter activity. In conclusion, this study shows that ECO and ICO have distinct lineage fate and that ECO provide a competent model to study extrahepatic bile duct diseases like cystic fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human extrahepatic and intrahepatic cholangiocyte organoids show region-specific differentiation potential and model cystic fibrosis-related bile duct disease

Verstegen

Roos

Burka

et al. 2020

Sci Rep

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“…(1)(2)(3)(4)(5)(6) Most in vitro research on biliary physiology and pathology, however, uses cells either cultured in two-dimensional (2D) monolayers or as organoids in three-dimensional (3D) extracellular matrix (ECM). (7)(8)(9)(10)(11) These conventional methods fail to replicate many key aspects of bile duct structural organization or to recapitulate important tissue-level integrated physiological functions, such as forming a protective barrier and compartmentalizing bile.…”

mentioning

confidence: 99%

A Bile Duct‐on‐a‐Chip With Organ‐Level Functions

Khandekar

Llewellyn

et al. 2019

Hepatology

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Background and Aims Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are frequently associated with damage to the barrier function of the biliary epithelium. Here, we report on a bile duct‐on‐a‐chip that phenocopies not only the tubular architecture of the bile duct in three dimensions, but also its barrier functions. Approach and Results We showed that mouse cholangiocytes in the channel of the device became polarized and formed mature tight junctions, that the permeability of the cholangiocyte monolayer was comparable to ex vivo measurements, and that cholangiocytes in the device were mechanosensitive (as demonstrated by changes in calcium flux under applied luminal flow). Permeability decreased significantly when cells formed a compact monolayer with cell densities comparable to those observed in vivo. This device enabled independent access to the apical and basolateral surfaces of the cholangiocyte channel, allowing proof‐of‐concept toxicity studies with the biliary toxin, biliatresone, and the bile acid, glycochenodeoxycholic acid. The cholangiocyte basolateral side was more vulnerable than the apical side to treatment with either agent, suggesting a protective adaptation of the apical surface that is normally exposed to bile. Further studies revealed a protective role of the cholangiocyte apical glycocalyx, wherein disruption of the glycocalyx with neuraminidase increased the permeability of the cholangiocyte monolayer after treatment with glycochenodeoxycholic acid. Conclusions This bile duct‐on‐a‐chip captured essential features of a simplified bile duct in structure and organ‐level functions and represents an in vitro platform to study the pathophysiology of the bile duct using cholangiocytes from a variety of sources.

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“…First the ductal ECM is generated using a variety of fabrication methods, such as rolling of a polymeric sheet, moulding, 3D printing, electrospinning and freeze-drying from synthetic or biological materials or through tissue decellularisation. 126 Subsequently, the matrices are populated with cells, generating bioengineered bile ducts. These ducts can be connected to bioreactors, which allow independent access to the luminal and extraluminal side of the construct and enable luminal flow of media without the challenge of small volume perfusates (Fig.…”

Section: Scaffolded Bioengineered Tissuementioning

confidence: 99%

Tissue engineering of the biliary tract and modelling of cholestatic disorders

Brevini

Tysoe

Sampaziotis

2020

Journal of Hepatology

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Our insight into the pathogenesis of cholestatic liver disease remains limited, partly owing to challenges in capturing the multitude of factors that contribute to disease pathogenesis in vitro. Tissue engineering could address this challenge by combining cells, materials and fabrication strategies into dynamic modelling platforms, recapitulating the multifaceted aetiology of cholangiopathies. Herein, we review the advantages and limitations of platforms for bioengineering the biliary tree, looking at how these can be applied to model biliary disorders, as well as exploring future directions for the field.

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Advances in the generation of bioengineered bile ducts

Cited by 20 publications

References 72 publications

Human extrahepatic and intrahepatic cholangiocyte organoids show region-specific differentiation potential and model cystic fibrosis-related bile duct disease

Human extrahepatic and intrahepatic cholangiocyte organoids show region-specific differentiation potential and model cystic fibrosis-related bile duct disease

A Bile Duct‐on‐a‐Chip With Organ‐Level Functions

Tissue engineering of the biliary tract and modelling of cholestatic disorders

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