LECT2 promotes liver regeneration across developmental stages by activating the ADAM10-NOTCH signaling pathway.
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| Format: | Artículo científico |
| Language: | en |
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Hepatology communications
2025
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| _version_ | 1868266074590412800 |
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| author | Zhang, Hui Wang, Wei Gao, Yufeng Qian, Yuting Xu, Wen Yin, Hehe Qiu, Qian Zhang, Lulu Zhu, Shiwei Li, Xutong Wu, Zihao Zuo, Li Wang, Juan Tang, Heng Hu, Huaiyuan Wei, Yuanyuan Xu, Feng Chen, Jiong Cao, Feng Xu, Honghai |
| author_facet | Zhang, Hui Wang, Wei Gao, Yufeng Qian, Yuting Xu, Wen Yin, Hehe Qiu, Qian Zhang, Lulu Zhu, Shiwei Li, Xutong Wu, Zihao Zuo, Li Wang, Juan Tang, Heng Hu, Huaiyuan Wei, Yuanyuan Xu, Feng Chen, Jiong Cao, Feng Xu, Honghai Zhang, Hui Wang, Wei Gao, Yufeng Qian, Yuting Xu, Wen Yin, Hehe Qiu, Qian Zhang, Lulu Zhu, Shiwei Li, Xutong Wu, Zihao Zuo, Li Wang, Juan Tang, Heng Hu, Huaiyuan Wei, Yuanyuan Xu, Feng Chen, Jiong Cao, Feng Xu, Honghai |
| collection | PubMed - marine biology |
| contents | LECT2 promotes liver regeneration across developmental stages by activating the ADAM10-NOTCH signaling pathway. Zhang, Hui Wang, Wei Gao, Yufeng Qian, Yuting Xu, Wen Yin, Hehe Qiu, Qian Zhang, Lulu Zhu, Shiwei Li, Xutong Wu, Zihao Zuo, Li Wang, Juan Tang, Heng Hu, Huaiyuan Wei, Yuanyuan Xu, Feng Chen, Jiong Cao, Feng Xu, Honghai Liver Regeneration Animals ADAM10 Protein Mice Signal Transduction Receptors, Notch Hepatectomy Amyloid Precursor Protein Secretases Intercellular Signaling Peptides and Proteins Humans Liver Membrane Proteins Hepatocytes Cell Proliferation Male Mice, Inbred C57BL Liver regeneration is a highly complex biological process, and the molecular mechanisms governing regenerative capacity exhibit significant divergence across distinct developmental stages. This study aimed to developmentally conserve pro-regenerative regulators of the liver and elucidate their mechanistic roles in the developmental stages of liver regeneration. Wild-type mice at distinct developmental stages, including 1-month-old (adolescent), 4-month-old (adult), 12-month-old (middle-aged), and 20-month-old (aged), underwent sham surgery or 2/3 partial hepatectomy. RNA sequencing and scRNA-seq identified the target gene and spatial expression. Hepatocyte proliferation was assessed by Ki-67, PCNA staining, and hematoxylin and eosin staining. Functional and mechanistic studies have employed bioinformatics, IF, coimmunoprecipitation, quantitative real-time PCR, and small-molecule inhibition. RNA sequencing across age groups identified leukocyte cell-derived chemotaxin 2 (LECT2) as a functionally significant mediator in liver regeneration processes. Longitudinal assessment of murine liver regeneration models and patients who underwent hepatectomy revealed dynamic LECT2 expression patterns. LECT2 expression positively correlated with regeneration markers Ki-67 and PCNA. Lect2-KO mice in 4 age groups exhibited impaired liver regeneration. Immunofluorescence staining and single-cell RNA sequencing demonstrated predominant hepatocyte-specific expression of LECT2. Hepatocyte-specific Lect2 knockout significantly impaired liver regeneration following 2/3 partial hepatectomy. Interestingly, there appeared to be no difference in the level of regeneration in mice with suppressed A Disintegrin and Metalloproteinase Domain 10 (ADAM10) expression despite Lect2 overexpression. Mechanistic investigations revealed that LECT2 potentiates hepatic regeneration by activating the ADAM10-NOTCH signaling pathway. Finally, our in vivo therapeutic model demonstrated that adeno-associated virus-mediated Lect2 overexpression significantly enhanced the posthepatectomy regenerative capacity. LECT2 promotes liver regeneration across developmental stages by activating the ADAM10-NOTCH signaling pathway, providing a promising therapeutic target for enhancing hepatic repair. |
