A non-canonical Notch complex regulates adherens junctions and vascular barrier function

Polacheck, William J.; Kutys, Matthew L.; Yang, Jer Yen; Eyckmans, Jeroen; Wu, Yinyu; Vasavada, Hema; Hirschi, Karen K.; Chen, Christopher

doi:10.1038/nature24998

Cited by 282 publications

(341 citation statements)

References 32 publications

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“…Diffusion of the dextran was imaged in real time with an EVOS FL Auto 2 Imaging System (Thermo Fisher Scientific) at 10× magnification. The diffusive permeability coefficient was calculated by measuring the flux of dextran into the collagen gel and fitting the resulting diffusion profiles to a dynamic mass conservation equation, as described …”

Section: Methodsmentioning

confidence: 99%

“…The diffusive permeability coefficient was calculated by measuring the flux of dextran into the collagen gel and fitting the resulting diffusion profiles to a dynamic mass conservation equation, as described. (21,23)…”

Section: Permeability Measurementsmentioning

confidence: 99%

“…The device was designed as per previously described models of endothelium-lined, vascular-mimetic channels. (21,22) To maximize cholangiocyte adhesion, the lumen was coated with laminin (100 μg/mL) for 4 hours. The channels described here were seeded with a line of mouse cholangiocytes.…”

Section: Fabrication Of the Bile Duct-on-a-chipmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Permeability Measurementsmentioning

confidence: 99%

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

Khandekar

Llewellyn

et al. 2019

Hepatology

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“…Microfluidic devices were fabricated using soft lithography as described previously (12,13) (Fig. 1A).…”

Section: Fabrication Of the Bile Duct-on-a-chipmentioning

confidence: 99%

“…Diffusion of the dextran was imaged in real time with an EVOS FL Auto 2 Imaging System (Thermo Fisher Scientific) at 10X magnification. The diffusive permeability coefficient (Pd) was calculated by measuring the flux of dextran into the collagen gel and fitting the resulting diffusion profiles to a dynamic mass conservation equation, as described previously (12,14) .…”

Section: Permeability Measurementsmentioning

confidence: 99%

A Bile Duct-on-a-Chip with Organ-Level Functions

Khandekar

Llewellyn

et al. 2019

Preprint

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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, but barrier function is difficult to study in vivo and has not been recapitulated in vitro. Here we report the development of 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. We demonstrated that mouse cholangiocytes in the channel of the device became polarized and formed mature tight junctions, and that the permeability of the cholangiocyte monolayer was comparable to that measured ex vivo for the rat bile duct. Permeability decreased significantly when cells formed a compacted monolayer with cell densities comparable to that seen 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. Conclusion: This bile ducton-a-chip captured essential features of a simplified bile duct in structure and organlevel functions and represents a novel in vitro platform to study the pathophysiology of the bile duct using cholangiocytes from a variety of sources. 4

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Cell Chirality as a Novel Measure for Cytotoxicity

Zhang

Wan

2021

Advanced Biology

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Cytotoxicity assessment has great importance in both research and pharmaceutical development. The mainstream in vitro cytotoxicity assays are mostly biochemical assays that evaluate a specific cellular activity such as proliferation and apoptosis. Few assays assess toxicity by characterizing overall functional outcomes in cellular physiology such as multicellular morphogenesis. The intrinsic cellular chiral bias (also known as cell chirality, left‐right asymmetry, or handedness), which determines cellular polarization along the left‐right axis, is demonstrated to play important roles in development and disease. This chiral property of cells gives insights not only into functions of individual cells, such as motility and polarity but also into emerging behaviors of cell clusters, such as collective cell migration. Therefore, cell chirality characterization can be potentially used as a biomarker for assessing the overall effects of pharmaceutical drugs and environmental factors on the health of the cell. In this review article, the current in vitro techniques for cell chirality characterization and their applications are discussed and the advantages and limitations of these cell chirality assays as potential tools for detecting cytotoxicity are discussed.

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A non-canonical Notch complex regulates adherens junctions and vascular barrier function

Cited by 282 publications

References 32 publications

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

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

A Bile Duct-on-a-Chip with Organ-Level Functions

Cell Chirality as a Novel Measure for Cytotoxicity

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