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Cited by 134Liver physiology and pathologyMesenchymal stem cell researchDrug-Induced Hepatotoxicity and Protection

Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers

Open access
Li, Lu, Cui, Lei, Lin, Ping, Liu, Zhaoyuan, Bao, Shujie, Ma, Xiaolong, Nan, Haitao, Zhu, Wencheng +9 more·2023·Cell Stem Cell
DOI 10.1016/j.stem.2023.01.009
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Abstract

Stem cell-independent reprogramming of differentiated cells has recently been identified as an important paradigm for repairing injured tissues. Following periportal injury, mature hepatocytes re-activate reprogramming/progenitor-related genes (RRGs) and dedifferentiate into liver progenitor-like cells (LPLCs) in both mice and humans, which contribute remarkably to regeneration. However, it remains unknown which and how external factors trigger hepatocyte reprogramming. Here, by employing single-cell transcriptional profiling and lineage-specific deletion tools, we uncovered that periportal-specific LPLC formation was initiated by regionally activated Kupffer cells but not peripheral monocyte-derived macrophages. Unexpectedly, using in vivo screening, the proinflammatory factor IL-6 was identified as the niche signal repurposed for RRG induction via STAT3 activation, which drove RRG expression through binding to their pre-accessible enhancers. Notably, RRGs were activated through injury-specific rather than liver embryogenesis-related enhancers. Collectively, these findings depict an injury-specific niche signal and the inflammation-mediated transcription in driving the conversion of hepatocytes into a progenitor phenotype.

AI snapshot

Written from the paper’s full text.

TL;DR

Kupffer-cell-derived IL-6 acts as a periportal niche signal that directly induces hepatocyte dedifferentiation into liver progenitor-like cells (LPLCs) through STAT3 activation. This repurposes proinflammatory IL-6/STAT3 signaling to reactivate progenitor genes from injury-specific enhancers, distinct from developmental regulation.

Key findings

  • Macrophage depletion reduced DDC-induced LPLC formation by 57.7%; KC depletion significantly reduced LPLC formation, whereas blocking monocyte-derived macrophage recruitment in Ccr2−/− mice did not alter LPLC formation.
  • Among 16 candidate factors delivered by hydrodynamic tail-vein injection, IL-6 was the only factor that robustly induced SOX9+HNF4a+ hepatocytes; KC-specific Il6 deletion reduced DDC-induced LPLCs comparably to macrophage or KC depletion, and hepatocyte-specific Il6ra or gp130 deletion reduced or abolished IL-6-induced LPLC formation.
  • STAT3 deletion in hepatocytes dramatically reduced DDC-induced LPLCs and abolished IL-6 HDTVi-induced LPLCs; ChIP-seq identified 27,685 STAT3-binding sites (11,196 genes), with 186 of 232 RRGs showing STAT3 binding (p = 2.42 × 10−17, chi-squared test).
  • STAT3-binding RRG sites overlapped Arid1a-opened chromatin and showed increased H3K27ac in LPLCs; 495 of 668 STAT3-binding RRG sites had increased H3K27ac specifically in LPLCs but not hepatoblasts, and 89.3% of these were distal (p < 8.4 × 10−46, chi-squared test), supporting injury-specific enhancer regulation.

Methods

  • Mouse periportal liver injury models (DDC, DAPM, APAP) with lineage-specific depletion/knockout lines (clodronate macrophage depletion, Clec4f-Cre;Rosa26-LSL-iDTR KC depletion, Ccr2−/−, Il6Dkc, Il6raDli, gp130Dli, Stat3Dli, Arid1aDli), HDTVi factor screening, immunofluorescence, flow cytometry, and serum biochemistry.
  • scRNA-seq (10X Chromium and Smart-seq2) of hepatocytes and macrophages, pseudotime ordering, pathway activity analysis, and identification of 232 reprogramming/progenitor-related genes (RRGs); bulk RNA-seq and qRT-PCR validation.
  • ChIP-seq for pSTAT3 and H3K27ac, ATAC-seq reuse, and in vivo reporter assays for Sox9 and Spp1 STAT3-binding sites; statistics included t tests and chi-squared tests.

Limitations

  • The paper states that periportal liver injury models were used and that it remains to be determined whether similar regulation occurs in other injuries such as pericentral liver injury and partial hepatectomy; preliminary APAP data suggest possible involvement but require further testing.
  • Evident from the text: some experiments used small sample sizes (e.g., n = 3 in several assays), sample processing was not blinded, and no statistical method was used to predetermine sample size.
  • Evident from the text: most mouse experiments used male mice, and the study is primarily mouse-based, so direct human relevance is not established.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.stem.2023.01.009

Cites

79 of 79 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

37 of 49 cited sources checked · 18 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    KCs and MoMFs function differently in tissue injury and regeneration.

