Transcriptomics of mouse hepatocyte maturation and human hepatic reprogramming
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ABSTRACT:
PROVIDER: PRJNA717728 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14078360_1.fastq.gz | Fastqsanger.gz | |||
| SRR14078360_2.fastq.gz | Fastqsanger.gz | |||
| SRR14078361_1.fastq.gz | Fastqsanger.gz | |||
| SRR14078361_2.fastq.gz | Fastqsanger.gz | |||
| SRR14078362_1.fastq.gz | Fastqsanger.gz |
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Project description:Here, we chemically induced liver progenitor cells (CLiPs) from mouse hepatocytes using a previously established protocol. To identify central protein kinases (PKs) that potentially promote the maturation of lpc-Hep cells, we profiled the transcriptomes and phosphoproteomes of freshly isolated primary mouse hepatocytes (MHs) and ALBUMIN+ hepatocytes (CLiP-Heps) cells. Based on the algorithm developed by us and experiment verification, we validated three PKs that promote mouse hepatocyte maturation. Then, we use RNA sequencing technology to identify potential regulators during hepatic reprogramming with samples from HDFs 2.25 days (FHH-2.25d) and 5 days (FHH-5d) after FOXA3, HNF1A, and HNF4A (FHH) transduction, as well as HDFs transduced with GFP for 2.25 days (GFP) as the control group. After combined analysis with phosphoproteomic data with the algorithm and experiment verification, we identified 2 PKs that may be involved in hepatic reprogramming regulation. One of the five potential regulator candidates is PIM1, which can promote the progress remarkably with overexpression. Therefore, we next perform another RNA-seq to drive the molecular mechanisms under undergoing the regulation by PIM1. Finally, we revealed that cell cycle and ferroptosis pathways are involved in the regulation via PIM1.
2022-08-06 | GSE169702 | GEO
Project description:To identify central protein kinases that potentially promote the maturation, we chemically induced liver progenitor cells (CLiPs) from mouse hepatocytes using a previously established protocol, and profiled the phosphoproteome and proteome of freshly isolated primary mouse hepatocytes (MHs) and ALBUMIN+ hepatocytes (CLiP-Hep) cells. To systematically interrogate the early regulatory events of hepatic reprogramming, we profiled the Phosphoproteome and proteome in human dermal fibroblasts (HDFs) at 2.25 days (FHH-2.25d) and 5 days (FHH-5d) after infection of lenti-virus encoding three liver-specific transcription factors, FOXA3, HNF1A and HNF4A (FHH). In this analysis, HDF infected with lenti-virus expressing GFP for 2.25 days (GFP) were used as control.
2022-08-05 | PXD035829 |
Project description:Liver fibrosis is a strong predictor of long-term mortality in patients with non-alcoholic fatty liver disease; yet the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely under-stood. Using a cell type-resolved genomics approach, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a partial loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a net-work of NASH-activated transcription factors (TFs), as exemplified by Elf3 and Glis2. Indeed, Elf3 and Glis2 controlled hepatocyte identity and fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell (HSC) gene programs. Thus, interconnected TF networks not only promoted hepatocyte dysfunction, but also directed the intra-hepatic crosstalk with HSCs necessary for NASH and fibrosis progression implying molecular “hub-centered” targeting strategies to be superior to existing mono-target approaches as currently used in NASH therapy.
2021-07-13 | PXD025691 | Pride
Project description:Postnatal lipids drive hepatocyte maturation
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Project description:The transcription factor Forkhead box protein O1 (FoxO1) is a well-established regulator of glucose and lipid metabolism, yet its role in metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis remains debated. This study investigates hepatocyte-specific FoxO1 mechanisms driving hepatic inflammation in MASH. Using hepatocyte-specific FoxO1-knockout (KO) mice fed a methionine-choline-deficient diet and LPS-treated FoxO1-KO cells, we demonstrate FoxO1 depletion exacerbates hepatic inflammation, ballooning degeneration, and upregulates TNF-alpha, CXCL8, and CXCL2 in vivo and in vitro. Transcriptomics linked FoxO1 deficiency to enriched pro-inflammatory pathways and suppressed cysteine/methionine metabolism.
