The DOI matches its Crossref record; 79 of the 79 references it cites were found in a registry or an index; 37 of the 49 sources its claims cite were checked for support.
Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers
Open accessAbstract
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.
Overview
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.
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Claims the paper makes
79 Own result · 24 Own interpretation · 16 Own method · 11 Partly supported · 8 Supported · 4 No full text of the sources · 3 Supported so far · 3 Couldn’t confirm · 1 No basis given · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These macrophages function differently in tissue injury and regeneration.18,19”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
What the sources say
- Partly supportedcites [18] Blériot, 2019, Understanding the heterogeneity of resident liver macrophages, Front. Immunol. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [19] Krenkel, 2017, Liver macrophages in tissue homeostasis and disease, Nat. Rev. Immunol. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Two subtypes of macrophages have been identified in injured livers: KCs and MoMFs.18”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
What the sources say
- Supportedcites [18] Blériot, 2019, Understanding the heterogeneity of resident liver macrophages, Front. Immunol. source
The ‘New Approaches to Improve Our Understanding of Liver Macrophages’ section describes an irradiated, damaged liver in which inflammatory monocytes give rise to monocyte-derived macrophages while some native KCs persist. This supports identifying KCs and monocyte-derived macrophages in injured livers; the sentence does not say they are the only populations present. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In periportal injury, LPLCs are mainly generated in the region 1-5 layers away from injured bile ducts.[7][8][9]12,13”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [7] Tarlow, 2014, Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes, Cell Stem Cell source
- Partly supportedcites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [9] Yanger, 2013, Robust cellular reprogramming occurs spontaneously during liver regeneration, Genes Dev. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [12] Yimlamai, 2014, Hippo pathway activity influences liver cell fate, Cell sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“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”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > STAT3 binds to pre-accessible RRG enhancers and reactivates RRG transcription
What the sources say
- Supportedcites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source
The Introduction says that Arid1a facilitates permissive chromatin at liver-progenitor-like-cell genes in resting hepatocytes, enabling them to respond to injury-associated YAP signaling. The “Hepatocyte-Derived Progenitor-Like Cells and Liver Regeneration” section likewise says this state is maintained before injury and establishes competence to respond to regenerative signals. The claim is a faithful paraphrase of that finding. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Importantly, mature hepatocytes were found reprogrammed into LPLCs to contribute to liver repair after periportal injury.7,9,13”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [7] Tarlow, 2014, Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes, Cell Stem Cell source
- Partly supportedcites [9] Yanger, 2013, Robust cellular reprogramming occurs spontaneously during liver regeneration, Genes Dev. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Proper transduction of the IL-6 signal requires IL-6 receptor IL-6RA and co-receptor gp130.23”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > IL-6 directly affects hepatocyte dedifferentiation
What the sources say
- Could not verifycites [23] Murakami, 2019, Pleiotropy and specificity: insights from the interleukin 6 family of cytokines, Immunity sourceExperimental — accuracy not yet measured
The supplied passages and further searches for IL-6RA, gp130, and the IL-6 receptor complex returned only reference links, with no substantive text or section/page labels. Our accessible copy therefore does not establish whether the paper says both receptors are required for IL-6 signal transduction. (LLM, conf=0.76)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this study, by employing single-cell RNA sequencing (scRNA-seq) and lineage-specific mouse lines, we identified that a subpopulation of liver-resident macrophages (Kupffer cells, KCs), locating around injured bile ducts, provided a periportal-specific niche for hepatocyte reprogramming.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Based on this dataset, we identified 232 RRGs enriched in LPLCs (Table S1; STAR Methods).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Dynamic cellular responses in hepatocyte reprogramming
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CLEC4F staining revealed that KCs were localized across the lobule in injured livers (Figures S3E and S3F).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“LPLC formation in DDC-injured Rag2 À/À ;Il2rgc À/À mice, Rag2 À/À mice, and Il2rgc À/À mice was comparable to that in wild-type (WT) mice as indicated by quantification of SOX9 + HNF4a + cells (Figures 2C and S2A).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 30
- It may state two separate claims as one. 45
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > INTRODUCTION
What the sources say
