Epithelial Plasticity during Liver Injury and Regeneration

Gadd, Victoria L.; Aleksieva, Niya; Forbes, Stuart J.

doi:10.1016/j.stem.2020.08.016

Cited by 90 publications

(69 citation statements)

References 126 publications

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“…BDL is a well-established model of cholestatic injury that is associated with ductular reaction and activation of BEC phenotype in some peribiliary hepatocytes. 40,41 We observed distinct levels of EGFP expression, along with expansion of EGFPþ BECs in portal fields and increase in GFP sub hepatocytes, consistent with ductular reaction to cholestasis (Figure 15). As in uninjured livers, all EPCAM þ and K19 þ BECs coexpressed the EGFP transgene (Figure 15A and B), whereas a portion of EGFP þ cells with hepatocyte morphology and relatively low levels of EGFP co-expressed HNF4A (Figure 15C).…”

Section: Sox9 Egfp Is Expressed In Becs and Peribiliary Hepatocytes After Cholestatic Injurysupporting

confidence: 55%

Sox9EGFP Defines Biliary Epithelial Heterogeneity Downstream of Yap Activity

Tulasi

Castaneda

Wager

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims Defining the genetic heterogeneity of intrahepatic biliary epithelial cells (BECs) is challenging, and tools for identifying BEC subpopulations are limited. Here, we characterize the expression of a Sox9 EGFP transgene in the liver and demonstrate that green fluorescent protein (GFP) expression levels are associated with distinct cell types. Methods Sox9 EGFP BAC transgenic mice were assayed by immunofluorescence, flow cytometry, and gene expression profiling to characterize in vivo characteristics of GFP populations. Single BECs from distinct GFP populations were isolated by fluorescence-activated cell sorting, and functional analysis was conducted in organoid forming assays. Intrahepatic ductal epithelium was grown as organoids and treated with a Yes-associated protein (Yap) inhibitor or bile acids to determine upstream regulation of Sox9 in BECs. Sox9 EGFP mice were subjected to bile duct ligation, and GFP expression was assessed by immunofluorescence. Results BECs express low or high levels of GFP, whereas periportal hepatocytes express sublow GFP. Sox9 EGFP+ BECs are differentially distributed by duct size and demonstrate distinct gene expression signatures, with enrichment of Cyr61 and Hes1 in GFP high BECs. Single Sox9 EGFP+ cells form organoids that exhibit heterogeneous survival, growth, and HNF4A activation dependent on culture conditions, suggesting that exogenous signaling impacts BEC heterogeneity. Yap is required to maintain Sox9 expression in biliary organoids, but bile acids are insufficient to induce BEC Yap activity or Sox9 in vivo and in vitro. Sox9 EGFP remains restricted to BECs and periportal hepatocytes after bile duct ligation. Conclusions Our data demonstrate that Sox9 EGFP levels provide readout of Yap activity and delineate BEC heterogeneity, providing a tool for assaying subpopulation-specific cellular function in the liver.

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Section: Sox9 Egfp Is Expressed In Becs and Peribiliary Hepatocytes After Cholestatic Injurysupporting

confidence: 55%

Sox9EGFP Defines Biliary Epithelial Heterogeneity Downstream of Yap Activity

Tulasi

Castaneda

Wager

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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“…Both hepatocytes and cholangiocytes exhibit remarkable plasticity in response to injury. The role of epithelial plasticity in liver regeneration has been elegantly reviewed by Stuart Forbes and colleagues (Gadd et al, 2020).…”

Section: Hepatocytes and Cholangiocytes Exhibit Remarkable Plasticitymentioning

confidence: 99%

“…The adult liver is a slowly self-renewing organ and does not exhibit a defined stem-cell compartment that maintains homeostasis, opposite to other organs that have excellent regenerative capacity, including intestine, stomach, and skin. A great number of experimental models indicate that cellular plasticity, intended as the capacity of liver cells to adopt alternative fates and functions in response to environmental changes, determines efficient adult liver regeneration following damage (Tetteh et al, 2015;Aloia et al, 2016;Kopp et al, 2016;Gadd et al, 2020). A key question is: what molecular mechanisms regulate cellular plasticity and cell-fate changes to achieve efficient liver regeneration upon injury?…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Regulation of Cell-Fate Changes That Determine Adult Liver Regeneration After Injury

Aloia

2021

Front. Cell Dev. Biol.

