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

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”

What the sources say

• Supported

  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)

  cites [1] Wells, 2018, Diverse mechanisms for endogenous regeneration and repair in mammalian organs, Nature source
• Supported

  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)

  cites [2] Jain, 2015, Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung, Nat. Commun. source
• ?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
• Supported

  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)

  cites [4] Chera, 2014, Diabetes recovery by age-dependent conversion of pancreatic delta-cells into insulin producers, Nature source
• Supported

  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)

  cites [5] Raven, 2017, Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration, Nature source
• Partly supported

  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)

  cites [6] Schaub, 2018, De novo formation of the biliary system by TGFbeta-mediated hepatocyte transdifferentiation, Nature sourceExperimental — accuracy not yet measured

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”

What the sources say

• Supported

  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)

  cites [9] Yanger, 2013, Robust cellular reprogramming occurs spontaneously during liver regeneration, Genes Dev. source

In the paper

“Following periportal injury, hepatocytes reactivated progenitor genes and underwent dedifferentiation into liver progenitor-like cells (LPLCs) to repair the injured liver.”

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
• Supported

  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)

  cites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source

In the paper

“When the formation of LPLCs was restrained, injured livers showed prolonged hepatocyte proliferation, enhanced biliary injury, and reduced fibrosis resolution.8”

What the sources say

• Partly supported

  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)

  cites [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

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”

What the sources say

• Supported

  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)

  cites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source

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”

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
• Supported

  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)

  cites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source

In the paper

“In addition, cell reprogramming often occurs in highly specialized regions of injured tissues.11”

What the sources say

• Partly supported

  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)

  cites [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

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]”

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
• Supported

  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)

  cites [8] Li, 2019, A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling, Cell Stem Cell source
• Partly supported

  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)

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

In the paper

“Several extrinsic signals have been proposed for LPLC formation, including Notch and Wnt.9,10”

What the sources say

• Partly supported

  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)

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

  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)

  cites [10] Russell, 2018, Wnt/beta-catenin signaling in liver development, homeostasis, and pathobiology, Annu. Rev. Pathol. sourceExperimental — accuracy not yet measured

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).”

What the sources say

• Partly supported

  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)

  cites [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 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).”

What the sources say

• Supported

  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)

  cites [31] Lee, 2019, Hepatocytes direct the formation of a pro-metastatic niche in the liver, Nature source
• Supported

  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)

  cites [32] Goldstein, 2017, Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading, Nat. Commun. source

In the paper

“Genes controlling embryonic development are often reused for adult tissue repair, 16,24”

What the sources say

• Supported

  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)

  cites [16] Goldman, 2020, Gene regulatory programmes of tissue regeneration, Nat. Rev. Genet. source
• Partly supported

  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)

  cites [24] Duncan, 2019, Regulation of genomic output and (pluri)potency in regeneration, Annu. Rev. Genet. sourceExperimental — accuracy not yet measured

In the paper

“Since H3K27ac modification reliably marks active enhancers located in the distal regions of a given gene, 34”

What the sources say

• Partly supported

  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)

  cites [34] Rada-Iglesias, 2011, A unique chromatin signature uncovers early developmental enhancers in humans, Nature sourceExperimental — accuracy not yet measured

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”

What the sources say

• ?Could not verify

  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)

  cites [23] Murakami, 2019, Pleiotropy and specificity: insights from the interleukin 6 family of cytokines, Immunity sourceExperimental — accuracy not yet measured

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.”

What the sources say

• ?Could not verify

  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)

  cites [23] Murakami, 2019, Pleiotropy and specificity: insights from the interleukin 6 family of cytokines, Immunity sourceExperimental — accuracy not yet measured

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.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [35] Karin, 2016, Reparative inflammation takes charge of tissue regeneration, Nature source

In the paper

“While sterile inflammation is common in injuries and is often involved in tissue regeneration, 35”

What the sources say

• Supported

  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)

  cites [35] Karin, 2016, Reparative inflammation takes charge of tissue regeneration, Nature source

In the paper

“Interestingly, several studies around 20 years ago have also shown that IL-6 protects hepatocytes from injuries.36,37”

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
• Supported

  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)

  cites [37] Kovalovich, 2000, Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice, Hepatology source

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”

What the sources say

• Supported

  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)

  cites [17] Machado, 2021, Tissue damage induces a conserved stress response that initiates quiescent muscle stem cell activation, Cell Stem Cell source

In the paper

“RRGs significantly distinguished LPLCs from other subpopulations, as LPLCs showed the highest module score of RRGs (Figure 1F).”

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.”

In the paper

“Cluster 4, expressing KC markers Clec4f, Timd4, and Vsig4, 20 was denoted as DDC_KC (Figure 3B).”

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

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).”

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).”

In the paper

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

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).”

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).”

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).”

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).”

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).”

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.”

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.”

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)”

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).”

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.”

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.”

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.”

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).”

In the paper

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

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).”

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).”

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).”

In the paper

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

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).”

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.”

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.”

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.”

In the paper

“These data suggested that T cells, B cells, NK cells, and neutrophils are dispensable for hepatocyte reprogramming.”

In the paper

“These data imply that both KCs and MoMFs are possible niche cells driving hepatocyte reprogramming.”

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.”

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).”

In the paper

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

In the paper

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

In the paper

“STAT3 binds to pre-accessible RRG enhancers and reactivates RRG transcription”

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.”

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.”

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.”

In the paper

“For macrophage dataset, cells with total gene detected > 1,500 and mitochondrial (MT) gene content < 5% were selected.”

In the paper

“Biological replicates showed high degree of similarity so the replicate data were subsequently combined and processed.”

In the paper

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

In the paper

“Sample processing was not blinded.”

In the paper

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

In the paper

“No statistical method was used to predetermine sample size.”

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.”

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.”

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.”

In the paper

“To guarantee the quality of downstream analysis, we only retained hepatocytes with MT gene content less than 10%.”

In the paper

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

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.”