Dynamic zonation of liver polyploidy

Tanami, Sivan; Ben‐Moshe, Shani; Elkayam, Anat; Mayo, Avi; Halpern, Keren Bahar; Itzkovitz, Shalev

doi:10.1007/s00441-016-2427-5

Cited by 63 publications

(65 citation statements)

References 25 publications

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“…Moreover, it should be noted that the number of nuclei visible in the optical microscope using routine histological sections is completely different from the cell ploidy hepatocytes assessed using advanced methods, such as single molecule fluorescence in situ hybridization. Hepatocytes with one or two nuclei may contain two, four, eight or even more haploid chromosome sets (Tanami et al 2016). In contrast to our findings (4% of BnHEP), Vinogradov et al (2001) reported in pig of unknown age that 54% of binuclear hepatocytes had 2 9 2c ploidy.…”

Section: Size Density and Fraction Of Bnhep Exhibit Considerable Intcontrasting

confidence: 99%

“…It may be hypothesized that the peripheral parts of the liver lobes represent the developmentally oldest hepatic regions and thus contain more large polyploid cells. Tanami et al (2016) mapped the zonation of liver polyploidy in rat, revealing that liver polyploidy proceeds in spatial waves, advancing more rapidly in the midlobule zone than the periportal and perivenous zones. The The smallest numerical density of hepatocytes N V (HEP) was identified in the peripheral regions of the liver.…”

Section: Peripheral Regions Of Hepatic Lobes Contain the Largest Mnhementioning

confidence: 99%

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Stereological analysis of size and density of hepatocytes in the porcine liver

et al. 2016

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The porcine liver is frequently used as a large animal model for verification of surgical techniques, as well as experimental therapies. Often, a histological evaluation is required that include measurements of the size, nuclearity or density of hepatocytes. Our aims were to assess the mean number-weighted volume of hepatocytes, the numerical density of hepatocytes, and the fraction of binuclear hepatocytes (BnHEP) in the porcine liver, and compare the distribution of these parameters among hepatic lobes and macroscopic regions of interest (ROIs) with different positions related to the liver vasculature. Using disector and nucleator as design-based stereological methods, the morphometry of hepatocytes was quantified in seven healthy piglets. The samples were obtained from all six hepatic lobes and three ROIs (peripheral, paracaval and paraportal) within each lobe. Histological sections (thickness 16 μm) of formalin-fixed paraffin-embedded material were stained with the periodic acid-Schiff reaction to indicate the cell outlines and were assessed in a series of 3-μm-thick optical sections. The mean number-weighted volume of mononuclear hepatocytes (MnHEP) in all samples was 3670 ± 805 μm (mean ± SD). The mean number-weighted volume of BnHEP was 7050 ± 2550 μm . The fraction of BnHEP was 4 ± 2%. The numerical density of all hepatocytes was 146 997 ± 15 738 cells mm of liver parenchyma. The porcine hepatic lobes contained hepatocytes of a comparable size, nuclearity and density. No significant differences were identified between the lobes. The peripheral ROIs of the hepatic lobes contained the largest MnHEP with the smallest numerical density. The distribution of a larger MnHEP was correlated with a larger volume of BnHEP and a smaller numerical density of all hepatocytes. Practical recommendations for designing studies that involve stereological evaluations of the size, nuclearity and density of hepatocytes in porcine liver are provided.

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Section: Size Density and Fraction Of Bnhep Exhibit Considerable Intcontrasting

confidence: 99%

Section: Peripheral Regions Of Hepatic Lobes Contain the Largest Mnhementioning

confidence: 99%

Stereological analysis of size and density of hepatocytes in the porcine liver

et al. 2016

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“…We observed a 1.3-times relative enrichment of 4n hepatocytes in the pericentral cluster, indicating that they reside close to the central vein. This is in agreement with recent studies in which polyploid hepatocytes have been preferably located by histological analysis in the pericentral zone, and diploid hepatocytes in the periportal zone using cell-lineage tracing [77,108].…”

