Actomyosin contractility drives bile regurgitation as an early response during obstructive cholestasis

Gupta, Kapish; Li, Qiushi; Fan, Jun; Fong, Eliza Li Shan; Song, Ziwei; Mo, Shupei; Tang, Haoyu; Ng, Inn Chuan; Ng, Chan Way; Pawijit, Pornteera; Zhuo, Shuangmu; Dong, Chongying; Low, Boon Chuan; Wee, Aileen; Dan, Yock Young; Kanchanawong, Pakorn; So, Peter T. C.; Viasnoff, Virgile; Yu, Hanry

doi:10.1016/j.jhep.2017.01.026

Cited by 23 publications

(32 citation statements)

References 48 publications

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“…However, the mechanism of the contraction process is poorly understood. Previous studies from ourselves and others suggested that the BC contractility is a cyclic process and each cycle consists of at least two phases 9,10,13,19,33,42 . The first phase is expansion, wherein the BC expands due to activity of transporter proteins such as MRP2, BSEP and others 2,[43][44][45] .…”

Section: Discussionmentioning

confidence: 99%

“…Inability to transfer BC Ca 2+ to cells halted contraction, which is presumed to impair the propulsion of contents and the release of ICP. In such cases, cells resort to remodeling through BCV, which resembles to some extent the cytoskeletal mechanics of blebbing 33 . The presence of GsMTx-4 caused ~8-fold higher frequency of BCV ( Figure 6E), leading to a complete suppression of BCV-independent contractions, which is a recognized BC response to cholestasis 33 .…”

Section: Piezo-1 Acts As a Tension Sensor In Bcmentioning

confidence: 99%

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Bile canaliculi contract autonomously by releasing calcium into hepatocytes via mechanosensitive calcium channel

Gupta

Nguyen

et al. 2018

Preprint

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Bile canaliculi (BC) are the smallest vessels of the biliary tree. They are formed from the apical surfaces of adjoining hepatocytes, resulting in lumenal conduits for bile flow. Bile is propelled along the BC by hepatocyte contractions that arise from cyclic waves of apico-basal Ca2+, but the source and regulation of Ca2+ has been unclear. We report that BC contraction correlates with cyclic transfer of Ca2+ from BC lumen to apico-basal Ca2+ waves in adjacent hepatocytes, and does not correlate with endoplasmic reticulum Ca2+. BC contractility was triggered by ionophore A23187 and unaffected by Thapsigargin. The cycles of Ca2+ transfer could be blocked by the mechanosensitive calcium channel inhibitor GsMTx-4, resulting in cholestatic generation of BC-derived vesicles. The mechanosensitive calcium channel Piezo-1 is preferentially localized at BC membranes, and its hyper-activation by Yoda1 causes increased Ca2+ transfer and increased BC contractility. We propose that canaliculi achieve biomechanical homeostasis through the following feedback system: the pressure of accumulated bile is sensed by mechanosensitive channel, which transmit biliary calcium into adjacent hepatocytes for contraction of the BC lumen and propulsion of the bile.

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Section: Discussionmentioning

confidence: 99%

Section: Piezo-1 Acts As a Tension Sensor In Bcmentioning

confidence: 99%

Bile canaliculi contract autonomously by releasing calcium into hepatocytes via mechanosensitive calcium channel

Gupta

Nguyen

et al. 2018

Preprint

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“…1). (7) Cytoplasmic blebs (vacuoles) up to 5 µm in diameter were visualized that contain both leaflets of the canalicular membrane from which they bud. These vacuoles then cross the cell to the sinusoidal membrane of the hepatocyte to discharge their contents into the blood.…”

Section: See Article On Page 666mentioning

confidence: 99%

“…A recent study used intravital laser imaging techniques to demonstrate herniation of vesicles and vacuoles from the bile canalicular membrane into the hepatocyte during the first 1 to 2 hours of BDL, when biliary pressure is at its maximum (#2 in Fig. ) . Cytoplasmic blebs (vacuoles) up to 5 µm in diameter were visualized that contain both leaflets of the canalicular membrane from which they bud.…”

