ArticleHepatology (Baltimore, Md.)2017
A single-cell transcriptomic analysis reveals precise pathways and regulatory mechanisms underlying hepatoblast differentiation.
Article in Hepatology (Baltimore, Md.), 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers.
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101 citing papers in PubMed.
- CellDiffusion: Enhancing scRNA-seq data integration with accurate inference of cell-cell association.Science advances · 2026Article
- Reverse bioengineering of the liver: developmental principles for next-generation liver-on-a-chip systems.Communications biology · 2026Review
- E- and N-cadherin drive hepatic polarity and lumen elongation via opposing effects on RhoA activity.The Journal of cell biology · 2026Article
- Engineered microtissue systems for identifying the roles of Wnt and YAP signaling in hepatoblast differentiation and organization.Materials today. Bio · 2026Article
- The instructive scar - the dynamic role of extracellular matrix in biliary pathophysiology.Disease models & mechanisms · 2026Review
- PAR3-mediated coordination of hepatocyte proliferation, maturation, and architecture in liver development and regeneration.Nature communications · 2026Article
- Dental pulp stem cells maintain epigenetic chromatin architecture remodeling primed by the etiological stimulus of biliary atresia.Stem cell research & therapy · 2026Article
- Conversion of Transplanted Mature Hepatocytes into AfpAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- GDSim: accurate simulation for single-cell transcriptomes based on the guided diffusion model.Briefings in bioinformatics · 2026Article
- Article
- Kupffer cells control neonatal hepatic metabolism via Igf1 signaling.Development (Cambridge, England) · 2026Article
- Transcriptomic Profile of Directed Differentiation of iPSCs into Hepatocyte-like Cells.International journal of molecular sciences · 2026Article
- PPARγ, a key modulator of metabolic reprogramming, stemness and chemoresistance associated with retrodifferentiation in human hepatocellular carcinomas.Cell death & disease · 2025Article
- Compositional data modeling of high-dimensional single cell RNA-seq (CoDA-hd): its advantages over commonly used normalization approaches.Journal of translational medicine · 2025Article
- Crosstalk via ICAM-1 enhances supportive phenotype of stellate cells and drives hepatocyte proliferation in iPSC-derived hepatic organoids.Stem cell reports · 2025Article
- E- and N-cadherin drive hepatic polarity and lumen elongation via opposing effects on RhoA activity.bioRxiv : the preprint server for biology · 2025Article
- RNA-seq identifies Amd1 as a regulator of hepatocyte proliferation via Skp2 during liver development and hepatocellular carcinoma progression in zebrafish.Genes & diseases · 2025Article
- Breaking the rules of cell biology: Lessons from the liver's exceptional regenerative capacity.Molecular biology of the cell · 2025Review
- Single-cell transcription reveals hepatocyte-to-cholangiocyte reprogramming and biliary gene profile in biliary atresia.Hepatology communications · 2025Article
- Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects.eLife · 2025Article
41 more citing papers are in PubMed but not listed here.
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Abstract
How bipotential hepatoblasts differentiate into hepatocytes and cholangiocytes remains unclear. Here, using single-cell transcriptomic analysis of hepatoblasts, hepatocytes, and cholangiocytes sorted from embryonic day 10.5 (E10.5) to E17.5 mouse embryos, we found that hepatoblast-to-hepatocyte differentiation occurred gradually and followed a linear default pathway. As more cells became fully differentiated hepatocytes, the number of proliferating cells decreased. Surprisingly, proliferating and quiescent hepatoblasts exhibited homogeneous differentiation states at a given developmental stage. This unique feature enabled us to combine single-cell and bulk-cell analyses to define the precise timing of the hepatoblast-to-hepatocyte transition, which occurs between E13.5 and E15.5. In contrast to hepatocyte development at almost all levels, hepatoblast-to-cholangiocyte differentiation underwent a sharp detour from the default pathway. New cholangiocyte generation occurred continuously between E11.5 and E14.5, but their maturation states at a given developmental stage were heterogeneous. Even more surprising, the number of proliferating cells increased as more progenitor cells differentiated into mature cholangiocytes. Based on an observation from the single-cell analysis, we also discovered that the protein kinase C/mitogen-activated protein kinase signaling pathway promoted cholangiocyte maturation.
conclusionOur studies have defined distinct pathways for hepatocyte and cholangiocyte development in vivo, which are critically important for understanding basic liver biology and developing effective strategies to induce stem cells to differentiate toward specific hepatic cell fates in vitro. (Hepatology 2017;66:1387-1401).
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