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Identification of LBH and SPP1 involved in hepatic stellate cell activation during liver fibrogenesis

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Abstract

Liver fibrosis is a pathological response driven by the activation of hepatic stellate cell (HSC). However, the mechanisms of liver fibrosis and HSC activation are complicated and far from being fully understood. We aimed to explore the candidate genes involved in HSC activation during liver fibrogenesis. Five genes (LBH, LGALS3, LOXL1, S100A6 and SPP1) were recurrent in the DEGs derived from the seven datasets. The expression of these genes gradually increased as liver fibrosis staging advanced, suggesting they might be candidate genes involved in HSC activation during hepatic fibrosis. These candidate genes were predicted to be coregulated by miRNAs such as hsa-miR-125a-5p and has-miR-125b, or by transcription factors including JUN, USF1, TP53 and TFAP2C. PPI analysis showed that LGALS3, LOXL1, S100A6 and SPP1 might interact with each other indirectly, but no interaction was found between them and LBH. The candidate genes and their interaction partners were enriched in focal adhesion, extracellular matrix organization and binding. Upregulation of LBH, S100A6 and SPP1 were further validated in TGF-β-treated LX-2 as well as in DDC or CCL4-treated mice models. Decreased LBH and SPP1 expression reduces the expression of HSC activation-related markers in TGF-β-treated LX-2. Our results indicated that LBH, LGALS3, LOXL1, S100A6 and SPP1 were candidate genes which may participate in the HSC activation during liver fibrosis.

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Availability of data and materials

The data analyzed in this study are available from the corresponding author upon reasonable request. All the datasets analyzed during the current study can be deposited in GEO, the detailed information can see in Supplementary Table 1.

Abbreviations

HSCs:

Hepatic stellate cells

GEO:

Gene Expression Omnibus

DEGs:

Differentially expressed genes

PPI:

Protein–protein interaction

GO:

Gene ontology

KEGG:

Kyoto Encyclopedia of Genes and Genomes

CCL4 :

Carbon tetrachloride

DDC:

3,5-Diethoxycarbonyl-1,4-dihydrocollidine

RT-PCR:

Reverse transcription polymerase chain reaction

LBH:

Limb bud and heart

LGALS3:

Galectin 3

LOXL1:

Lysyl oxidase like 1

S100A6:

S100 calcium-binding protein A6

SPP1:

Secreted phosphoprotein 1

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Funding

This work was supported by the National Natural Science Foundation of China (Grant 81970528), Shanghai Municipal Science and Technology Commission Research Project (22ZR1449700), and Shanghai General Hospital Start-up Fund (02.06.01.20.01). The funders had no role in the study design, data analysis, or manuscript preparation.

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Author notes

  1. Weiming Dai, Yuecheng Guo and Zhenyang Shen have contributed equally to this study.

Authors and Affiliations

  1. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Weiming Dai, Yuecheng Guo, Zhenyang Shen, Junjun Wang, Lungen Lu, Hui Dong & Xiaobo Cai

  2. Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Weiming Dai, Yuecheng Guo, Zhenyang Shen, Junjun Wang, Lungen Lu & Hui Dong

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  1. Weiming Dai
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Contributions

XC, HD and LL designed and conceived the study. WD and YG conducted the experiments. WD, YG, ZS and JW analyzed the data and prepared figures. WD and YG wrote the original draft. XC, HD and LL reviewed and edited the paper. All authors read and approved the final version.

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Correspondence to Hui Dong or Xiaobo Cai.

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The authors declare that no conflicts of interest exist.

Ethical approval

All experimental protocols were approved by the Institutional Animal Care and Use Committee of the Shanghai General Hospital (2020AW075). All methods were executed out in compliance with relevant guidelines and regulations and reported in consistent with the ARRIVE guidelines for reporting animal experiments.

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Dai, W., Guo, Y., Shen, Z. et al. Identification of LBH and SPP1 involved in hepatic stellate cell activation during liver fibrogenesis. Human Cell 36, 1054–1067 (2023). https://doi.org/10.1007/s13577-023-00889-4

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