- Supportedcites [1] Wells, 2018, Diverse mechanisms for endogenous regeneration and repair in mammalian organs, Nature source
The Figure legends (page not supplied) describe differentiated epidermal cells dedifferentiating after wounding and contributing to the stem-cell compartment. The Injury-induced plasticity section (page not supplied) reports intestinal progenitors acquiring stem-cell-like properties and contributing to regeneration after stem-cell ablation. Together, these support injury repair through cell plasticity beyond the activity of pre-existing adult stem cells. (LLM, conf=0.89)
- Supportedcites [2] Jain, 2015, Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung, Nat. Commun. source
The citation to this paper follows “the lung,” so it supports the lung example rather than the list of other tissues. The Abstract reports that differentiated Hopx+ Type I alveolar cells proliferate and generate Type II cells during adult lung regrowth after partial pneumonectomy; it also identifies Type II cells as progenitors. The Discussion says the study cannot determine whether that conversion passes through a dedifferentiated intermediate. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [3] Tetteh, 2016, Replacement of lost Lgr5-positive stem cells through plasticity of their enterocyte-lineage daughters, Cell Stem Cell source
- Supportedcites [4] Chera, 2014, Diabetes recovery by age-dependent conversion of pancreatic delta-cells into insulin producers, Nature source
This source is cited for the pancreatic example, not the examples in other tissues. In the supplied Abstract passages (page unavailable), lineage tracing after β-cell ablation in young mice supports a sequence in which differentiated pancreatic δ-cells dedifferentiate, proliferate, express the precursor-associated marker Ngn3, and give rise to insulin-producing cells. (LLM, conf=0.90)
- Supportedcites [5] Raven, 2017, Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration, Nature source
This citation is attached to the liver example, not to the claims about lung, intestine, or pancreas. The Abstract (page not available) reports that cholangiocytes give rise to functional hepatocytes during liver injury when hepatocyte proliferation is impaired, supporting the cited liver example of differentiated-cell plasticity in repair. (LLM, conf=0.88)
- Partly supportedcites [6] Schaub, 2018, De novo formation of the biliary system by TGFbeta-mediated hepatocyte transdifferentiation, Nature sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“It is noteworthy that LPLCs were also detected in various human liver diseases, suggesting the relevance of these cells in human pathogenesis.9”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > INTRODUCTION
What the sources say
- Supportedcites [9] Yanger, 2013, Robust cellular reprogramming occurs spontaneously during liver regeneration, Genes Dev. source
In Results and Discussion (page unavailable), the authors report abundant cells coexpressing hepatocyte and biliary markers in patients with several types of liver disease, but not in controls. They suggest that the associated cellular plasticity may also occur during human liver injury, supporting the claim's hedged statement about relevance to human disease. (LLM, conf=0.88)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Following periportal injury, hepatocytes reactivated progenitor genes and underwent dedifferentiation into liver progenitor-like cells (LPLCs) to repair the injured liver.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [7] Tarlow, 2014, Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes, Cell Stem Cell source
- Supportedcites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source
The Introduction states that periportal injury activates LPLC-enriched genes as hepatocytes convert into liver progenitor-like cells. The “Hepatocyte-Derived Progenitor-Like Cells and Liver Regeneration” section says this conversion contributes to liver repair. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“When the formation of LPLCs was restrained, injured livers showed prolonged hepatocyte proliferation, enhanced biliary injury, and reduced fibrosis resolution.8”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > INTRODUCTION
What the sources say
- Partly supportedcites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > INTRODUCTION
What the sources say
- Supportedcites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source
The Introduction says that chromatin at liver-progenitor-like-cell-enriched genes is permissive in resting hepatocytes and that this state enables a response to injury-associated Hippo/Yap signaling, which activates those genes. The discussion section, “Hepatocyte-Derived Progenitor-Like Cells and Liver Regeneration,” likewise says this permissive state is maintained before injury and establishes hepatocyte competence to respond to regenerative signals. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [7] Tarlow, 2014, Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes, Cell Stem Cell source
- Supportedcites [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 periportal-injury-induced regeneration reports that, after DDC injury and recovery, an estimated 24.2% of hepatocytes in regenerated livers derived from Hnf4a+ Sox9+ cells. The same section reports a small proportion (0.71%) of labeled bile duct cells, supporting a bile duct fate as well. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In addition, cell reprogramming often occurs in highly specialized regions of injured tissues.11”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > INTRODUCTION