    “These macrophages function differently in tissue injury and regeneration.18,19”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [18] Blériot, 2019, Understanding the heterogeneity of resident liver macrophages, Front. Immunol. source

      The “New Approaches to Improve Our Understanding of Liver Macrophages” section reports a functional difference between native KCs and monocyte-derived replacements after irradiation: the replacements lose the native cells’ radioresistance. The “Diversity of Liver Macrophages” section also describes monocyte-derived macrophages replacing depleted KCs during inflammation, but says some later assume similar functions. The paper does not establish distinct KC and MoMF roles in tissue regeneration. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [19] Krenkel, 2017, Liver macrophages in tissue homeostasis and disease, Nat. Rev. Immunol. source
  • Premisecitation

    Two subtypes of macrophages have been identified in injured livers: KCs and MoMFs.

    “Two subtypes of macrophages have been identified in injured livers: KCs and MoMFs.18”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [18] Blériot, 2019, Understanding the heterogeneity of resident liver macrophages, Front. Immunol. source
  • Premisecitation

    In 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”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [7] Tarlow, 2014, Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes, Cell Stem Cell source
    • cites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source

      The section 'Arid1a Facilitates Liver-Progenitor-Like Cell Formation in Periportal Liver Injury' reports LPLC formation after periportal injury, and the figure discussion places related cells in the periportal area (page not provided). Our copy does not say that LPLCs are mainly generated one to five cell layers from injured bile ducts; searches for that distance and for 'layers' did not find it. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [9] Yanger, 2013, Robust cellular reprogramming occurs spontaneously during liver regeneration, Genes Dev. source

      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 measured
    • cites [12] Yimlamai, 2014, Hippo pathway activity influences liver cell fate, Cell source

      The Introduction (page unavailable) says oval cells emerge from bile ducts under extreme stress or chronic injury. The Results report that YAP-induced progenitor-like changes initially appear around portal areas, but this is not a measurement of periportal injury. Neither passage supports the claim that LPLCs are mainly generated 1–5 cell layers from injured bile ducts. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [13] Tanimizu, 2014, Sry HMG box protein 9-positive (Sox9+) epithelial cell adhesion molecule-negative (EpCAM-) biphenotypic cells derived from hepatocytes are involved in mouse liver regeneration, J. Biol. Chem. source

      The Results report Sox9+EpCAM− biphenotypic cells appearing in DDC-injured mouse livers, and the paper describes them near ductular structures. It does not establish that LPLCs are mainly generated 1–5 cell layers from injured bile ducts; the Discussion also distinguishes these cells from LPCs. No page number is available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    Genes expressed in liver progenitors remained accessible in mature hepatocytes via Arid1a regulation, endowing hepatocytes with competence to respond rapidly to reprogramming signals.

    “We previously found that genes expressed in liver progenitors remained accessible in mature hepatocytes via Arid1a regulation, endowing hepatocytes with the competence to respond rapidly to reprogramming signals.8”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source
  • Premisecitation

    Mature 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”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [7] Tarlow, 2014, Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes, Cell Stem Cell source
    • cites [9] Yanger, 2013, Robust cellular reprogramming occurs spontaneously during liver regeneration, Genes Dev. source

      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
    • cites [13] Tanimizu, 2014, Sry HMG box protein 9-positive (Sox9+) epithelial cell adhesion molecule-negative (EpCAM-) biphenotypic cells derived from hepatocytes are involved in mouse liver regeneration, J. Biol. Chem. source

      The Discussion identifies Sox9+EpCAM− cells derived from mature hepatocytes and says they may contribute to repair in DDC-injured mouse livers. It distinguishes these cells from LPCs, however, and speculates rather than establishes that hepatocytes near portal triads convert to cholangiocyte-like cells. The claim overstates the evidence for repair after periportal injury. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 30
  • May combine two claims. 45

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reprogramming of differentiated cells into progenitor-like cells is an important injury-repair paradigm independent of adult stem cells in various epithelial tissues in mammals.

    “The reprogramming of differentiated cells into progenitor-like cells has recently been discovered as an important injury-repair paradigm independent of adult stem cells in a variety of epithelial tissues in mammals, 1 such as the lung, 2 intestine, 3 pancreas, 4 and liver.5,6”
    Quote in the paperNot a substantial claim5 of 6 sources checked
    • cites [1] Wells, 2018, Diverse mechanisms for endogenous regeneration and repair in mammalian organs, Nature source
    • cites [2] Jain, 2015, Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung, Nat. Commun. source
    • cites [3] Tetteh, 2016, Replacement of lost Lgr5-positive stem cells through plasticity of their enterocyte-lineage daughters, Cell Stem Cell source
    • cites [4] Chera, 2014, Diabetes recovery by age-dependent conversion of pancreatic delta-cells into insulin producers, Nature source
    • cites [5] Raven, 2017, Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration, Nature source
    • cites [6] Schaub, 2018, De novo formation of the biliary system by TGFbeta-mediated hepatocyte transdifferentiation, Nature source

