Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration
Open accessAbstract
Adult liver has enormous regenerative capacity; it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver balances dual demands for increased proliferative activity with maintenance of organ function is unknown but essential to prevent liver failure. Using partial hepatectomy (PHx) in mice to model liver regeneration, we integrated single-cell RNA- and ATAC-Seq to map state transitions in approximately 13,000 hepatocytes at single-cell resolution as livers regenerated, and validated key findings with IHC, to uncover how the organ regenerates hepatocytes while simultaneously fulfilling its vital tissue-specific functions. After PHx, hepatocytes rapidly and transiently diversified into multiple distinct populations with distinct functional bifurcation: some retained the chromatin landscapes and transcriptomes of hepatocytes in undamaged adult livers, whereas others transitioned to acquire chromatin landscapes and transcriptomes of fetal hepatocytes. Injury-related signaling pathways known to be critical for regeneration were activated in transitioning hepatocytes, and the most fetal-like hepatocytes exhibited chromatin landscapes that were enriched with transcription factors regulated by those pathways.
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Several studies suggest that hepatocyte proliferation leads to metabolic remodelling and that hepatocytes across the liver can adapt dynamically to changes during regeneration.
“Several studies suggest that hepatocyte proliferation leads to metabolic remodelling and that hepatocytes across the liver can adapt dynamically to changes during regeneration106,107,[131], [132], [133], [134], [135]”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [107]
The Results section reports changes in hepatocyte-specific gene expression when proliferation was maximal, and the Discussion describes dynamic changes in hepatocyte states during regeneration. But the paper does not establish that proliferation causes metabolic remodelling: it describes heterogeneous responses, with some hepatocytes retaining metabolic functions while others change state to become more proliferative. The findings concern regenerating mouse liver after partial hepatectomy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSome hepatocytes retained chromatin landscapes and transcriptomics of metabolically active uninjured hepatocytes, while others showed changing chromatin and expression signatures suggesting transient fetal reprogramming.
“Interestingly, some hepatocytes retained chromatin landscapes and transcriptomics of metabolically active uninjured hepatocytes, while others showed changing chromatin and expression signatures suggesting transient fetal reprogramming.107”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [107]
During pan-zonal regeneration induced by partial hepatectomy, hepatocytes across the liver underwent transient fetal reprogramming to acquire proliferative potential.
“During pan-zonal regeneration induced by partial hepatectomy, hepatocytes across the liver underwent transient fetal reprogramming to acquire proliferative potential.106,107”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [107]
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Additional file 8 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
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Additional file 1 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
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Additional file 5 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
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Additional file 13 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
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Additional file 10 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
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Additional file 11 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
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Additional file 12 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
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Additional file 6 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
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Additional file 9 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
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Additional file 4 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
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Additional file 2 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
Zhu, J., Guan, X., Yi, L.-L., Xu, H., Li, Q.-Y., Cheng, W.-J., Xie, Y., Li, W.-Z., Zhao, H., Wei, H.-J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26652840
Additional file 7 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
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Additional file 3 of Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs
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- Authors
- Chen, T., Oh, S., Gregory, S., Shen, X., & Diehl, A. M.
- Affiliations
- Duke University (US)
- Department of Medicine and
- Corresponding author
- Shen, Xiling
- Diehl, Anna Mae
- Venue
- JCI Insight
- Published
- 2020-11-19
- Volume
- 5
- Issue
- 22
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC7710279
- OpenAlex
- W3100507307
- Cited by
- 79
- References
- 63
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 13 · 2023: 15 · 2022: 13 · 2021: 11
- FWCI
- 5.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Duke University (RO1-DK077794,RO1-AA010154,R35GM122465,U01CA217514,CZF2019-002451)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- liver regeneration, hepatocytes, partial hepatectomy, single-cell RNA sequencing, single-cell ATAC-seq, hepatocyte heterogeneity, fetal hepatocytes, chromatin accessibility, transcription factors, cell state transitions, liver failure
- MeSH terms
- Animals, Liver, Liver Regeneration, Male, Mice, Inbred C57BL, Signal Transduction, Biomarkers, Hepatocytes, Cell Proliferation, Mice, Single-Cell Analysis
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