What the sources say
- Partly supportedcites [11] Merrell, 2016, Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style, Nat. Rev. Mol. Cell Biol. sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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]”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Dynamic cellular responses in hepatocyte reprogramming
What the sources say
- Not checked — no full text of the sourcecites [7] Tarlow, 2014, Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes, Cell Stem Cell source
- Supportedcites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source
In “Arid1a Facilitates Liver-Progenitor-Like Cell Formation in Periportal Liver Injury” (page unavailable), the paper describes LPLCs arising after periportal injury, retaining hepatocyte morphology, and expressing both Hnf4a and Sox9. Its lineage-tracing passage confirms that these LPLCs originate from mature hepatocytes. (LLM, conf=0.91)
- Partly supportedcites [9] Yanger, 2013, Robust cellular reprogramming occurs spontaneously during liver regeneration, Genes Dev. sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Several extrinsic signals have been proposed for LPLC formation, including Notch and Wnt.9,10”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > INTRODUCTION
What the sources say
- Partly supportedcites [9] Yanger, 2013, Robust cellular reprogramming occurs spontaneously during liver regeneration, Genes Dev. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [10] Russell, 2018, Wnt/beta-catenin signaling in liver development, homeostasis, and pathobiology, Annu. Rev. Pathol. sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Cluster 2, negative for KC markers and positive for macrophage markers Adgre1, Trem2, Cd68, Gpnmb, and Cx3cr1, was designated as MoMF 21 (Figure 3B).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
What the sources say
- Partly supportedcites [21] Remmerie, 2020, Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver, Immunity sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Markedly, in mouse fetal livers, STAT3 was not activated (Figure S6D) and canonical STAT3 target genes 31,32 were not induced (Figure S6E).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > STAT3-dependent RRG transcription specifically in liver injury but not in embryogenesis
What the sources say
- Supportedcites [31] Lee, 2019, Hepatocytes direct the formation of a pro-metastatic niche in the liver, Nature source
The citation is attached to the description of STAT3 target genes, not to the fetal-liver findings, which the citing sentence assigns to its own Figure S6D/E. The source’s Main Text (page not provided) reports that deleting Stat3 in hepatocytes prevented SAA production, supporting SAA as a STAT3-dependent hepatic gene. (LLM, conf=0.84)
- Supportedcites [32] Goldstein, 2017, Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading, Nat. Commun. source
The citation is attached to the identification of canonical STAT3 target genes, not to the fetal-liver results, which the citing sentence attributes to its own Figure S6. The Results section identifies hepatic genes including Saa1/2 and Fgg in its analysis of STAT3 binding and cytokine-responsive expression; it does not report the fetal-liver observations. (LLM, conf=0.83)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Genes controlling embryonic development are often reused for adult tissue repair, 16,24”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > STAT3-dependent RRG transcription specifically in liver injury but not in embryogenesis
What the sources say
- Supportedcites [16] Goldman, 2020, Gene regulatory programmes of tissue regeneration, Nat. Rev. Genet. source
The section “Regeneration programmes have unique signatures” states that genes employed for embryonic development are often repurposed for regeneration. The section “Regeneration deploys genes that function in embryogenesis” also describes activation of embryogenesis genes across most regeneration models. (LLM, conf=0.95)
- Partly supportedcites [24] Duncan, 2019, Regulation of genomic output and (pluri)potency in regeneration, Annu. Rev. Genet. sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Since H3K27ac modification reliably marks active enhancers located in the distal regions of a given gene, 34”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > STAT3-dependent RRG transcription specifically in liver injury but not in embryogenesis
What the sources say
- Partly supportedcites [34] Rada-Iglesias, 2011, A unique chromatin signature uncovers early developmental enhancers in humans, Nature sourceExperimental — accuracy not yet measured
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)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Binding of IL-6 to IL-6RA and gp130 leads to activation of JAK/ STAT3 and, to a lesser extent, YAP.23”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > IL-6/STAT3 signaling is repurposed for hepatocyte reprogramming
What the sources say
- Could not verifycites [23] Murakami, 2019, Pleiotropy and specificity: insights from the interleukin 6 family of cytokines, Immunity sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > STAT3 binds to pre-accessible RRG enhancers and reactivates RRG transcription
What the sources say
- Could not verifycites [23] Murakami, 2019, Pleiotropy and specificity: insights from the interleukin 6 family of cytokines, Immunity sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > DISCUSSION
What the sources say
