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

Abstract

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 Ca 2+ , but the source and regulation of Ca 2+ has been unclear. We report that BC contraction correlates with cyclic transfer of Ca 2+ from BC lumen to apico-basal Ca 2+ waves in adjacent hepatocytes, and does not correlate with endoplasmic reticulum Ca 2+ . BC contractility was triggered by ionophore A23187 and unaffected by Thapsigargin. The cycles of Ca 2+ 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 Ca 2+ 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.

Hepatocyte apical bulkheads provide a mechanical means to oppose bile pressure

“…F-actin is enriched along the tight junction in comparison with the rest of the apical cortex ( Belicova et al, 2021 ; Porat-Shliom et al, 2016 ). It is possible that such inhomogeneity in actomyosin meshwork, in combination with increased actomyosin contractility in response to pressure ( Gupta et al, 2020 ; Sethi et al, 2017 ), generates a disbalance in tension, resulting in folds of the apical surface centered around the tight junctions. In this case, the height of the apical bulkheads would depend on the luminal pressure.…”

Piezo1 in Digestive System Function and Dysfunction

“…Human liver produces bile from the rate of 0.5–1 mL/min during fasting to 2–3 mL/min after feeding [ 118 ], resulting in sharply increasing biliary pressure. A study has reported that Piezo1 acts as the tension sensor in bile canaliculi membrane, and is activated to provoke the contraction of peritubular actin cortex, thereby propelling bile acid into the intrahepatic bile duct from hepatocyte and bile canaliculus [ 74 ]. When the bile acid flows to intrahepatic bile duct, hypotonic stress of cholangiocytes during cholestasis activates Piezo1 and further promotes the secretion of bile acid and bicarbonate via Pannexin1-ATP-P2X4R axis [ 75 ].…”

Role of Ion Channels in the Chemotransduction and Mechanotransduction in Digestive Function and Feeding Behavior

“…Whether intestinal secretion is associated with mechanosensitive ion channels still needs further investigation. One study found that bile ducts cause elevated Ca via Piezo1 [ 40 ], which causes constriction of the bile ducts and secretion of bile. This suggests that mechanical factors may be an under-explored area of intestinal secretion.…”