2025-07-30 | GSE293003 | GEO
Project description:Background: Hepatocytes are crucial for drug screening, disease modeling, and clinical transplantation, yet generating large numbers of hepatocytes in vitro faces challenges, particularly with traditional direct reprogramming methods. These methods often result in cells with limited functionality and residual memory of their original state. To address these issues, we have a novel two-step lineage reprogramming strategy, which converts fibroblasts into human induced hepatocytes (hiHeps) via an intermediate hepatic progenitor-like cell stage. hiHeps resembled closely with primary human hepatocytes in molecular and functional identity, showing great potential for hepatocyte-based application, however the mechanism underlying the two-step reprogramming is unclear. Methods: This study employs high-throughput single-cell RNA sequencing (scRNA-seq) to explore the molecular and cellular dynamics of this process. Besides, we applied fluorescence-activated cell sorting, RT-qPCR, and shRNA knockdown to validate the key findings of the scRNA-seq results. Results: The findings reveal that the two-step reprogramming mimics a trajectory of liver development, with similar transcriptional waves of developmental genes during reprogramming process. CD24 and DLK1 were identified as markers for two different hepatic progenitor populations, both contributing to hepatocyte maturation. Notably, Lipid metabolism was found to enhance the maturation of progenitors into functional hepatocytes. Additionally, HNF4A and HHEX play roles in determining cell fate between hepatocytes and intestinal cells in the late reprogramming stages. Conclusions: This research provides a comprehensive single-cell roadmap for generating hiHeps in vitro, enhancing our understanding and optimization of the two-step reprogramming protocol.
2025-04-16 | GSE278249 | GEO
Project description:While demonstrated safety and efficacy in treating liver diseases, hepatocyte-based therapy faces the challenge of limited engraftment of transplanted hepatocytes (Tx-Heps) in clinical settings, akin to issues encountered in cell therapy for other solid organs. Here, we identified a conserved reprogramming state of Tx-Heps during engraftment, marked by the activation of liver progenitor genes and bipotential differentiation capacity. Transplantation reprogramming of Tx-Heps is crucial for successful engraftment, as proven by transplantation failure upon hepatocyte-specific ablation of Arid1a, which is required for Tx-Hep reprogramming. To validate translational potential, we artificially induced Tx-Hep reprogramming by in vivo treatment of either IL6 or IC7, a chimeric IL6 family protein, both of which significantly enhance hepatocyte engraftment. Our findings unveil early-stage cell fate reprogramming during transplantation and also propose a promising strategy to augment hepatocyte engraftment, which is an interesting framework to be studied in cell transplantation for other solid organs.
2025-08-18 | GSE275278 | GEO
Project description:Backgruound and aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). However, the mechanisms and the impact of hepatocyte reprogramming in liver disease are poorly understood. Here we show that both hepatocytes expressing KRT7 (hepatobiliary (HB) cells) and ductular reaction cells were increased in decompensated cirrhotic patients and AH, but only HB cells correlated with poor liver function, reduced liver synthetic capacity and poor outcome. Transcriptomic analysis of microdissected HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming together with inflammatory, stemness and cancer gene programs. In this context, CXCR4 pathway was highly enriched in HB cells, and CXCR4 correlated with disease severity and reduced expression of hepatocyte transcription factors and albumin. Mechanistically, TGFβ induced the expression of CXCR4 in primary hepatocytes, and its ligand CXCL12 promoted hepatocyte reprogramming. Liver overexpression of CXCR4 in chronic liver injury decreased hepatocyte gene expression and promoted liver injury. Pharmacological inhibition of CXCR4 reverted hepatocyte loss of identity and reduced ductular reaction and fibrosis progression. Conclusions: This study shows the association of hepatocyte reprogramming with disease progression and poor outcome in AH. Moreover, we identify CXCR4 as a driver of hepatocyte reprogramming as well as a potential therapeutic target in chronic liver injury.
2023-04-06 | GSE199168 | GEO
Project description:Epigenetic reprogramming in hepatic carcinogenesis
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