Single-cell spatial reconstruction reveals global division of labour in the mammalian liver

Halpern, Keren Bahar; Shenhav, Rom; Matcovitch-Natan, Orit; Tóth, Beáta; Lemze, Doron; Golan, Matan; Massasa, Efi E.; Baydatch, Shaked; Landen, Shanie; Moor, Andreas E.; Brandis, Alexander; Giladi, Amir; Stokar-Avihail, Avigail; David, Eyal; Itzkovitz, Shalev

doi:10.1038/nature21065

Cited by 838 publications

(1,238 citation statements)

References 38 publications

(75 reference statements)

Supporting

Mentioning

1,138

Contrasting

Unclassified

Order By: Relevance

“…Recently, analysis of gene expression involved in liver zonation in a mouse model showed that ASS1 and ASL were key proteins involved in the periportal program of liver zonation . We hypothesized that GLI1 activation in shHCA could induce an alteration of the zonation program.…”

Section: Methodsmentioning

confidence: 98%

Argininosuccinate synthase 1 and periportal gene expression in sonic hedgehog hepatocellular adenomas

et al. 2018

View full text Add to dashboard Cite

show abstract

Section: Methodsmentioning

confidence: 98%

Argininosuccinate synthase 1 and periportal gene expression in sonic hedgehog hepatocellular adenomas

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The liver parenchyma comprises two major cell types: hepatocytes (~80 %) and bile-duct epithelial cells (BEC, ~20 %). BECs are responsible for bile-acid transport whereas hepatocytes execute varied functions including metabolism, detoxification, and protein production (Halpern et al, 2017; Miyajima et al, 2014). Moreover, hepatocytes are diverse and their function and gene expression differs depending on their location within the liver lobule (the functional unit of the liver), which is organized along a spatial axis spanning from the central vein (CV) to the portal vein (PV) (Kietzmann, 2017).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture

Peng

Logan

Fish

et al. 2018

Cell

225

251

View full text Add to dashboard Cite

SUMMARY In the healthy adult liver, most hepatocytes proliferate minimally. Yet upon physical or chemical injury to the liver, hepatocytes intensely proliferate in vivo under the direction of multiple extracellular cues, including Wnt and pro-inflammatory signals. Currently, liver organoids can be readily generated in vitro from bile-duct epithelial cells, but not hepatocytes. Here we show that TNFα, an injury-induced inflammatory cytokine, promotes the expansion of hepatocytes in 3D culture and enables serial passaging and long-term culture for more than 6 months. Single-cell RNA sequencing reveals broad expression of hepatocyte markers. Strikingly, in vitro-expanded hepatocytes engrafted, and significantly repopulated, the injured livers of Fah−/− mice. We anticipate tissue repair signals can be harnessed to promote the expansion of otherwise hard-to-culture cell-types, with broad implications.

show abstract

“…A pivotal 2017 report using single-cell transcriptome analysis of fixed in vivo mouse liver found 50% of the liver genes are zonated, including genes that are most abundantly expressed in zone 2, an often over-looked zone in research. 3 This report suggests that many more activities and functions of the liver than are currently known may have spatial preferences that are likely to impact liver disease.…”

Section: Introductionmentioning

confidence: 99%

“…gene expression profiles and biochemical activities) vary based on the physical location within the hepatic lobule. [1][2][3] In the adult liver, the hepatocyte is structurally and functionally polarized and has three separate membrane domains: sinusoidal (basal), lateral (or interhepatocytic), and canalicular (apical). Sinusoids carry the blood flow from the portal vein and hepatic artery to the central vein and are lined with endothelial cells, Kupffer cells (resident macrophages), and stellate cells ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Pre-clinical and clinical investigations of metabolic zonation in liver diseases: The potential of microphysiology systems

Soto-Gutiérrez

Gough

Vernetti

et al. 2017

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

The establishment of metabolic zonation within a hepatic lobule ascribes specific functions to hepatocytes based on unique, location-dependent gene expression patterns. Recently, there have been significant developments in the field of metabolic liver zonation. A little over a decade ago, the role of β-catenin signaling was identified as a key regulator of gene expression and function in pericentral hepatocytes. Since then, additional molecules have been identified that regulate the pattern of Wnt/β-catenin signaling within a lobule and determine gene expression and function in other hepatic zones. Currently, the molecular basis of metabolic zonation in the liver appears to be a ‘push and pull’ between signaling pathways. Such compartmentalization not only provides an efficient assembly line for hepatocyte functions but also can account for restricting the initial hepatic damage and pathology from some hepatotoxic drugs to specific zones, possibly enabling effective regeneration and restitution responses from unaffected cells. Careful analysis and experimentation have also revealed that many pathological conditions in the liver lobule are spatially heterogeneous. We will review current research efforts that have focused on examination of the role and regulation of such mechanisms of hepatocyte adaptation and repair. We will discuss how the pathological organ-specific microenvironment affects cell signaling and metabolic liver zonation, especially in steatosis, viral hepatitis, and hepatocellular carcinoma. We will discuss how the use of new human microphysiological platforms will lead to a better understanding of liver disease progression, diagnosis, and therapies. In conclusion, we aim to provide insights into the role and regulation of metabolic zonation and function using traditional and innovative approaches. Impact statement Liver zonation of oxygen tension along the liver sinusoids has been identified as a critical liver microenvironment that impacts specific liver functions such as intermediary metabolism of amino acids, lipids, and carbohydrates, detoxification of xenobiotics and as sites for initiation of liver diseases. To date, most information on the role of zonation in liver disease including, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC) have been obtained from animal models. It is now possible to complement animal studies with human liver, microphysiology systems (MPS) containing induced pluripotent stem cells engineered to create disease models where it is also possible to control the in vitro liver oxygen microenvironment to define the role of zonation on the mechanism(s) of disease progression. The field now has the tools to investigate human liver disease progression, diagnosis, and therapeutic development.

show abstract

Single-cell spatial reconstruction reveals global division of labour in the mammalian liver

Cited by 838 publications

References 38 publications

Argininosuccinate synthase 1 and periportal gene expression in sonic hedgehog hepatocellular adenomas

Argininosuccinate synthase 1 and periportal gene expression in sonic hedgehog hepatocellular adenomas

Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture

Pre-clinical and clinical investigations of metabolic zonation in liver diseases: The potential of microphysiology systems

Contact Info

Product

Resources

About