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Cited by 146Single-cell and spatial transcriptomicsLiver physiology and pathologyDevelopmental Biology and Gene Regulation

Single-cell atlas of human liver development reveals pathways directing hepatic cell fates

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Wesley, Brandon T., Ross, Alexander D. B., Muraro, Daniele, Miao, Zhichao, Saxton, Sarah, Tomaz, Rute A., Morell, Carola M., Ridley, Katherine +24 more·2022·Nature Cell Biology
DOI 10.1038/s41556-022-00989-7PMC PMC7617064

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Abstract

The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances have been hampered by the lack of knowledge concerning human hepatic development. Here, we addressed this limitation by describing the developmental trajectories of different cell types that make up the human liver at single-cell resolution. These transcriptomic analyses revealed that sequential cell-to-cell interactions direct functional maturation of hepatocytes, with non-parenchymal cells playing essential roles during organogenesis. We utilized this information to derive bipotential hepatoblast organoids and then exploited this model system to validate the importance of signalling pathways in hepatocyte and cholangiocyte specification. Further insights into hepatic maturation also enabled the identification of stage-specific transcription factors to improve the functionality of hepatocyte-like cells generated from human pluripotent stem cells. Thus, our study establishes a platform to investigate the basic mechanisms directing human liver development and to produce cell types for clinical applications.

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  • A pericentral-to-periportal gradient of Rspo3 in HSCs was observed.

    “Consistent with previous studies31–33 and befitting the zonal alterations in HSC-depleted livers, we observed a pericentral-to-periportal gradient of Rspo3 in HSCs (Fig. 3f).”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [32]

    The ‘Dynamic intercellular interactions of the developing liver’ section (page unavailable) reports RSPO3-LGR4/5 interactions between hepatoblasts and stellate cells at 5–6 PCW. It does not report a pericentral-to-periportal RSPO3 gradient. In the citing sentence, ‘we observed’ also identifies the gradient as the citing authors’ own observation, rather than a finding directly attributed to this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Rspo3 is expressed in HSCs during development.

    “As Rspo3 is expressed in HSCs during development32, we generated mice with an inducible knockout of Rspo3 in HSCs through Pdgfrb-creERT2 (Rspo3ΔHSC-ind) mice for postnatal deletion.”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [32]

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References 68 · Cited by 146

Research works printed but not linked: 49

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Authors
Wesley, B. T., Ross, A. D. B., Muraro, D., Miao, Z., Saxton, S., Tomaz, R. A., Morell, C. M., Ridley, K., Zacharis, E. D., Petrus-Reurer, S., Kraiczy, J., Mahbubani, K. T., Brown, S., Garcia-Bernardo, J., Alsinet, C., Gaffney, D., Horsfall, D., Tysoe, O. C., Botting, R. A., Stephenson, E., Popescu, D.-M., MacParland, S., Bader, G., McGilvray, I. D., Ortmann, D., Sampaziotis, F., Saeb-Parsy, K., Haniffa, M., Stevens, K. R., Zilbauer, M., Teichmann, S. A., & Vallier, L.
Affiliations
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • European Bioinformatics Institute (GB)
  • University of Washington (US)
  • University of Cambridge (GB)
  • Wellcome Sanger Institute (GB)
  • Newcastle University (GB)
  • University of Toronto (CA)
  • Toronto General Hospital Research Institute (CA)
  • Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
Corresponding author
Vallier, Ludovic
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2022-09-15
Volume
24
Issue
10
Pages
1487-1498
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/s41556-022-00989-7
PMC
PMC7617064
OpenAlex
W4295950911
Cited by
146
References
68
Citations by year
2026: 36 · 2025: 48 · 2024: 35 · 2023: 26 · 2022: 1
FWCI
9.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Cell Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • University of Washington
  • Wellcome Trust (WT206194, 206194)
  • Chan Zuckerberg Initiative
  • National Institute for Health and Care Research (CL-2017-14-001)
  • Academy of Medical Sciences (SGL019\1071)
  • University of Cambridge
  • Rosetrees Trust
  • National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/R001987/1, NC/T2T0419, NC/N001540/1)
  • Cambridge University Hospitals
  • Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
hepatocyte maturation, non-parenchymal cells, cell-cell interactions, developmental trajectories, transcription factors, single-cell transcriptomics, liver organogenesis
MeSH terms
Cell Differentiation, Humans, Liver, Organoids, Transcription Factors, Hepatocytes

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