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Bile Infarcts: New Insights Into the Pathogenesis of Obstructive Cholestasis

Cai

Boyer

2019

Hepatology

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“…In the case of multicellular lumens (eg: cysts (5-7)), tension results from the contraction of the cells surrounding the lumen. In the case of the intercellular domain, the tension arises from the cortical actin layer surrounding the cavity (8). Fig.…”

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Physics of Lumen growth

Dasgupta

Gupta²,

Zhang³

et al. 2018

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We model the dynamics of formation of intercellular secretory lumens. Using conservation laws, we quantitatively study the balance between paracellular leaks and the build-up of osmotic pressure in the lumen. Our model predicts a critical pumping threshold to expand stable lumens. Consistently with experimental observations in bile canaliculi, the model also describes a transition between a monotonous and oscillatory regime during luminogenesis as a function of ion and water transport parameters. We finally discuss the possible importance of regulation of paracellular leaks in intercellular tubulogenesis.osmoregulation | membrane pumps | lumens | tissue mechanics | E pithelial lumens are ubiquitous in organs. They originate from cavities or tubes surrounded by one (seamless lumen) or multiple cells (1). Ions and other bioactive molecules are secreted into the cavities and, if the lumen is open, flow with the physiological medium. The creation of the lumens orginates from several classes of morphogenetic events (1). In the case of closed lumens (such as acini, blastocytes, canaliculi), ion secretion into the forming cavity creates an osmotic pressure. This results in the passive transport of water into the lumen (most often mediated by aquaporins), which constitutes a major driving component for lumen expansion. This osmotic pressure hypothesis was experimentally proposed in the 1960s (2-4). The expansion is mechanically restrained by periluminal tension. In the case of multicellular lumens (eg: cysts (5-7)), tension results from the contraction of the cells surrounding the lumen. In the case of the intercellular domain, the tension arises from the cortical actin layer surrounding the cavity (8). Fig. 1a illustrates a lumen separating adjacent membranes between two primary rat hepatocytes (liver cells). The contact area between both cells presents an intercellular cleft of around 30-50 nm (9) that accommodates transcellular proteins, adhesion proteins and peptidoglycans. The development of the lumen occurs within 5 to 6 hours. In vivo, closed lumens eventually merge into a network of tubules called canaliculi (2µm diameter and 500 µm long). We recently showed that the shape of these lumen is controlled by the balance of osmotic pressure and anisotropic cortical tension (10). Hepatocyte doublets can be used as meaningful simplified surrogates to study lumen formation (8,11,12). In this instance functional canaliculi grow as spherical caps spanning part of the intercellular space. The simple geometry of the system constitutes an appealing case for quantitative studies.However, this process is rather generic for many kinds of lumen such as Ciona Notochord lumen (1,13,14) or kidney lumens(15). Fig. 1b-c also shows that the steady shape of the lumen depends on the secretory activity, which is boosted by the addition of Ursodeoxycholic acid (UDCA). The growth of the lumen can either be monotonous (Fig. 1c) or pulsatile ( Fig.1d) depending on the periluminal tension and secretory activity. A steady secretion in a closed ...

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Actomyosin contractility drives bile regurgitation as an early response during obstructive cholestasis

Abstract: Bile canaliculi expand and contract in response to the amount of secreted bile, and resistance from the surrounding actin bundles. Further expansion due to bile duct blockade leads to the formation of inward blebs, which carry away excess bile to prevent bile build up in the canaliculi.

Cited by 23 publications

References 48 publications

Bile canaliculi contract autonomously by releasing calcium into hepatocytes via mechanosensitive calcium channel

Bile canaliculi contract autonomously by releasing calcium into hepatocytes via mechanosensitive calcium channel

Bile Infarcts: New Insights Into the Pathogenesis of Obstructive Cholestasis

Physics of Lumen growth

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