      The Abstract (page not provided) describes transdifferentiation as an alternative to stem-cell-mediated regeneration and reports hepatocytes forming mature cholangiocytes during liver injury. It also describes similar cell plasticity in other mammalian epithelia. It does not establish the claimed transition into progenitor-like cells; its demonstrated endpoint is another differentiated cell type. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    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”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [9] Yanger, 2013, Robust cellular reprogramming occurs spontaneously during liver regeneration, Genes Dev. source

  • May combine two claims.

    Premisecitation

    Following periportal injury, hepatocytes reactivate progenitor genes and undergo dedifferentiation into liver progenitor-like cells (LPLCs) to repair the injured liver.

    “Following periportal injury, hepatocytes reactivated progenitor genes and underwent dedifferentiation into liver progenitor-like cells (LPLCs) to repair the injured liver.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [7] Tarlow, 2014, Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes, Cell Stem Cell source
    • cites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source

  • May combine two claims.

    Premisecitation

    When LPLC formation is restrained, injured livers show prolonged hepatocyte proliferation, enhanced biliary injury, and reduced fibrosis resolution.

    “When the formation of LPLCs was restrained, injured livers showed prolonged hepatocyte proliferation, enhanced biliary injury, and reduced fibrosis resolution.8”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source

      The section on Arid1a-dependent LPLC formation and liver regeneration reports that, after eight weeks of recovery, hepatocytes continued to proliferate in Arid1a-KO mice, in which LPLC formation was impaired. It does not establish enhanced biliary injury or reduced fibrosis resolution; it says DDC-induced ductular reactions resolved in both knockout and control mice. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Chromatin regions of liver progenitor genes remain accessible in mature hepatocytes, endowing hepatocytes with intrinsic reprogramming competence for rapid response to extrinsic injury signals and expression of these genes.

    “Our previous study has revealed that the chromatin regions of liver progenitor genes remain accessible in mature hepatocytes, thereby endowing hepatocytes with intrinsic ''reprogramming competence'' for the rapid response to extrinsic injury signals and expression of these genes.8”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In DDC-induced periportal injury, LPLCs give rise to approximately 25% of newly regenerated hepatocytes and, to some extent, cholangiocytes.

    “For example, in 3,5-diethoxycarbonyl-1,4-dihydrocollidin (DDC)-induced periportal injury, LPLCs gave rise to approximately 25% of the newly regenerated hepatocytes and, to some extent, cholangiocytes.7,8”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [7] Tarlow, 2014, Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes, Cell Stem Cell source
    • cites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source

  • Classified as probably not a substantial claim.

    Premisecitation

    Cell reprogramming often occurs in highly specialized regions of injured tissues.

    “In addition, cell reprogramming often occurs in highly specialized regions of injured tissues.11”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Merrell, 2016, Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style, Nat. Rev. Mol. Cell Biol. source

      The section “Microenvironment as a de-differentiation driver or obstacle” (page unavailable) describes reprogramming that depends on localized structures, including the hair-follicle niche and intestinal crypt. The amphibian limb-regeneration section (page unavailable) also places de-differentiation near an amputation site. These examples support reprogramming in particular regions after injury, but the review does not establish that it often occurs in highly specialized regions across injured tissues generally. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    LPLCs 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]”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [7] Tarlow, 2014, Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes, Cell Stem Cell source
    • cites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source
    • cites [9] Yanger, 2013, Robust cellular reprogramming occurs spontaneously during liver regeneration, Genes Dev. source

      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 measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several 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”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [9] Yanger, 2013, Robust cellular reprogramming occurs spontaneously during liver regeneration, Genes Dev. source

      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 measured
    • cites [10] Russell, 2018, Wnt/beta-catenin signaling in liver development, homeostasis, and pathobiology, Annu. Rev. Pathol. source

      In “Wnt/β-Catenin Signaling in Biliary Epithelial Cells” (page unavailable), the review describes Notch and Wnt signals affecting the differentiation of liver progenitor cells (LPCs). It does not establish that those signals drive the formation of liver progenitor-like cells (LPLCs), as the citing sentence says. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Findingown data

    In DDC-injured livers, cluster 2 negative for KC markers and positive for macrophage markers Adgre1, Trem2, Cd68, Gpnmb, and Cx3cr1 was designated MoMF.

