Robust cellular reprogramming occurs spontaneously during liver regeneration
Open accessAbstract
Cellular reprogramming—the ability to interconvert distinct cell types with defined factors—is transforming the field of regenerative medicine. However, this phenomenon has rarely been observed in vivo without exogenous factors. Here, we report that activation of Notch, a signaling pathway that mediates lineage segregation during liver development, is sufficient to reprogram hepatocytes into biliary epithelial cells (BECs). Moreover, using lineage tracing, we show that hepatocytes undergo widespread hepatocyte-to-BEC reprogramming following injuries that provoke a biliary response, a process requiring Notch. These results provide direct evidence that mammalian regeneration prompts extensive and dramatic changes in cellular identity under injury conditions.
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During injury, mouse hepatocytes can be reprogrammed to proliferative biliary-like progenitor cells (HepPDs).
“Specifically, during injury, mouse hepatocytes can be reprogrammed to proliferative biliary-like progenitor cells (HepPDs) (Tarlow et al., 2014; Yanger et al., 2013”
From In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation Capacity (2018) · cites this paper as Yanger et al., 2013
The Results and Discussion (page unavailable) show that, after DDC-induced injury in mice, lineage-labeled hepatocytes acquired biliary markers and morphology. The paper describes conversion toward biliary epithelial cells, but does not identify the resulting cells as HepPDs or establish that they are proliferative progenitors; it says whether proliferation is required for reprogramming remains unknown. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn periportal injury, LPLCs are mainly generated in the region 1-5 layers away from injured bile ducts.
“In periportal injury, LPLCs are mainly generated in the region 1-5 layers away from injured bile ducts.[7][8][9]12,13”
From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [9]
The Results and Discussion report that biphenotypic intermediate cells were most abundant in periportal regions after DDC-induced injury. Our copy does not specify that they were generated one to five cell layers from injured bile ducts. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLPLCs formed specifically around periportal regions are parenchymal cells showing hepatocyte morphology and expressing both HNF4a and SOX9.
“LPLCs, formed specifically around periportal regions, were determined as parenchymal cells both showing a hepatocyte morphology and expressing both the hepatic marker HNF4a, and the progenitor marker SOX9 (Figures 1A and 1B).[7][8][9]”
From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [9]
The Results and Discussion report hepatocyte-derived biphenotypic cells that were most abundant in periportal regions, while the Figure 2 legend describes HNF4a- and Sox9-positive cells with hepatocyte morphology. The paper does not say they formed specifically or exclusively around periportal regions, and it calls them intermediate cells rather than LPLCs. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSeveral extrinsic signals, including Notch and Wnt, have been proposed for LPLC formation.
“Several extrinsic signals have been proposed for LPLC formation, including Notch and Wnt.9,10”
From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [9]
The Results and Discussion report that Notch activation produces hepatocyte-derived cells with an intermediate phenotype and that Notch signaling is required for reprogramming after injury. Our copy does not identify Wnt as a signal involved in this process, so it supports the Notch part of the claim but not the Wnt part. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMature hepatocytes were found reprogrammed into LPLCs to contribute to liver repair after periportal injury.
“Importantly, mature hepatocytes were found reprogrammed into LPLCs to contribute to liver repair after periportal injury.7,9,13”
From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [9]
The Results and Discussion report that lineage-labeled hepatocytes acquired biliary markers and became atypical ductal or biliary epithelial cells after DDC injury; intermediate cells were most abundant in periportal regions. The paper does not identify those cells as LPLCs or establish repair specifically after periportal injury. It describes their contribution to regeneration more broadly. (LLM, conf=0.85)
Experimental — accuracy not yet measured
AAV8-TBG-Cre tail vein injection in adult Egfr Fl/Fl mice leads to >99% Cre-mediated recombination specifically in hepatocytes.
“an approach that leads to >99% Cre-mediated recombination specifically in hepatocytes (Fig. S6I) 62,63”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [63]
The Results and Discussion report hepatocyte-specific labeling in Rosa YFP reporter mice given AAV8-TBG-Cre or AAV8-CMV-Cre, with >99% of hepatocytes labeled. That supports the efficiency and specificity attributed to the approach, but the paper does not establish >99% recombination in Egfr Fl/Fl mice after tail-vein injection; the Viral infections section describes retro-orbital injection for a separate AAV-TBG-Cre experiment. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNot all hepatocytes transdifferentiate with the same capacity; zone 1 periportal hepatocytes transdifferentiated readily to BECs, but even with NOTCH activation, zone 3 hepatocytes did not transdifferentiate.
“Curiously, not all hepatocytes transdifferentiate with the same capacity; zone 1 periportal hepatocytes transdifferentiated readily to BECs, but even with activation of NOTCH signalling, which is a strong inducer of biliary fate in hepatocytes, zone 3 hepatocytes did not transdifferentiate.99”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [99]
Lineage-tracing studies in animal models have confirmed that hepatocytes contribute to bile duct remodeling following cholangiocyte injury.
“Lineage-tracing studies in animal models have confirmed that hepatocytes contribute to bile duct remodeling following cholangiocyte injury10,43–48”
From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [45]
Hepatocyte-to-HepPD conversion is likely to take place through a bi-phenotypic 'intermediate' status characterized by the co-expression of hepatocyte markers and progenitor-associated markers.
“Hepatocyte-to-HepPD conversion is likely to take place through a bi-phenotypic “intermediate” status characterized by the co-expression of hepatocyte markers and progenitor-associated markers (Tanimizu et al., 2014; Yanger et al., 2013”
From In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation Capacity (2018) · cites this paper as Yanger et al., 2013
LPLCs are detected in various human liver diseases, suggesting relevance in human pathogenesis.
“It is noteworthy that LPLCs were also detected in various human liver diseases, suggesting the relevance of these cells in human pathogenesis.9”
From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [9]
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- Authors
- Yanger, K., Zong, Y., Maggs, L. R., Shapira, S. N., Maddipati, R., Aiello, N. M., Thung, S. N., Wells, R. G., Greenbaum, L. E., & Stanger, B. Z.
- Affiliations
- University of Pennsylvania (US)
- Icahn School of Medicine at Mount Sinai (US)
- Thomas Jefferson University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2013-03-21
- Volume
- 27
- Issue
- 7
- Pages
- 719-724
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3713433
- OpenAlex
- W2084074847
- Cited by
- 484
- References
- 3
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 30 · 2023: 53 · 2022: 36 · 2021: 32 · 2020: 35 · 2019: 43 · 2018: 53 · 2017: 47 · 2016: 41 · 2015: 39 · 2014: 31 · 2013: 10
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pew Charitable Trusts
- Cancer Research Institute
- University of Pennsylvania
- National Cancer Institute (P30CA016520)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK090306, T32DK007066, R01DK083355, DK083355)
- Abramson Family Cancer Research Institute
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- cellular reprogramming, liver regeneration, Notch signaling, hepatocytes, cholangiocytes, liver injury, lineage tracing, cell identity, hepatocyte differentiation
- MeSH terms
- Animals, Epithelial Cells, Liver Regeneration, Stem Cells, Signal Transduction, Cell Lineage, Hepatocytes, Mice, Receptors, Notch
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