C‐C motif chemokine ligand 5 confines liver regeneration by down‐regulating reparative macrophage‐derived hepatocyte growth factor in a forkhead box O 3a–dependent manner

Hao, Miao; Jiao, Junzhe; Cai, Hao; Zhang, Yichi; Xia, Yuhan; Lin, Jiacheng; Shang, Zhi; Qian, Yongxiang; Wang, Fang; Wu, Hailong; Kong, Xiaoni; Gu, Jinyang

doi:10.1002/hep.32458

Cited by 16 publications

(14 citation statements)

References 47 publications

(85 reference statements)

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“…The high expression of inflammatory factors in the long-term expanded proliferating human hepatocytes established by Zhang et al [ 17 ] was found to trigger exacerbated macrophage activation which reduced engraftment efficiency [ 46 ]. Also, Huang et al [ 47 ] found that CCL5 can negatively regulate liver regeneration; blockade of the chemokine CCL5 in a partial hepatectomy (PHx) mouse model improved regeneration and greatly optimized survival. In our study, promoter accessibility of inflammatory factors was found to be increased, while distal accessibility of aging- and inflammatory-related genes was also increased in aged HepLPCs.…”

Section: Discussionmentioning

confidence: 99%

Integration of ATAC-Seq and RNA-Seq reveals FOSL2 drives human liver progenitor-like cell aging by regulating inflammatory factors

et al. 2023

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Background Human primary hepatocytes (PHCs) are considered to be the best cell source for cell-based therapies for the treatment of end-stage liver disease and acute liver failure. To obtain sufficient and high-quality functional human hepatocytes, we have established a strategy to dedifferentiate human PHCs into expandable hepatocyte-derived liver progenitor-like cells (HepLPCs) through in vitro chemical reprogramming. However, the reduced proliferative capacity of HepLPCs after long-term culture still limits their utility. Therefore, in this study, we attempted to explore the potential mechanism related to the proliferative ability of HepLPCs in vitro culture. Results In this study, analysis of assay for transposase accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were performed for PHCs, proliferative HepLPCs (pro-HepLPCs) and late-passage HepLPCs (lp-HepLPCs). Genome-wide transcriptional and chromatin accessibility changes during the conversion and long-term culture of HepLPCs were studied. We found that lp-HepLPCs exhibited an aged phenotype characterized by the activation of inflammatory factors. Epigenetic changes were found to be consistent with our gene expression findings, with promoter and distal regions of many inflammatory-related genes showing increased accessibility in the lp-HepLPCs. FOSL2, a member of the AP-1 family, was found to be highly enriched in the distal regions with increased accessibility in lp-HepLPCs. Its depletion attenuated the expression of aging- and senescence-associated secretory phenotype (SASP)-related genes and resulted in a partial improvement of the aging phenotype in lp-HepLPCs. Conclusions FOSL2 may drive the aging of HepLPCs by regulating inflammatory factors and its depletion may attenuate this phenotypic shift. This study provides a novel and promising approach for the long-term in vitro culture of HepLPCs.

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Section: Discussionmentioning

confidence: 99%

Integration of ATAC-Seq and RNA-Seq reveals FOSL2 drives human liver progenitor-like cell aging by regulating inflammatory factors

et al. 2023

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“…Mouse primary hepatocytes were isolated from C57BL/6J male mice according to a two-step perfusion method as previously described ( Huang et al, 2022 ). Briefly, cells were maintained in DMEM (Gibco, C11885500CP, United States of America) supplemented with 10% FBS (Gibco, 10100147, United States of America) plus 1% penicillin/streptomycin (Gibco, 10378016, United States of America).…”