Section: Hepatic Metabolic Zonation Determines Gene Expression Levelssupporting

confidence: 92%

“…Furthermore, the broad spatial heterogeneity in the liver shows that key liver functions are zonated [9], and recently it has been shown that the zonation can be perturbed during liver fibrosis [14,15]. In this context, the spatial distribution of polyploid hepatocytes and its functional consequences are still in debate [8,40,77,85,108]. We used diffusion pseudotime to infer the pseudospatial ordering of 2n and 4n hepatocytes according to defined markers of liver zonation, and we found that 4n nuclei are distributed throughout the hepatic lobe with an enrichment in the pericentral zone (Fig.…”

Section: Discussionmentioning

confidence: 99%

“Single-nucleus RNA-seq2 reveals a functional crosstalk between liver zonation and ploidy”

Richter

Deligiannis

Danese

et al. 2020

Preprint

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Single-cell RNA-seq reveals the role of pathogenic cell populations in development and progression of chronic diseases. In order to expand our knowledge on cellular heterogeneity we have developed a single-nucleus RNA-seq-2 method that allows deep characterization of nuclei isolated from frozen archived tissues. We have used this approach to characterize the transcriptional profile of individual hepatocytes with different levels of ploidy, and have discovered that gene expression in tetraploid mononucleated hepatocytes is conditioned by their position within the hepatic lobe. Our work has revealed a remarkable crosstalk between gene dosage and spatial distribution of hepatocytes.

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“…Mouse Axin2‐labeled perivenous hepatocytes are two‐thirds diploid and one‐third tetraploid, whereas other lobular hepatocytes are mostly polyploid, reflecting the proliferative potential of perivenous cells in hepatic homeostasis (Wang et al, ). Tanami et al () found a relatively higher abundance of diploid hepatocytes in both the perivenous and periportal zones of mice, assessed by nuclear staining with DAPI and smFISH for Pck1. The midlobular zone is enriched with polyploid hepatocytes, and the rate of polyploidization there is higher than in other lobular zones.…”

Section: Ploidy Classes Of Perivenous Hepatocytesmentioning

confidence: 99%

The Hepatic Central Vein: Structure, Fibrosis, and Role in Liver Biology

Mak

Png

2019

The Anatomical Record

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The hepatic central vein is a primary source of Wnt2, Wnt9b, and R‐spondin3. These angiocrines activate ß‐catenin signaling to regulate hepatic metabolic zonation and perivenous gene expression in mice. Little is known about the central vein ultrastructure. Here, we describe the morphological–functional correlates of the central vein and its draining and branching patterns. Central vein fibrosis occurs in liver disease and is often accompanied by perivenous perisinusoidal fibrosis, which may affect perivenous gene expression. We review the biological properties of perivenous hepatocytes and glutamine synthetase that serve as a biomarker of perivenous hepatocytes. Glutamine synthetase and P4502E1 are indicators of ß‐catenin activity in centrilobular liver injury and regeneration. The Wnt/ß‐catenin pathway is the master regulator of hepatic metabolic zonation and perivenous gene expression and is modulated by the R‐spondin‐LGR4/5‐ZNRF3/RNF43 module. We examined the structures of the molecules of these pathways and their involvements in liver biology. Central vein‐derived Wnts and R‐spondin3 participate in the cellular–molecular circuitry of the Wnt/ß‐catenin and R‐spondin‐LGR4/5‐ZNRF3/RNF43 module. The transport and secretion of lipidated Wnts in Wnt‐producing cells require Wntless protein. Secreted Wnts are carried on exosomes in the extracellular matrix to responder cells. The modes of release of Wnts and R‐spondin3 from central veins and their transit in the venular wall toward perivenous hepatocytes are unknown. We hypothesize that central vein fibrosis may impact perivenous gene expression. The proposal that the central vein constitutes an anatomical niche of perivenous stem cells that subserve homeostatic hepatic renewal still needs studies using additional mouse models for validation. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1747–1767, 2020. © 2019 American Association for Anatomy

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Dynamic zonation of liver polyploidy

Cited by 63 publications

References 25 publications

Stereological analysis of size and density of hepatocytes in the porcine liver

Stereological analysis of size and density of hepatocytes in the porcine liver

“Single-nucleus RNA-seq2 reveals a functional crosstalk between liver zonation and ploidy”

The Hepatic Central Vein: Structure, Fibrosis, and Role in Liver Biology

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