    “Cluster 2, negative for KC markers and positive for macrophage markers Adgre1, Trem2, Cd68, Gpnmb, and Cx3cr1, was designated as MoMF 21 (Figure 3B).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [21] Remmerie, 2020, Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver, Immunity source

      In Results, ‘Recruited Macs Exist in Distinct Subsets’ (page unavailable), the paper identifies cluster 2 as a macrophage cluster distinct from resident Kupffer-cell clusters. But its cluster 2 comes from Western-diet-fed mice and is called Mac1, not MoMF; the passage does not establish the stated marker profile for a cluster in DDC-injured livers. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    In mouse fetal livers, STAT3 was not activated and canonical STAT3 target genes were not induced.

    “Markedly, in mouse fetal livers, STAT3 was not activated (Figure S6D) and canonical STAT3 target genes 31,32 were not induced (Figure S6E).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [31] Lee, 2019, Hepatocytes direct the formation of a pro-metastatic niche in the liver, Nature source
    • cites [32] Goldstein, 2017, Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading, Nat. Commun. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Genes controlling embryonic development are often reused for adult tissue repair.

    “Genes controlling embryonic development are often reused for adult tissue repair, 16,24”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [16] Goldman, 2020, Gene regulatory programmes of tissue regeneration, Nat. Rev. Genet. source
    • cites [24] Duncan, 2019, Regulation of genomic output and (pluri)potency in regeneration, Annu. Rev. Genet. source

      The review’s “Pioneers of Regeneration” section gives a relevant example: ascl1a is required for retinal regeneration in zebrafish, while its mammalian homolog Ascl1 has a developmental role. It does not establish the broader claim that genes controlling embryonic development are often reused for adult tissue repair; it also notes that Ascl1 is not upregulated after retinal damage in mice. No page number is available in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    H3K27ac modification reliably marks active enhancers located in the distal regions of a given gene.

    “Since H3K27ac modification reliably marks active enhancers located in the distal regions of a given gene, 34”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] Rada-Iglesias, 2011, A unique chromatin signature uncovers early developmental enhancers in humans, Nature source

      The Abstract identifies H3K27ac as part of the signature of putative active enhancers in human embryonic stem cells and reports that over 95% of these regions lie away from promoters. It does not establish H3K27ac alone as a reliable marker of active enhancers generally; it also reports no enrichment for the tested modifications at previously described adult tissue-specific enhancers. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Binding of IL-6 to IL-6RA and gp130 leads to activation of JAK/STAT3 and, to a lesser extent, YAP.

    “Binding of IL-6 to IL-6RA and gp130 leads to activation of JAK/ STAT3 and, to a lesser extent, YAP.23”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] Murakami, 2019, Pleiotropy and specificity: insights from the interleukin 6 family of cytokines, Immunity source

      The supplied passages and further searches for IL-6 receptor signaling, STAT3, and YAP returned only reference URLs, with no substantive text or section/page labels. Our accessible copy therefore cannot establish whether the paper supports the claimed activation of JAK/STAT3 and, to a lesser extent, YAP. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    IL-6/STAT3 signaling is mainly involved in the proinflammatory response.

    “As IL-6/STAT3 signaling is mainly involved in the proinflammatory response, 23 it was unexpected that it controlled cell identity conversion in liver injury.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] Murakami, 2019, Pleiotropy and specificity: insights from the interleukin 6 family of cytokines, Immunity source

      The supplied passages and searches for IL-6/STAT3 inflammation and “pro-inflammatory” returned only reference URLs, with no substantive passage or section/page text. Our available copy therefore does not establish whether the paper characterizes IL-6/STAT3 signaling as mainly proinflammatory. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationown data

    While sterile inflammation is common in injuries and is often involved in tissue regeneration, results suggest a concept that proinflammatory signaling may directly induce transcription of progenitor-related genes for injury-induced cell dedifferentiation in mammals.

    “While sterile inflammation is common in injuries and is often involved in tissue regeneration, 35 our results suggest a concept that proinflammatory signaling may directly induce the transcription of progenitor-related genes for injury-induced cell dedifferentiation in mammals.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [35] Karin, 2016, Reparative inflammation takes charge of tissue regeneration, Nature source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Sterile inflammation is common in injuries and is often involved in tissue regeneration.

    “While sterile inflammation is common in injuries and is often involved in tissue regeneration, 35”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [35] Karin, 2016, Reparative inflammation takes charge of tissue regeneration, Nature source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-6 protects hepatocytes from injuries.

    “Interestingly, several studies around 20 years ago have also shown that IL-6 protects hepatocytes from injuries.36,37”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [36] Cressman, 1996, Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice, Science source
    • cites [37] Kovalovich, 2000, Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice, Hepatology source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    To evaluate the effects of liver dissociation on scRNA-Seq datasets, AddModuleScore function was used to assess module scores of stress response genes in hepatocytes.