- Supportedcites [35] Karin, 2016, Reparative inflammation takes charge of tissue regeneration, Nature source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“While sterile inflammation is common in injuries and is often involved in tissue regeneration, 35”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > DISCUSSION
What the sources say
- Supportedcites [35] Karin, 2016, Reparative inflammation takes charge of tissue regeneration, Nature source
The “Sterile inflammation and its sensors” section says tissue damage evokes sterile inflammation even without microbes. It also says the response is involved in wound repair and regeneration, supporting both parts of the claim. (LLM, conf=0.91)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Interestingly, several studies around 20 years ago have also shown that IL-6 protects hepatocytes from injuries.36,37”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [36] Cressman, 1996, Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice, Science source
- Supportedcites [37] Kovalovich, 2000, Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice, Hepatology source
The Discussion reports that IL-6 treatment reduced CCl4-induced liver injury and the number of apoptotic hepatocytes in mice. This supports the cited claim that IL-6 protects hepatocytes from injury, as demonstrated in this toxin-injury model. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Every source the paper cites for this claim was checked and supports it.
In the paper
“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”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Quality control of scRNA-Seq data
What the sources say
- Supportedcites [17] Machado, 2021, Tissue damage induces a conserved stress response that initiates quiescent muscle stem cell activation, Cell Stem Cell source
The section ‘Definition of a core stress signature in muscle and liver in response to cell dissociation’ (p. 4) defines a 98-gene stress signature and scores its expression to assess dissociation effects in liver cells. Figure 1 (p. 12) identifies hepatocytes among the liver cell populations studied. The citation supports the choice of stress-response genes for this assessment; the statement that the citing authors used AddModuleScore describes their own method. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“RRGs significantly distinguished LPLCs from other subpopulations, as LPLCs showed the highest module score of RRGs (Figure 1F).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Dynamic cellular responses in hepatocyte reprogramming
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Dynamic cellular responses in hepatocyte reprogramming
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Cluster 4, expressing KC markers Clec4f, Timd4, and Vsig4, 20 was denoted as DDC_KC (Figure 3B).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
What the sources say
- Not checked — no full text of the sourcecites [20] Seidman, 2020, Niche-specific reprogramming of epigenetic landscapes drives myeloid cell diversity in nonalcoholic steatohepatitis, Immunity source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Dynamic cellular responses in hepatocyte reprogramming
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No differences in serum bilirubin levels, glucose levels, and activated partial thromboplastin time were detected during the recovery (Figures S2K-S2M).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Dynamic cellular responses in hepatocyte reprogramming
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Dynamic cellular responses in hepatocyte reprogramming
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Dynamic cellular responses in hepatocyte reprogramming
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > STAT3 binds to pre-accessible RRG enhancers and reactivates RRG transcription
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > IL-6 derived from activated periportal KCs triggers reprogramming
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > IL-6/STAT3 signaling is repurposed for hepatocyte reprogramming
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > STAT3 binds to pre-accessible RRG enhancers and reactivates RRG transcription
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, LPLC formation remained unchanged in DDC-injured Ccr2 À/À livers (Figure 3G), largely excluding the role of MoMFs in LPLC induction.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > IL-6 derived from activated periportal KCs triggers reprogramming
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > IL-6 derived from activated periportal KCs triggers reprogramming
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, all SOX9 + HNF4a + hepatocytes formed neighboring IL-6-secreting cells, showing a paracrine effect.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > IL-6 derived from activated periportal KCs triggers reprogramming
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ccr2 À/À mice displayed a reduced number of MoMFs after DDC injury (Figure 3F), while the KC population was not altered (Figure S3I).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, Il6 and other feature genes of activated KCs were induced (Figures S4J and S4K), while the number of KCs appeared unchanged (Figure S4L).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > IL-6 derived from activated periportal KCs triggers reprogramming
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > STAT3-dependent RRG transcription specifically in liver injury but not in embryogenesis
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“IL-6-induced LPLCs were confirmed in both mouse lines.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Additional information
