Identification of Lineage-Specific Transcription Factors That Prevent Activation of Hepatic Stellate Cells and Promote Fibrosis Resolution

Liu, Xiao; Xu, Jun; Rosenthal, Sara Brin; Zhang, Ling-juan; McCubbin, Ryan; Meshgin, Nairika; Shang, Linshan; Koyama, Yukinori; Yen, Hsiao; Sharma, Sonia; Heinz, Sven; Glass, Chris K.; Benner, Chris; Brenner, David A.; Kisseleva, Tatiana

doi:10.1053/j.gastro.2020.01.027

Cited by 122 publications

(122 citation statements)

References 35 publications

(56 reference statements)

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“…leaky) we were unable to detect GFP expression ( Figure S3G). Interestingly however, we found that DesLO established endogenous GATA6 expression in the hepatobiliary and stellate clusters in line with past reports (Figure S3H) (De Franco et al, 2013;Liu et al, 2020). In fact, a recent study has identified a key role for GATA6 in regulation of mouse and human stellate cell lineages (Liu et al, 2020).…”

Section: Figuresupporting

confidence: 92%

“…The endothelial-like cell (ELC) cluster 5 was then identified by expression of genes including vascular endothelial growth factor receptor 1 (VEGFR1 or FLT1), VE-cadherin (CDH5), CD34, ERG, and CD31 (Figures 3I). The DES + /PDGFRB + cluster 4 expressed stellate cell markers delineated in a recent single cell report on primary isolated liver samples (Figures 3I and S3F) (MacParland et al, 2018).…”

Section: Single Cell Rna-seq In Deslo Confirms Heterotypic Cell Typesmentioning

confidence: 56%

“…These stellate-like cells (SLCs) were enriched in DES and structural genes including collagen type I alpha 1 chain (COL1A1), transgelin (TAGLN), and smooth muscle actin (ACTA2) (Figure 3I). Clustering of DesLO ELC-and SLC-upregulated genes with overlapping primary liver stellate and endothelial cell scRNA-Seq data from the primary liver single cell dataset also grouped DesLO ELCs closest to zone 1 liver sinusoidal endothelial cells (LSECs) and SLCs closest to stellate cells ( Figure S3F) (MacParland et al, 2018).…”

Section: Figurementioning

confidence: 87%

“…PROX1 is required for hepatocyte migration and endothelial cell development, and loss of PROX1 leads to decreased hepatocyte counts and liver size (Kamiya et al, 2008;Seth et al, 2014). ATF5 is associated with differentiation, survival, and maturation of several cell types, including hepatocytes (Nakamori et al, 2016;Pascual et al, 2008;Wang et al, 2014). Furthermore, overexpression of the transcription factors HNF1A, HNF4A, HNF6, and CEBPA along with ATF5 and PROX1 has been used to convert fibroblasts into hepatocytes .…”

Section: Computational Assessment Of Tissue Grns and Identification Omentioning

confidence: 99%

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Synthetic Maturation of Multilineage Human Liver Organoids via Genetically Guided Engineering

Velazquez

LeGraw

Moghadam

et al. 2020

Preprint

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Graphical AbstractHIGHLIGHTS  In vitro tissue maturation via genetically encoded molecular programs  Computational analysis to identify maturation transcription factors in liver organoids  Promoting vascularization of organoids via genetically encoded molecular programs  Single cell analysis of parenchymal and non-parenchymal cells  Modeling of native liver functions and in vivo therapeutic potential SUMMARY Pluripotent stem cell (PSC)-derived organoids are emerging as novel human-based microphysiological models but display immature phenotypes with limited subsets of endothelial or stromal cells. Here we demonstrate that in vitro manipulation of gene regulatory networks (GRNs) in PSC-derived liver organoids selected either through computational analysis or targeted tissue design can advance tissue maturation in vitro. Through an unbiased comparison with the genetic signature of mature livers, we identify downregulated GRNs in fetal liver organoids compared to adult livers. We demonstrate that overexpression of PROX1 and ATF5, together with targeted CRISPR-based transcriptional activation of endogenous CYP3A4, drives maturation in vitro. Single cell analyses reveal hepatobiliary-, endothelial-, and stellate-like cell populations. The engineered organoids demonstrate enhanced vasculogenesis, capture native liver characteristics (e.g. FXR signaling, CYP3A4 activity), and exhibit therapeutic potential in mice. Collectively, our approach provides a genetically guided framework for engineering developmentally advanced multilineage tissues from hiPSCs.