    “To evaluate the effects of liver dissociation to our scRNA-Seq datasets, AddModuleScore function was used to assess the module scores of stress response genes in hepatocytes.17”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] Machado, 2021, Tissue damage induces a conserved stress response that initiates quiescent muscle stem cell activation, Cell Stem Cell source

  • May combine two claims.

    Findingown data

    RRGs significantly distinguished LPLCs from other subpopulations, as LPLCs showed the highest module score of RRGs.

    “RRGs significantly distinguished LPLCs from other subpopulations, as LPLCs showed the highest module score of RRGs (Figure 1F).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Proinflammatory IL-6 and TNF response pathways were not immediately induced in InjuredHeps but were gradually elevated in PreLPLCs and LPLCs, displaying patterns closely correlated with LPLC formation.

    “Notably, the proinflammatory IL-6 and TNF response pathways were not immediately induced in InjuredHeps but were gradually elevated in PreLPLCs and LPLCs (Figure S1H), displaying patterns closely correlated with LPLC formation.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    In DDC-injured livers, cluster 4 expressing KC markers Clec4f, Timd4, and Vsig4 was denoted DDC_KC.

    “Cluster 4, expressing KC markers Clec4f, Timd4, and Vsig4, 20 was denoted as DDC_KC (Figure 3B).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Seidman, 2020, Niche-specific reprogramming of epigenetic landscapes drives myeloid cell diversity in nonalcoholic steatohepatitis, Immunity source

  • May combine two claims.

    Findingown data

    Upon damage, immune responses were significantly activated in InjuredHeps, further enhanced in PreLPLCs, and showed the strongest activation in LPLCs.

    “Upon damage, immune responses were significantly activated in InjuredHeps, which were further enhanced in PreLPLCs and showed the strongest activation in LPLCs (Figures 1I and S1H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MoMFs were almost undetectable in normal livers, whereas around 1x10^6 MoMFs were recruited per injured liver as early as three days after injury.

    “MoMFs were almost undetectable in normal livers, whereas around 1 3 10 6 MoMFs were recruited per injured liver as early as three days after injury (Figure 3C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No differences in serum bilirubin levels, glucose levels, and activated partial thromboplastin time were detected during recovery.

    “No differences in serum bilirubin levels, glucose levels, and activated partial thromboplastin time were detected during the recovery (Figures S2K-S2M).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Numbers of innate immune cells, including macrophages, neutrophils, and NK cells, and adaptive immune cells, including T cells and B cells, were increased in injured livers.

    “In line with the elevated immune response, numbers of innate immune cells, including macrophages, neutrophils, and natural killer (NK) cells, and adaptive immune cells, including T cells and B cells, were increased in injured livers (Figure 2A; STAR Methods).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Smart-seq2 analysis of LPLCs isolated from DDC-injured Sox9-EGFP mice identified a trajectory from normal hepatocytes to LPLCs, and RRG module score distinguished LPLCs from non-LPLCs.

    “A trajectory from normal hepatocytes to LPLCs was identified using this dataset (Figure S1L), and the module score of RRGs also distinguished LPLCs from non-LPLCs (Figure S1M).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The ratio of Ki67+ hepatocytes was decreased at 1 week after DDC injury but remained continuously detectable at higher levels in macrophage-depleted mice.

    “The ratio of Ki67 + hepatocytes was decreased at 1 week after DDC injury but remained to be continuously detectable at higher levels in macrophage-depleted mice (Figures 2K and S2N).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pseudotime ordering showed that normal hepatocytes projected through injured hepatocytes (InjuredHep1 and InjuredHep2), PreLPLCs to LPLCs, which then progressed to PostLPLC1 and PostLPLC2.

    “The reprogramming trajectory showed that normal hepatocytes projected through injured hepatocytes (InjuredHep1 and InjuredHep2), PreLPLCs to LPLCs, which then progressed to the stage showing reduced expression of progenitor markers (PostLPLC1 and PostLPLC2; Figure 1D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The number of KCs remained unchanged at day 3 and increased 2.4-fold at 1 week.

    “The number of KCs remained unchanged at day 3 and increased 2.4-fold at 1 week (Figure 3C), likely due to the augmented proliferation of KCs in injured livers (Figures S3B-S3D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    RRGs were enriched in hepatoblasts by analyzing expression of E12.5 fetal livers, confirming that hepatocyte reprogramming re-activated genes expressed during liver embryogenesis.

    “Notably, we validated that RRGs were enriched in hepatoblasts by analyzing the expression of E12.5 fetal livers (Figure 1G), confirming that hepatocyte reprogramming re-activated genes expressed during liver embryogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LPLC formation induced by IL-6 HDTVi was decreased after Arid1a deletion, suggesting that Arid1a-controlled chromatin accessibility is required for IL-6/STAT3-signaling-mediated reprogramming.