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Limitations of the study
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, NormalHep showed low expression levels of stress response genes 17 activated during tissue dissociation (Figure S1F), suggesting limited hepatocyte damage during isolation.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Dynamic cellular responses in hepatocyte reprogramming
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > INTRODUCTION
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggested that T cells, B cells, NK cells, and neutrophils are dispensable for hepatocyte reprogramming.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data imply that both KCs and MoMFs are possible niche cells driving hepatocyte reprogramming.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Macrophages drive hepatocyte reprogramming
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > IL-6 derived from activated periportal KCs triggers reprogramming
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings provide a paradigm to understand reprogramming in other injured tissues.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Il6 deletion did not affect KC numbers and the expression of KC activated genes (Figures S4G and S4H).”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > IL-6 derived from activated periportal KCs triggers reprogramming
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“STAT3 binds to pre-accessible RRG enhancers and reactivates RRG transcription”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > STAT3 binds to pre-accessible RRG enhancers and reactivates RRG transcription
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data illustrate an injury-responsive, regeneration-specific transcriptional mechanism by which the reprogramming of differentiated cells in other tissues might follow.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
- Rests on an assumption: STAT3 is not involved in hepatocyte lineage specification.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Quality control of scRNA-Seq data
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For macrophage dataset, cells with total gene detected > 1,500 and mitochondrial (MT) gene content < 5% were selected.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Quality control of scRNA-Seq data
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Biological replicates showed high degree of similarity so the replicate data were subsequently combined and processed.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Additional information
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“None of the mice used in these studies had been subjected to prior procedures and were drug and test naive.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > STAR+METHODS
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sample processing was not blinded.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Additional information
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All siblings with indicated genotypes were randomly used in this study.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Additional information
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No statistical method was used to predetermine sample size.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Additional information
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Quality control of scRNA-Seq data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Quality control of scRNA-Seq data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To guarantee the quality of downstream analysis, we only retained hepatocytes with MT gene content less than 10%.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Schematic cartoons in Figures
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To further decrease the false positive rate, bulk RNA-Seq samples of enriched normal hepatocytes and LPLCs were also used.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Identification of RRGs
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Cells expressing high level of immune markers (Cd163, Cd68, Clec4f, and Timd4) were found in hepatocyte datasets.These were excluded from downstream analysis.”
§ Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers > Quality control of scRNA-Seq data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition to cell intrinsic transcription factors for cellular reprogramming, modulators such as vitamin C [62][63][64][65] , IL-6 [66][67][68] , TGFβ 69 and bone morphogenetic proteins 70 have been shown to regulate cellular reprogramming by affecting DNA methylation levels, thereby adjusting the expression of certain microRNAs or facilitating the mesenchymal-to-epithelial transition (MET).”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [66]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“A recent study showed that Kupffer cell-derived IL6 induced SOX9 in hepatocytes via STAT3 signalling,103”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [103]
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Metadata
- 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
- OpenAlex
- W4320487022
- Cited by
- 134
- References
- 79
- Citations by year
- 2026: 38 · 2025: 48 · 2024: 24 · 2023: 23
- FWCI
- 18.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Ministry of Science and Technology of the People'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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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