Bile canaliculi contract autonomously by releasing calcium into hepatocytes via mechanosensitive calcium channel
Open accessPublished version of a preprint
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 (Ca 2+). However, the source of increased intracellular Ca 2+ and its relationship to transporter activity remains elusive. We identify the source of the intracellular Ca 2+ involved in triggering BC contractions, and we elucidate how biliary pressure regulates Ca 2+ homeostasis and associated BC contractions. Primary rat hepatocytes were cultured in collagen sandwich. Intra-canalicular Ca 2+ was measured with fluo-8; and intra-cellular Ca 2+ was measured with GCaMP. Pharmacological modulators of canonical Ca 2+-channels were used to study the Ca 2+-mediated regulation of BC contraction. BC contraction correlates with cyclic transfer of Ca 2+ from BC to adjacent hepatocytes, and not with endoplasmic reticulum Ca 2+. A mechanosensitive Ca 2+ channel (MCC), Piezo-1, is preferentially localized at BC membranes. The Piezo-1 inhibitor GsMTx-4 blocks the Ca 2+ transfer, resulting in cholestatic generation of BC-derived vesicles whereas Piezo-1 hyper-activation by Yoda1 increases the frequency of Ca 2+ 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.
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Piezo1 expression in liver cells follows a multimodal distribution pattern, with varying degrees of expression in the biliary system, liver sinusoidal microvasculature, portal vein narrow areas, and liver parenchyma.
“Several studies have demonstrated that Piezo1 expression in cells follows a multimodal distribution pattern, with varying degrees of expression in the biliary system,39 liver sinusoidal microvasculature, portal vein narrow areas,34,43 and liver parenchyma.”
From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [39]
The section “Piezo-1 acts as a tension sensor in BC” (page unavailable) reports that Piezo1 is localized at the bile-canaliculus membrane, supporting its presence in the biliary system—the part immediately followed by this citation. It does not establish a multimodal expression pattern or varying degrees of expression; the other liver sites are accompanied by other citations. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThese observations derive from cell-based assays.
“However, these observations derive from cell-based assays, and in vivo hepatocyte-specific validation is needed to confirm causality.39,40,41”
From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [39]
A neural tube model showed that geometry constraints imposed by micropatterning can control the final morphology of neural tube-like structures.
“A recent neural tube model dissected the folding process and demonstrated that geometry constraints by micropatterning can control the final morphology of neural tube-like structures26.”
From Organoids (2022) · cites this paper as [26]
The Results section describes tube-like bile canaliculi in cultured hepatocytes, and the Discussion addresses their Piezo1-regulated contractions; neither addresses a neural tube model. Searches for neural tube micropatterning, geometry constraints, and final morphology found no passage supporting the attributed claim. The passages supplied and retrieved do not give page numbers. (LLM, conf=0.76)
Experimental — accuracy not yet measuredMicrofabricated patterns of Laminin-512 reproducibly support human pluripotent stem cells to form lumen structures in Matrigel and differentiate into human neural tube-like structures.
“microfabricated patterns of Laminin-512 were shown to reproducibly support human pluripotent stem cells to form lumen structures in Matrigel and differentiate into human neural tube-like structures26.”
From Organoids (2022) · cites this paper as [26]
The Material and Methods passages describe rat hepatocytes cultured in collagen, and the Discussion concerns bile canaliculi. Searches for Laminin-512, Matrigel, and neural tube-like structures found no passage addressing the claimed stem-cell result; page numbers were not available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredHuman neural tube morphogenesis was simulated using micropatterning that created mechano-chemical gradients to regulate cell-cell/matrix interactions and soluble factor presentation.
“human neural tube morphogenesis26 was simulated using micropatterning which created mechano-chemical gradients to regulate cell-cell/matrix interactions, and soluble factor presentation to orchestrate morphogenesis.”
From Organoids (2022) · cites this paper as [26]
The Material and Methods section (page unavailable) describes cultured rat hepatocytes, and the Discussion (page unavailable) addresses bile canaliculi contraction. Searches for neural tube morphogenesis, micropatterning, and mechano-chemical gradients found no passage addressing the attributed simulation. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Variants of ECM combinations, micropatterned 2D mono-culture or co-culture, cell sheets, stacked 3D structures, and micro-positioned ECM substrates allow formation of reproducible tissue structures and functions with high spatiotemporal control.
“Variants of ECM combinations, micropatterned 2D mono-culture or co-culture237,238, cell sheets239, stacked 3D structures26, and micro-positioned ECM substrates70,240 allow the formation of reproducible tissue structures and functions with a high degree of spatiotemporal control such as stretching241 and osmotic forces242 (FIG. 5).”