    “Moreover, in line with reduced chromatin accessibility in livers lacking Arid1a, LPLC formation induced by IL-6 HDTVi was decreased after Arid1a deletion (Figure 6F), suggesting that Arid1a-controlled chromatin accessibility is required for IL-6/STAT3-signaling-mediated reprogramming.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    KCs were distributed across the lobule in injured livers, whereas LPLCs were formed specifically in the periportal regions.

    “Given that KCs were distributed across the lobule in the injured livers (Figure S3F), whereas LPLCs were formed specifically in the periportal regions (Figure 1B)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In Stat3 Dli mice the number of LPLCs was dramatically reduced following DDC injury and completely abolished by IL-6 HDTVi.

    “Notably, in Stat3 Dli mice the number of LPLCs was dramatically reduced following DDC injury (Figure 5D) and completely abolished by IL-6 HDTVi (Figure S5K).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Upon IL-6 HDTVi, mCherry expression was strongly induced from both Sox9-site and Spp1-site sequences, and Sox9-site- and Spp1-site-driven expression of mCherry was abolished in Stat3 Dli livers, demonstrating that transcription from these enhancers was STAT3 dependent.

    “Upon IL-6 HDTVi, mCherry expression was strongly induced from both Sox9-site and Spp1-site sequences.Moreover, Sox9-site-and Spp1-site-driven expression of mCherry was abolished in Stat3 Dli livers (Figures 6H and S6C), demonstrating that transcription from these enhancers was STAT3 dependent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LPLC formation remained unchanged in DDC-injured Ccr2-/- livers, largely excluding the role of MoMFs in LPLC induction.

    “Interestingly, LPLC formation remained unchanged in DDC-injured Ccr2 À/À livers (Figure 3G), largely excluding the role of MoMFs in LPLC induction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL-6-induced cells highly expressed Il6 and RRGs, including Sox9, Spp1, Bicc1, Cd44, and Cd24a, and displayed dramatically downregulated liver function pathways, confirming that IL-6 induces hepatocyte reprogramming.

    “It was remarkable that these cells highly expressed Il6 (Figure S4C) and RRGs (Figure 4C), including the progenitor marker genes-Sox9, Spp1, Bicc1, Cd44, and Cd24a-and displayed dramatically downregulated liver function pathways (Figure 4C), confirming that IL-6 induces hepatocyte reprogramming.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL-6 was produced from KCs, but not other types of cells, by measuring IL-6 protein levels in all non-parenchymal cells from injured livers.

    “and that IL-6 was produced from KCs, but not other types of cells, by measuring IL-6 protein levels in all non-parenchymal cells from injured livers (Figures S4E and S4F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All SOX9+HNF4a+ hepatocytes formed neighboring IL-6-secreting cells, showing a paracrine effect.

    “Notably, all SOX9 + HNF4a + hepatocytes formed neighboring IL-6-secreting cells, showing a paracrine effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ccr2-/- mice displayed a reduced number of MoMFs after DDC injury, while the KC population was not altered.

    “Ccr2 À/À mice displayed a reduced number of MoMFs after DDC injury (Figure 3F), while the KC population was not altered (Figure S3I).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    DDC directly activated KCs in vitro, inducing Il6 and other feature genes of activated KCs, while the number of KCs appeared unchanged.

    “Interestingly, Il6 and other feature genes of activated KCs were induced (Figures S4J and S4K), while the number of KCs appeared unchanged (Figure S4L).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The first group (173 of 668 STAT3-binding RRG sites) showed similar H3K27ac levels between LPLCs and hepatoblasts and was mainly located at proximal regions.

    “The first group (173 of 668 STAT3-binding RRG sites) showed similar H3K27ac levels between LPLCs and hepatoblasts (Figure 6J) and was mainly located at proximal regions (Figure 6K).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    IL-6-induced LPLCs were confirmed in both mouse lines.

    “IL-6-induced LPLCs were confirmed in both mouse lines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    APAP induces the formation of SOX9+ HNF4a+ hepatocytes at multiple time points, which are also positive for STAT3 staining.

    “Furthermore, our preliminary data showed that APAP induced the formation of SOX9 + HNF4a + hepatocytes at multiple time points, which were also positive for STAT3 staining (Figures S6I-S6N).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Normal hepatocytes showed low expression levels of stress response genes activated during tissue dissociation, suggesting limited hepatocyte damage during isolation.

    “Notably, NormalHep showed low expression levels of stress response genes 17 activated during tissue dissociation (Figure S1F), suggesting limited hepatocyte damage during isolation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    STAT3, which is inactivated in hepatocyte specification during liver embryogenesis, drives reprogramming through directly binding to pre-accessible enhancers of RRGs, demonstrating an injury-specific rather than development-related transcriptional regulation.