Section: Methodsmentioning

confidence: 99%

Quantitative proteomics reveals Polygonum perfoliatum L. ameliorates hepatic steatosis by promoting PPARs/CPT1A/CPT2-mediated fatty acid β-oxidation

et al. 2023

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Non-alcoholic fatty liver disease (NAFLD) is a predominant contributor to end-stage liver disease in the forthcoming decades. Polygonum perfoliatum L. (PPL) is an herbal medicine with anti-lipid peroxidation and anti-inflammatory properties. However, detailed hepatoprotective effects of PPL against NAFLD and its underlying mechanisms are not fully understood. Here, we found that PPL protects against high fat diet (HFD)-induced hepatic steatosis, lipid peroxidation, and glucose-lipid metabolism dysfunction in NAFLD mice. We therefore performed a label-free quantitative proteomic profiling analysis to determine the effect of PPL treatment on liver tissue proteomics and identified that activated PPARs/CPT1A/CPT2-mediated hepatic fatty acid β-oxidation (FAO) process was significantly altered. In vitro treatment of hepatocytes with PPL confirmed this altered process and FAO inhibitor etomoxir (ETO) attenuated the lipid-lowering activity of PPL in hepatocytes. Ultra-high-performance liquid chromatography/Q Exactive-HFX (UPLC/QE-HFX) was used to determine the material basis of anti-NAFLD activity of PPL. Our results have demonstrated the efficacy and potential mechanisms of PPL as an effective pharmacological therapy of NAFLD.

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“…After digestion, the liver cells were filtered through a 70 μm cell strainer, followed by centrifugation at 50 × g for 3 min. Live hepatocytes were isolated by centrifugation in Percoll solution (0.48 mL 10× PBS + 4.32 mL Percoll + 5 mL DMEM) for 10 min at 800 rpm and then seeded on collagen (Sigma-Aldrich, 08-115)-coated plates in high- glucose DMEM containing 10% fetal bovine serum and 1% penicillin/streptomycin for 3 hours, followed by treatment with 100 ng/mL of HGF (Sino Biological, 50038-MNAH-20) or 20 ng/mL of EGF (Sino Biological, 50482-M01H-100) for 48 hours 84 . For in vitro adenoviral infection, hepatocytes isolated from C57BL/6J mice were incubated with control adenovirus or LIFR- expressing adenovirus for 24 hours before HGF or EGF treatment.…”

Section: Methodsmentioning

confidence: 99%

LIFR recruits HGF-producing neutrophils to promote liver injury repair and regeneration

Deng

Zhao

Sheldon

et al. 2023

Preprint

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The molecular links between tissue repair and tumorigenesis remain elusive. Here, we report that loss of the liver tumor suppressor Lifr in mouse hepatocytes impairs the recruitment and activity of reparative neutrophils, resulting in the inhibition of liver regeneration after partial hepatectomy or toxic injuries. On the other hand, overexpression of LIFR promotes liver repair and regeneration after injury. Interestingly, LIFR deficiency or overexpression does not affect hepatocyte proliferation ex vivo or in vitro. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of the neutrophil chemoattractant CXCL1 (which binds CXCR2 to recruit neutrophils) and cholesterol in a STAT3-dependent manner. Cholesterol, in turn, acts on the recruited neutrophils to secrete hepatocyte growth factor (HGF) to accelerate hepatocyte proliferation and regeneration. Altogether, our findings reveal a LIFR-STAT3-CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-HGF axis that mediate hepatic damage-induced crosstalk between hepatocytes and neutrophils to repair and regenerate the liver.

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C‐C motif chemokine ligand 5 confines liver regeneration by down‐regulating reparative macrophage‐derived hepatocyte growth factor in a forkhead box O 3a–dependent manner

Cited by 16 publications

References 47 publications

Integration of ATAC-Seq and RNA-Seq reveals FOSL2 drives human liver progenitor-like cell aging by regulating inflammatory factors

Integration of ATAC-Seq and RNA-Seq reveals FOSL2 drives human liver progenitor-like cell aging by regulating inflammatory factors

Quantitative proteomics reveals Polygonum perfoliatum L. ameliorates hepatic steatosis by promoting PPARs/CPT1A/CPT2-mediated fatty acid β-oxidation

LIFR recruits HGF-producing neutrophils to promote liver injury repair and regeneration

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