Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic ...development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.
Bile, the central metabolic product of the liver, is transported by the bile canaliculi network. The impairment of bile flow in cholestatic liver diseases has urged a demand for insights into its ...regulation. Here, we developed a predictive 3D multi-scale model that simulates fluid dynamic properties successively from the subcellular to the tissue level. The model integrates the structure of the bile canalicular network in the mouse liver lobule, as determined by high-resolution confocal and serial block-face scanning electron microscopy, with measurements of bile transport by intravital microscopy. The combined experiment-theory approach revealed spatial heterogeneities of biliary geometry and hepatocyte transport activity. Based on this, our model predicts gradients of bile velocity and pressure in the liver lobule. Validation of the model predictions by pharmacological inhibition of Rho kinase demonstrated a requirement of canaliculi contractility for bile flow in vivo. Our model can be applied to functionally characterize liver diseases and quantitatively estimate biliary transport upon drug-induced liver injury.
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•The bile canaliculi network displays geometric heterogeneity within the liver lobule•Bile flow is driven by osmotic effects and bile canaliculi contractility•A multi-scale model reveals gradients of bile velocity and pressure within the lobule•The multi-scale model predicts drug-induced alterations of bile flow
Meyer et al. developed a 3D multi-scale model of biliary fluid dynamics in the mouse liver lobule to predict drug-induced alterations of bile flow. They demonstrate two inversely related gradients of bile velocity and pressure in the lobule and show that bile flow is driven by the osmotic effects of bile secretion and bile canaliculi contractility.
We study a model for a thin liquid film dewetting from a periodic heterogeneous substrate (template). The amplitude and periodicity of a striped template heterogeneity necessary to obtain a stable ...periodic stripe pattern, i.e., pinning, are computed. This requires a stabilization of the longitudinal and transversal modes driving the typical coarsening dynamics during dewetting of a thin film on a homogeneous substrate. If the heterogeneity has a larger spatial period than that of the critical dewetting mode, weak heterogeneities are sufficient for pinning. Our results imply a large region of coexistence between coarsening dynamics and pinning.
Replacement of dysfunctional β-cells in the islets of Langerhans by transdifferentiation of pancreatic acinar cells has been proposed as a regenerative therapy for diabetes. Adult acinar cells ...spontaneously revert to a multipotent state upon tissue dissociation in vitro and can be stimulated to redifferentiate into β-cells. Despite accumulating evidence that contact-mediated signals are involved, the mechanisms regulating acinar-to-islet cell transdifferentiation remain poorly understood.
In this study, we propose that the crosstalk between two contact-mediated signaling mechanisms, lateral inhibition and lateral stabilization, controls cell fate stability and transdifferentiation of pancreatic cells. Analysis of a mathematical model combining gene regulation with contact-mediated signaling reveals the multistability of acinar and islet cell fates. Inhibition of one or both modes of signaling results in transdifferentiation from the acinar to the islet cell fate, either by dedifferentiation to a multipotent state or by direct lineage switching.
This study provides a theoretical framework to understand the role of contact-mediated signaling in pancreatic cell fate control that may help to improve acinar-to-islet cell transdifferentiation strategies for β-cell neogenesis.
Physiological liver cell replacement is central to maintaining the organ’s high metabolic activity, although its characteristics are difficult to study in humans. Using retrospective radiocarbon ...(14C) birth dating of cells, we report that human hepatocytes show continuous and lifelong turnover, allowing the liver to remain a young organ (average age <3 years). Hepatocyte renewal is highly dependent on the ploidy level. Diploid hepatocytes show more than 7-fold higher annual birth rates than polyploid hepatocytes. These observations support the view that physiological liver cell renewal in humans is mainly dependent on diploid hepatocytes, whereas polyploid cells are compromised in their ability to divide. Moreover, cellular transitions between diploid and polyploid hepatocytes are limited under homeostatic conditions. With these findings, we present an integrated model of homeostatic liver cell generation in humans that provides fundamental insights into liver cell turnover dynamics.
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•Retrospective 14C birth dating establishes the age of the human liver (<3 years)•Renewal rates of adult hepatocytes are independent of subject age•Diploid hepatocytes show more than 7-fold higher birth rates compared with polyploid•Contribution of higher ploidy levels to the diploid hepatocyte pool is limited
Based on radiocarbon birth dating, a comprehensive model of hepatocyte renewal in humans shows that the liver remains a young organ. Hepatocytes display a continuous and lifelong turnover, which is highly dependent on their ploidy level.
Many internal epithelial organs derive from cysts, which are tissues comprised of bent epithelial cell layers enclosing a lumen. Ion accumulation in the lumen drives water influx and consequently ...water accumulation and cyst expansion. Lumen-size recognition is important for the regulation of organ size. When lumen size and cyst size are not controlled, diseases can result; for instance, renal failure of the kidney. We develop a mechanistic mathematical model of lumen expansion in order to investigate the mechanisms for saturation of cyst growth. We include fluid accumulation in the lumen, osmotic and elastic pressure, ion transport and stretch-induced cell division. We find that the lumen volume increases in two phases: first, due to fluid accumulation stretching the cells, then in the second phase, the volume increase follows the increase in cell number until proliferation ceases as stretch forces relax. The model is quantitatively fitted to published data of
in vitro cyst growth and predicts steady state lumen size as a function of the model parameters.