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Cited by 42Liver physiology and pathologyTGF-β signaling in diseasesLiver Diseases and Immunity

Dynamic Transcriptional and Epigenetic Changes Drive Cellular Plasticity in the Liver

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Merrell, Allyson J., Peng, Tao, Li, Jinyang, Sun, Kathryn, Li, Bin, Katsuda, Takeshi, Grompe, Markus, Tan, Kai +1 more·2021·Hepatology
DOI 10.1002/hep.31704PMC PMC8271088
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Abstract

Background and Aims: Following liver injury, a fraction of hepatocytes adopt features of biliary epithelial cells (BECs) in a process known as biliary reprogramming. The aim of this study was to elucidate the molecular events accompanying this dramatic shift in cellular identity. Approach and Results: We applied the techniques of bulk RNA‐sequencing (RNA‐seq), single‐cell RNA‐seq, and assay for transposase‐accessible chromatin with high‐throughput sequencing to define the epigenetic and transcriptional changes associated with biliary reprogramming. In addition, we examined the role of TGF‐β signaling by profiling cells undergoing reprogramming in mice with hepatocyte‐specific deletion in the downstream TGF‐β signaling component mothers against decapentaplegic homolog 4 (Smad4). Biliary reprogramming followed a stereotyped pattern of altered gene expression consisting of robust induction of biliary genes and weaker repression of hepatocyte genes. These changes in gene expression were accompanied by corresponding modifications at the chromatin level. Although some reprogrammed cells had molecular features of “fully differentiated” BECs, most lacked some biliary characteristics and retained some hepatocyte characteristics. Surprisingly, single‐cell analysis of Smad4 mutant mice revealed a dramatic increase in reprogramming. Conclusion: Hepatocytes undergo widespread chromatin and transcriptional changes during biliary reprogramming, resulting in epigenetic and gene expression profiles that are similar to, but distinct from, native BECs. Reprogramming involves a progressive accumulation of biliary molecular features without discrete intermediates. Paradoxically, canonical TGF‐β signaling through Smad4 appears to constrain biliary reprogramming, indicating that TGF‐β can either promote or inhibit biliary differentiation depending on which downstream components of the pathway are engaged. This work has implications for the formation of BECs and bile ducts in the adult liver.

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Cited by

Sorted by citations

Authors
Merrell, A. J., Peng, T., Li, J., Sun, K., Li, B., Katsuda, T., Grompe, M., Tan, K., & Stanger, B. Z.
Affiliations
  • University of Pennsylvania (US)
  • Children's Hospital of Philadelphia (US)
  • Oregon Health & Science University (US)
Corresponding author
Stanger, Ben Z.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2021-07
Volume
74
Issue
1
Pages
444-457
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.31704
PMC
PMC8271088
OpenAlex
W3119139808
Cited by
42
References
7
Citations by year
2026: 4 · 2025: 13 · 2024: 7 · 2023: 11 · 2022: 6 · 2021: 1
FWCI
3.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Leona M. and Harry B. Helmsley Charitable Trust (2008-04062)
  • National Cancer Institute (CA233285, U2CCA233285)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK083355, DK08335)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
cellular plasticity, liver injury, TGF-beta signaling, SMAD4, chromatin accessibility, epigenetic modifications, gene expression changes, cholangiocytes, bile duct formation, hepatocyte differentiation
MeSH terms
Cell Plasticity, RNA-Seq, Animals, Bile Ducts, Cell Differentiation, Epithelial Cells, Humans, Liver, Liver Regeneration, Male, Mice, Transgenic, Hepatocytes, Epigenesis, Genetic, Mice, Smad4 Protein, Single-Cell Analysis

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