A versatile pipeline for the multi-scale digital reconstruction and quantitative analysis of 3D tissue architecture

Morales‐Navarrete, Hernán; Segovia-Miranda, Fabián; Klukowski, Piotr; Meyer, Kirstin; Nonaka, Hiroshi; Marsico, Giovanni; Chernykh, Mikhail; Kalaidzidis, Alexander; Zerial, Marino; Kalaidzidis, Yannis

doi:10.7554/elife.11214

Cited by 95 publications

(157 citation statements)

References 89 publications

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“…In contrast, we have found that the zonation of polypoidy is non-monotonic, proceeding more slowly in both the periportal and perivenous zones. A recent study identified enrichment of polyploid hepatocytes in the mid-lobule zone in young mice (Morales-Navarrete et al 2015). Our study extends these results to mice throughout development and aging, and uncovers the spatio-temporal dynamics of liver polyploidization.…”

Section: Discussionsupporting

confidence: 80%

Dynamic zonation of liver polyploidy

et al. 2016

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The liver is a polyploid organ, consisting of hepatocytes with one or two nuclei each containing 2, 4, 8 or more haploid chromosome sets. The dynamic changes in the spatial distributions of polyploid classes across the liver lobule, its repeating anatomical unit, have not been characterized. Identifying these spatial patterns is important for understanding liver homeostatic and regenerative turnover, as well as potential division of labor among ploidy classes. Here, we use single molecule-based tissue imaging to reconstruct the spatial zonation profiles of liver polyploid classes in mice of different ages. We find that liver polyploidy proceeds in spatial waves, advancing more rapidly in the mid-lobule zone compared to the periportal and perivenous zones. We also measure the spatial zonation profiles of S-phase entry at different ages and identify more rapid S-phase entry in the mid-lobule zone at older ages. Our findings reveal fundamental features of liver spatial heterogeneity and highlight their dynamic changes during development and aging.

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Section: Discussionsupporting

confidence: 80%

Dynamic zonation of liver polyploidy

et al. 2016

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“…Assuming simple mass action and Michaelis–Menten kinetics for the considered reactions (see Fig A), the model has 16 parameters. Of these, the compartment volumes of hepatocyte nuclei and cytoplasm were experimentally measured (Morales‐Navarrete et al , ) (see Appendix Table S4). Five parameters were set to the value 1, as the analytical analysis of the model revealed that they do not affect the steady‐state solution.…”

Section: Resultsmentioning

confidence: 99%

“…A more detailed analysis of liver tissue function and architecture in YAP KO mice after PH may link our findings to its downstream functions paving the way toward a systems understanding of liver regeneration. A wide array of apical actin interacting, polarity, and cell junction‐associated proteins have already been reported to regulate the Hippo pathway (Chen et al , ; Oka et al , ). Given the collective properties of the apical plasma membrane and associated actin cytoskeleton, a systems‐level analysis of its complex super‐molecular network will be required to identify the precise underlying molecular mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration

Meyer

Morales‐Navarrete

Seifert

et al. 2020

Molecular Systems Biology

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The mechanisms of organ size control remain poorly understood. A key question is how cells collectively sense the overall status of a tissue. We addressed this problem focusing on mouse liver regeneration. Using digital tissue reconstruction and quantitative image analysis, we found that the apical surface of hepatocytes forming the bile canalicular network expands concomitant with an increase in F‐actin and phospho‐myosin, to compensate an overload of bile acids. These changes are sensed by the Hippo transcriptional co‐activator YAP, which localizes to apical F‐actin‐rich regions and translocates to the nucleus in dependence of the integrity of the actin cytoskeleton. This mechanism tolerates moderate bile acid fluctuations under tissue homeostasis, but activates YAP in response to sustained bile acid overload. Using an integrated biophysical–biochemical model of bile pressure and Hippo signaling, we explained this behavior by the existence of a mechano‐sensory mechanism that activates YAP in a switch‐like manner. We propose that the apical surface of hepatocytes acts as a self‐regulatory mechano‐sensory system that responds to critical levels of bile acids as readout of tissue status.

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“…This is particularly visible in Figure 2 provided by Sato et al [24]. The principles of sequential cellular kinetics in the regenerating liver following partial resection were shown in a study by Morales-Navarrete et al [25]. Ready hepatocytes with polyploidy divide rapidly from binucleated to mononucleated cells, and the mononucleated cells increment their ploidy early with a parallel increase in the cell volume.…”

Section: Discussionmentioning

confidence: 82%

Kinetics of Hepatic Volume Evolution and Architectural Changes after Major Resection in a Porcine Model

et al. 2019

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Background: The hepatic volume gain following resection is essential for clinical recovery. Previous studies have focused on cellular regeneration. This study aims to explore the rate of hepatic regeneration of the porcine liver following major resection, highlighting estimates of the early microarchitectural changes that occur during the cellular regeneration. Methods: Nineteen large white pigs had 75% resection with serial measurements of the hepatic volume, density, blood flow, and architectural changes. Results: The growth rate initially was 45% per day, then rapidly decreased and was accompanied by a similar pattern of hepatic fat deposition. The architectural changes showed a significant increase in the Ki67 expression (p < 0.0001) in the days following resection with a peak on the 2nd day and nearly normalized on day 7. The expression of CD31 increased significantly on the 2nd and 3rd days compared to the pre-resection samples (p = 0.03). Hepatic artery flow per liver volume remained at baseline ranges during regeneration. Portal flow per liver volume increased after liver resection (p < 0.001), was still elevated on the 1st postoperative day, then decreased. Correlations were significantly negative between the hepatic volume increase on day 3 and the hepatic oxygen consumption and the net lactate production at the end of the procedure (r = –0.82, p = 0.01, and r = –0.70, p = 0.03). Conclusion: The volume increase in the first days – a fast process – is not explained by cellular proliferation alone. The liver/body weight ratio is back to 50% of the preoperative value after 3 days to close to 100% volume regain on days 10–15.

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A versatile pipeline for the multi-scale digital reconstruction and quantitative analysis of 3D tissue architecture

Cited by 95 publications

References 89 publications

Dynamic zonation of liver polyploidy

Dynamic zonation of liver polyploidy

Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration

Kinetics of Hepatic Volume Evolution and Architectural Changes after Major Resection in a Porcine Model

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