Bile canaliculi contract autonomously by releasing calcium into hepatocytes via mechanosensitive calcium channel.
Biomaterials
; 259: 120283, 2020 11.
Article
en En
| MEDLINE
| ID: mdl-32827796
ABSTRACT
Drug-induced hepatocellular cholestasis leads to altered bile flow. Bile is propelled along the bile canaliculi (BC) by actomyosin contractility, triggered by increased intracellular calcium (Ca2+). However, the source of increased intracellular Ca2+ and its relationship to transporter activity remains elusive. We identify the source of the intracellular Ca2+ involved in triggering BC contractions, and we elucidate how biliary pressure regulates Ca2+ homeostasis and associated BC contractions. Primary rat hepatocytes were cultured in collagen sandwich. Intra-canalicular Ca2+ was measured with fluo-8; and intra-cellular Ca2+ was measured with GCaMP. Pharmacological modulators of canonical Ca2+-channels were used to study the Ca2+-mediated regulation of BC contraction. BC contraction correlates with cyclic transfer of Ca2+ from BC to adjacent hepatocytes, and not with endoplasmic reticulum Ca2+. A mechanosensitive Ca2+ channel (MCC), Piezo-1, is preferentially localized at BC membranes. The Piezo-1 inhibitor GsMTx-4 blocks the Ca2+ transfer, resulting in cholestatic generation of BC-derived vesicles whereas Piezo-1 hyper-activation by Yoda1 increases the frequency of Ca2+ transfer and BC contraction cycles. Yoda1 can recover normal BC contractility in drug-induced hepatocellular cholestasis, supporting that Piezo-1 regulates BC contraction cycles. Finally, we show that hyper-activating Piezo-1 can be exploited to normalize bile flow in drug-induced hepatocellular cholestasis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Canalículos Biliares
/
Calcio
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Biomaterials
Año:
2020
Tipo del documento:
Article
País de afiliación:
Singapur