    “Importantly, STAT3, which was inactivated in hepatocyte specification during liver embryogenesis, drove reprogramming through directly binding to pre-accessible enhancers of RRGs, demonstrating an injury-specific rather than development-related transcriptional regulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    IL-6, as the key niche signal secreted by regionally activated KCs, but not by monocyte-derived macrophages (MoMFs), is repurposed to induce expression of reprogramming/progenitor-related genes (RRGs) through STAT3 activation.

    “Surprisingly, using in vivo screening, we identified that the proinflammatory factor IL-6, as the key niche signal secreted by regionally activated KCs, but not by monocyte-derived macrophages (MoMFs), was repurposed to induce the expression of reprogramming/progenitor-related genes (RRGs) through STAT3 activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    T cells, B cells, NK cells, and neutrophils are dispensable for hepatocyte reprogramming.

    “These data suggested that T cells, B cells, NK cells, and neutrophils are dispensable for hepatocyte reprogramming.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Both KCs and MoMFs are possible niche cells driving hepatocyte reprogramming.

    “These data imply that both KCs and MoMFs are possible niche cells driving hepatocyte reprogramming.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Regionally activated KCs directly induce periportal LPLC formation via IL-6, and proinflammatory IL-6/STAT3 signaling is repurposed for expression of RRGs through an injury-specific transcriptional program.

    “We demonstrated here that regionally activated KCs directly induce periportal LPLC formation via IL-6 and that proinflammatory IL-6/STAT3 signaling is repurposed for the expression of RRGs through an injury-specific transcrip-tional program.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Following injury, an activated and enlarged subset of KCs highly produce IL-6 and induce periportal LPLC formation.

    “Together, these data suggested that following injury an activated and enlarged subset of KCs highly produce IL-6 and induce periportal LPLC formation (Figure 4M).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    These findings provide a paradigm to understand reprogramming in other injured tissues.

    “These findings provide a paradigm to understand reprogramming in other injured tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Il6 deletion did not affect KC numbers and the expression of KC activated genes.

    “Il6 deletion did not affect KC numbers and the expression of KC activated genes (Figures S4G and S4H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    STAT3 binds to pre-accessible RRG enhancers and reactivates RRG transcription.

    “STAT3 binds to pre-accessible RRG enhancers and reactivates RRG transcription”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    IL-6/STAT3 signaling is sufficient to induce a large group of liver progenitor genes, which is an entirely different proinflammatory role for IL-6.

    “IL-6/STAT3 signaling is sufficient to induce a large group of liver progenitor genes, which is an entirely different proinflammatory role for IL-6.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationown data

    The data illustrate an injury-responsive, regeneration-specific transcriptional mechanism by which reprogramming of differentiated cells in other tissues might follow.

    “These data illustrate an injury-responsive, regeneration-specific transcriptional mechanism by which the reprogramming of differentiated cells in other tissues might follow.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: STAT3 is not involved in hepatocyte lineage specification.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    For hepatocytes, cells with total UMI > 4,000, number of detected genes > 800, and mitochondrial gene proportion < 10% in the 10X dataset, and cells with total UMI > 100,000 and mitochondrial gene content < 10% in the Smart-seq2 dataset, were selected for analysis.

    “For hepatocyte, cells with total UMI > 4,000, number of detected gene > 800, and MT gene proportion < 10% in 10X dataset and cells with total UMI > 100,000 and MT gene content < 10% in Smart-seq2 dataset were selected for the following analysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For the macrophage dataset, cells with total gene detected > 1,500 and mitochondrial gene content < 5% were selected.

    “For macrophage dataset, cells with total gene detected > 1,500 and mitochondrial (MT) gene content < 5% were selected.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Biological replicates showed a high degree of similarity.

    “Biological replicates showed high degree of similarity so the replicate data were subsequently combined and processed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    None of the mice used in these studies had been subjected to prior procedures and were drug and test naive.

    “None of the mice used in these studies had been subjected to prior procedures and were drug and test naive.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Sample processing was not blinded.

    “Sample processing was not blinded.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All siblings with indicated genotypes were randomly used in this study.

    “All siblings with indicated genotypes were randomly used in this study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    No statistical method was used to predetermine sample size.

    “No statistical method was used to predetermine sample size.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    To validate the cellular subpopulations and trajectory found in the 10X dataset, Smart-seq2 data was analyzed independently using the same pipeline.

    “To validate the cellular subpopulations and trajectory found in 10X dataset, Smart-seq2 data containing cells assessed in two batches was analyzed independently using the same pipeline descripted above.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    The findings may provide a framework to understand tissue repair and a potential strategy to develop treatments for repair-related liver diseases by unlocking RRG expression.