From Organoids (2022) · cites this paper as [26]
Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn an APAP-induced liver injury model, hepatocyte-specific overexpression of Piezo1 reduced serum ALT/AST levels by 38% and enhanced mitochondrial membrane potential retention by 55%.
“In an APAP-induced liver injury model, hepatocyte-specific overexpression of Piezo1 reduced serum ALT/AST levels by 38% and enhanced mitochondrial membrane potential retention by 55%.”
From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [39]
The ‘Piezo-1 acts as a tension sensor in BC’ section reports effects of a Piezo1 activator and inhibitor on bile-canaliculus contractions and calcium transfer. Searches for APAP-induced injury, Piezo1 overexpression, ALT/AST, and mitochondrial membrane potential found no passage supporting the claimed 38% or 55% effects. Page numbers are unavailable in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredHepatocyte-specific Piezo1 knockout (Alb-Cre; Piezo1fl/fl) mice exhibited a 2.1-fold increase in hepatocyte apoptosis compared with wild-type controls.
“Conversely, Alb-Cre; Piezo1fl/fl mice (hepatocyte-specific Piezo1 knockout) exhibited a 2.1-fold increase in hepatocyte apoptosis compared with wild-type controls, demonstrating the protective role of Piezo1 in hepatocytes.”
From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [39]
The Methods describe experiments with isolated rat hepatocytes, and “Piezo-1 acts as a tension sensor in BC” reports effects on calcium transfer and bile-canaliculus contractions. Searches for Alb-Cre; Piezo1fl/fl, knockout mice, apoptosis, and the 2.1-fold figure found no passage reporting the claimed mouse comparison. Page numbers were not available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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6.28 Liver Tissue Engineering ☆
Gupta, K., Song, Z., Tang, H., Fong, E. L. S., Ng, I. C., & Yu, H. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-803581-8.10163-8 · Cited by 6 · see citing works
Self-citationWatanabe, N. (2006) · World Journal of Gastroenterology · doi:10.3748/wjg.v12.i33.5320 · Cited by 5 · see citing works
Flagged first, then by citations
3 of the 84 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Zhao, Z., Chen, X., Dowbaj, A. M., Sljukic, A., Bratlie, K., Lin, L., Fong, E. L. S., Balachander, G. M., Chen, Z., Soragni, A., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-022-00174-y · Cited by 1,001 · see citing works
Self-citationForce Sensing by Piezo Channels in Cardiovascular Health and Disease
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Mechanosensitive Piezo1 channel in physiology and pathophysiology of the central nervous system
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Piezo channels in the urinary system
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Organoids as preclinical models of human disease: progress and applications
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Hepatocyte apical bulkheads provide a mechanical means to oppose bile pressure
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Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease
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“Consequently, researchers are increasingly focusing on utilizing human tissues for research, primarily employing monolayer (2D) cultures, collagen sand-wich cultures (semi-or partial 3D models), or human liver organoids which more precisely maintain tissue-specific functions [3,4].”
BackgroundA modular analysis of bile canalicular function and its implications for cholestasis
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Self-citationIsolation of Primary Rat Hepatocytes with Multiparameter Perfusion Control
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Self-citationPIEZO1 channel mechanosensing in hepatobiliary physiology and disease
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Fascial Manual Medicine: A Continuous Evolution
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How Physics Can Regulate Stem Cells’ Fate: An Overview on Cellular Interactions with Their Substrate
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- Authors
- Gupta, K., Ng, I. C., Balachander, G. M., Nguyen, B. P., Tucker-Kellogg, L., Low, B. C., & Yu, H.
- Affiliations
- National University of Singapore (SG)
- Victoria University of Wellington (NZ)
- Agency for Science, Technology and Research (SG)
- Corresponding author
- Low, Boon Chuan
- Yu, Hanry
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 259
- Pages
- 120283
- ISSN
- 0142-9612 (ISSN-L)
- OpenAlex
- W3048537035
- Cited by
- 23
- References
- 84
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 2 · 2019: 1
- FWCI
- 0.90
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Biomaterials (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- National University of Singapore (R-714-006-008-271)
- National Medical Research Council (R-185-000-294- 511)
- National University Health System (R-185-000-343-733)
- National Research Foundation Singapore
- Ministry of Health -Singapore (NMRC/OFIRG/0007/2016)
- Mechanobiology Institute, Singapore
- Agency for Science, Technology and Research
- Biomedical Research Council
- Ministry of Education - Singapore (R-185-000-342-112)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- bile canaliculi, mechanosensitive calcium channels, Piezo1, intracellular calcium, calcium transfer, actomyosin contractility, biliary pressure, calcium homeostasis, Yoda1, GsMTx4, bile flow, hepatocytes
- MeSH terms
- Animals, Bile Canaliculi, Calcium, Cells, Cultured, Liver, Calcium Channels, Hepatocytes, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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