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The adult liver has excellent regenerative potential following injury. In contrast to other organs of the body that have high cellular turnover during homeostasis (e.g., intestine, stomach, and skin), the adult liver is a slowly self-renewing organ and does not contain a defined stem-cell compartment that maintains homeostasis. However, tissue damage induces significant proliferation across the liver and can trigger cell-fate changes, such as trans-differentiation and de-differentiation into liver progenitors, which contribute to efficient tissue regeneration and restoration of liver functions. Epigenetic mechanisms have been shown to regulate cell-fate decisions in both embryonic and adult tissues in response to environmental cues. Underlying their relevance in liver biology, expression levels and epigenetic activity of chromatin modifiers are often altered in chronic liver disease and liver cancer. In this review, I examine the role of several chromatin modifiers in the regulation of cell-fate changes that determine efficient adult liver epithelial regeneration in response to tissue injury in mouse models. Specifically, I focus on epigenetic mechanisms such as chromatin remodelling, DNA methylation and hydroxymethylation, and histone methylation and deacetylation. Finally, I address how altered epigenetic mechanisms and the interplay between epigenetics and metabolism may contribute to the initiation and progression of liver disease and cancer.

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“…As estimated, about 844 million people worldwide are suffering from CLD and 2 million deaths each year (Asrani et al, 2019). Starting with diverse etiology-related chronic hepatitis, CLD might develop into cirrhosis and hepatocellular carcinoma after repetitive liver damage (Gadd et al, 2020). Environment risk factors associated with CLD are virus, diet, drug, and autoimmune (Marcellin and Kutala, 2018).…”

Section: Introductionmentioning

confidence: 99%

Leveraging Single-Cell RNA-seq Data to Uncover the Association Between Cell Type and Chronic Liver Diseases

Wei

Yue

et al. 2021

Front. Genet.

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BackgroundComponents of liver microenvironment is complex, which makes it difficult to clarify pathogenesis of chronic liver diseases (CLD). Genome-wide association studies (GWASs) have greatly revealed the role of host genetic background in CLD pathogenesis and prognosis, while single-cell RNA sequencing (scRNA-seq) enables interrogation of the cellular diversity and function of liver tissue at unprecedented resolution. Here, we made integrative analysis on the GWAS and scRNA-seq data of CLD to uncover CLD-related cell types and provide clues for understanding on the pathogenesis.MethodsWe downloaded three GWAS summary data and three scRNA-seq data on CLD. After defining the cell types for each scRNA-seq data, we used RolyPoly and LDSC-cts to integrate the GWAS and scRNA-seq. In addition, we analyzed one scRNA-seq data without association to CLD to validate the specificity of our findings.ResultsAfter processing the scRNA-seq data, we obtain about 19,002–32,200 cells and identified 10–17 cell types. For the HCC analysis, we identified the association between B cell and HCC in two datasets. RolyPoly also identified the association, when we integrated the two scRNA-seq datasets. In addition, we also identified natural killer (NK) cell as HCC-associated cell type in one dataset. In specificity analysis, we identified no significant cell type associated with HCC. As for the cirrhosis analysis, we obtained no significant related cell type.ConclusionIn this integrative analysis, we identified B cell and NK cell as HCC-related cell type. More attention and verification should be paid to them in future research.

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Epithelial Plasticity during Liver Injury and Regeneration

Cited by 90 publications

References 126 publications

Sox9EGFP Defines Biliary Epithelial Heterogeneity Downstream of Yap Activity

Sox9EGFP Defines Biliary Epithelial Heterogeneity Downstream of Yap Activity

Epigenetic Regulation of Cell-Fate Changes That Determine Adult Liver Regeneration After Injury

Leveraging Single-Cell RNA-seq Data to Uncover the Association Between Cell Type and Chronic Liver Diseases

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