    “Our findings may provide not only a framework to understand tissue repair, but also supply a potential strategy to develop treatments for repair-related liver diseases by unlocking the expression of RRGs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    To ensure consistency between hepatocyte subpopulations and cellular trajectory, pseudo-temporal analysis was conducted in a semi-supervised manner using principal component values from the Seurat integrated dataset as input.

    “To ensure consistency between hepatocyte subpopulations and cellular trajectory, we conducted pseudo-temporal analysis in a semi-supervised manner that the principal component (PC) values generated from Seurat integrated dataset were used as the input of 'reduce_dimension' function in monocle3.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    To guarantee the quality of downstream analysis, only hepatocytes with mitochondrial gene content less than 10% were retained.

    “To guarantee the quality of downstream analysis, we only retained hepatocytes with MT gene content less than 10%.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To further decrease the false positive rate, bulk RNA-Seq samples of enriched normal hepatocytes and LPLCs were also used.

    “To further decrease the false positive rate, bulk RNA-Seq samples of enriched normal hepatocytes and LPLCs were also used.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Cells expressing high levels of immune markers (Cd163, Cd68, Clec4f, and Timd4) found in hepatocyte datasets were excluded from downstream analysis.

    “Cells expressing high level of immune markers (Cd163, Cd68, Clec4f, and Timd4) were found in hepatocyte datasets.These were excluded from downstream analysis.”
    Quote in the paperSubstantial claim
69 of 69

  • The paper relies on this without support.

    Notch and Wnt signals exist under both pathological and physiological conditions.

    “However, these signals exist under both pathological and physiological conditions, leading to the question of whether there are injury-specific signals for LPLC induction.”

  • The paper relies on this without support.

    The 16 candidate factors screened (13 inflammatory factors and 3 Wnt ligands) include the relevant KC-derived niche signal(s) for LPLC induction.

    “In total, 13 inflammatory factors were selected as candidate factors, and 3 Wnt ligands commonly expressed in the liver were additionally included (Figure 4A).”

  • The paper relies on this without support.

    LPLCs induced by HDTVi-mediated IL-6 expression are representative of DDC-induced LPLCs for STAT3 ChIP-seq analysis.

    “LPLCs were induced by HDTVi-mediated IL-6 expression, and chromatin immunoprecipitation sequencing (ChIPseq) of pSTAT3 was performed specifically in these cells (STAR Methods).”

  • The paper relies on this without support.

    STAT3 is not involved in hepatocyte lineage specification.

    “Intriguingly, our findings demonstrate that STAT3, a transcription factor not involved in hepatocyte lineage specification, re-activates almost the entire set of RRGs.”

  • The paper relies on this without support.

    scRNA-seq data are highly noised.

    “Given the highly noised nature of scRNA-seq data, we performed de-noising processing before clustering.”

  • The paper relies on this without support.

    Cells under the same state are likely assigned similar pseudotime.

    “Given that cells under same state were likely assigned similar pseudotime, we divided the whole time to 0.05 size long time bins.”
6 of 6

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Authors
Li, L., Cui, L., Lin, P., Liu, Z., Bao, S., Ma, X., Nan, H., Zhu, W., Cen, J., Mao, Y., Ma, X., Jiang, L., Nie, Y., Ginhoux, F., Li, Y., Li, H., & Hui, L.
Affiliations
  • Chinese Academy of Sciences (CN)
  • Shanghai Institute of Nutrition and Health (CN)
  • Shanghai Jiao Tong University (CN)
  • Peking University (CN)
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • Agency for Science, Technology and Research (SG)
Corresponding author
  • Li, Yixue
  • Hui, Lijian
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2023-03
Volume
30
Issue
3
Pages
283-299.e9
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2023.01.009
OpenAlex
W4320487022
Cited by
134
References
79
Citations by year
2026: 38 · 2025: 48 · 2024: 24 · 2023: 23 · 2022: 1
FWCI
18.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Ministry of Science and Technology of the People&apos;s Republic of China (2021YFF1200902, 2019YFA0802001)
  • Chinese Academy of Sciences (XDA16020201)
  • Youth Innovation Promotion Association of the Chinese Academy of Sciences
  • Peking University
  • National Key Research and Development Program of China (2019YFA0801503)
  • National Institutes of Health
  • Science and Technology Commission of Shanghai Municipality (22JC1403000, 22YF1458000)
  • National Natural Science Foundation of China (92168202, 91942313, 31930030, 32221002, 2021YFF1200902, 2019YFA0802001)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
Kupffer cells, interleukin-6, hepatocyte dedifferentiation, liver regeneration, STAT3 signaling, enhancer accessibility
MeSH terms
Animals, Cell Differentiation, Humans, Kupffer Cells, Liver, Liver Regeneration, Interleukin-6, Hepatocytes, Mice

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.

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