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Section: Figuresupporting

confidence: 92%

Section: Single Cell Rna-seq In Deslo Confirms Heterotypic Cell Typesmentioning

confidence: 56%

Section: Figurementioning

confidence: 87%

Section: Computational Assessment Of Tissue Grns and Identification Omentioning

confidence: 99%

See 2 more Smart Citations

Synthetic Maturation of Multilineage Human Liver Organoids via Genetically Guided Engineering

Velazquez

LeGraw

Moghadam

et al. 2020

Preprint

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“…The regulon of interferon regulatory factor 1 (IRF1) was strongly activated by IFN-4 expression ( Table S7). IRF1 is a transcription factor that enhances the antiviral response but reduces liver cirrhosis by inhibiting proliferation of hepatic stellate cells (HSCs) (26,27); IRF1 activity is antagonized by the closely related IRF2 (28). Gene set enrichment analysis (GSEA) (29) showed that the IRF1 regulon enrichment scores were higher for IFN-4, compared to IFN-3 and IFNLR1 KO (Fig.…”

Section: Ifn-4 Inhibits Proliferation Of Hepatic Cells By Inducing Irf1mentioning

confidence: 99%

IFN-λ4 may contribute to HCV persistence by increasing ER stress and enhancing IRF1 signaling

Onabajo¹,

Wang²,

Lee³

et al. 2020

Preprint

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Chronic hepatitis C virus (HCV) infection and cirrhosis are major risk factors for developing hepatocellular carcinoma (HCC). Genetic polymorphisms in the IFNL3/IFNL4 locus have been associated both with impaired clearance of HCV and protection from liver fibrosis, an early stage of cirrhosis. Here, we aimed to address the genetic and functional relationships between IFNL3/IFNL4 polymorphisms, HCV-related cirrhosis, and HCC risk. We evaluated associations between IFNL4 genotype, defined as the presence of rs368234815-dG or rs12979860-T alleles, with cirrhosis and HCC risk in patients with chronic HCV - 2,931 from Taiwan and 3,566 from Japan. We detected associations between IFNL4 genotype and decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwan), but increased risk of HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058, in Japan). In-vitro, IFN-λ4 expression increased ER stress, and enhanced positive regulation of IFN responses via IRF1 induction, which mediated antiproliferative effects in hepatic cells. Our data present novel IFN-λ4-associated pathways that may be contributing to HCV persistence and development of HCC.

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Survivin inhibition ameliorates liver fibrosis by inducing hepatic stellate cell senescence and depleting hepatic macrophage population

Sharma,

Ghufran,

Aftab

et al. 2024

Journal of Cell Communication and Signaling

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Persistent activation of hepatic stellate cells (HSCs) in the injured liver leads to the progression of liver injury from fibrosis to detrimental cirrhosis. In a previous study, we have shown that survivin protein is upregulated during the early activation of HSCs, which triggers the onset of liver fibrosis. However, the therapeutic potential of targeting survivin in a fully established fibrotic liver needs to be investigated. In this study, we chemically induced hepatic fibrosis in mice using carbon tetrachloride (CCl4) for 6 weeks, which was followed by treatment with a survivin suppressant (YM155). We also evaluated survivin expression in fibrotic human liver tissues, primary HSCs, and HSC cell line by histological analysis. αSMA+ HSCs in human and mice fibrotic liver tissues showed enhanced survivin expression, whereas the hepatocytes and quiescent (qHSCs) displayed minimal expression. Alternatively, activated M2 macrophage subtype induced survivin expression in HSCs through the TGF‐β‐TGF‐β receptor‐I/II signaling. Inhibition of survivin in HSCs promoted cell cycle arrest and senescence, which eventually suppressed their activation. In vivo, YM155 treatment increased the expression of cell senescence makers in HSCs around fibrotic septa such as p53, p21, and β‐galactosidase. YM155 treatment in vivo also reduced the hepatic macrophage population and inflammatory cytokine expression in the liver. In conclusion, downregulation of survivin in the fibrotic liver decreases HSC activation by inducing cellular senescence and modulating macrophage cytokine expression that collectively ameliorates liver fibrosis.

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Identification of Lineage-Specific Transcription Factors That Prevent Activation of Hepatic Stellate Cells and Promote Fibrosis Resolution

Cited by 122 publications

References 35 publications

Synthetic Maturation of Multilineage Human Liver Organoids via Genetically Guided Engineering

Synthetic Maturation of Multilineage Human Liver Organoids via Genetically Guided Engineering

IFN-λ4 may contribute to HCV persistence by increasing ER stress and enhancing IRF1 signaling

Survivin inhibition ameliorates liver fibrosis by inducing hepatic stellate cell senescence and depleting hepatic macrophage population

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