| format | Artículo científico |
| id | pubmed_41811354 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Hepatology communications |
| record_format | pubmed |
| spellingShingle | LECT2 promotes liver regeneration across developmental stages by activating the ADAM10-NOTCH signaling pathway. Zhang, Hui Wang, Wei Gao, Yufeng Qian, Yuting Xu, Wen Yin, Hehe Qiu, Qian Zhang, Lulu Zhu, Shiwei Li, Xutong Wu, Zihao Zuo, Li Wang, Juan Tang, Heng Hu, Huaiyuan Wei, Yuanyuan Xu, Feng Chen, Jiong Cao, Feng Xu, Honghai Liver Regeneration Animals ADAM10 Protein Mice Signal Transduction Receptors, Notch Hepatectomy Amyloid Precursor Protein Secretases Intercellular Signaling Peptides and Proteins Humans Liver Membrane Proteins Hepatocytes Cell Proliferation Male Mice, Inbred C57BL LECT2 promotes liver regeneration across developmental stages by activating the ADAM10-NOTCH signaling pathway. Zhang, Hui Wang, Wei Gao, Yufeng Qian, Yuting Xu, Wen Yin, Hehe Qiu, Qian Zhang, Lulu Zhu, Shiwei Li, Xutong Wu, Zihao Zuo, Li Wang, Juan Tang, Heng Hu, Huaiyuan Wei, Yuanyuan Xu, Feng Chen, Jiong Cao, Feng Xu, Honghai Liver Regeneration Animals ADAM10 Protein Mice Signal Transduction Receptors, Notch Hepatectomy Amyloid Precursor Protein Secretases Intercellular Signaling Peptides and Proteins Humans Liver Membrane Proteins Hepatocytes Cell Proliferation Male Mice, Inbred C57BL Liver regeneration is a highly complex biological process, and the molecular mechanisms governing regenerative capacity exhibit significant divergence across distinct developmental stages. This study aimed to developmentally conserve pro-regenerative regulators of the liver and elucidate their mechanistic roles in the developmental stages of liver regeneration. Wild-type mice at distinct developmental stages, including 1-month-old (adolescent), 4-month-old (adult), 12-month-old (middle-aged), and 20-month-old (aged), underwent sham surgery or 2/3 partial hepatectomy. RNA sequencing and scRNA-seq identified the target gene and spatial expression. Hepatocyte proliferation was assessed by Ki-67, PCNA staining, and hematoxylin and eosin staining. Functional and mechanistic studies have employed bioinformatics, IF, coimmunoprecipitation, quantitative real-time PCR, and small-molecule inhibition. RNA sequencing across age groups identified leukocyte cell-derived chemotaxin 2 (LECT2) as a functionally significant mediator in liver regeneration processes. Longitudinal assessment of murine liver regeneration models and patients who underwent hepatectomy revealed dynamic LECT2 expression patterns. LECT2 expression positively correlated with regeneration markers Ki-67 and PCNA. Lect2-KO mice in 4 age groups exhibited impaired liver regeneration. Immunofluorescence staining and single-cell RNA sequencing demonstrated predominant hepatocyte-specific expression of LECT2. Hepatocyte-specific Lect2 knockout significantly impaired liver regeneration following 2/3 partial hepatectomy. Interestingly, there appeared to be no difference in the level of regeneration in mice with suppressed A Disintegrin and Metalloproteinase Domain 10 (ADAM10) expression despite Lect2 overexpression. Mechanistic investigations revealed that LECT2 potentiates hepatic regeneration by activating the ADAM10-NOTCH signaling pathway. Finally, our in vivo therapeutic model demonstrated that adeno-associated virus-mediated Lect2 overexpression significantly enhanced the posthepatectomy regenerative capacity. LECT2 promotes liver regeneration across developmental stages by activating the ADAM10-NOTCH signaling pathway, providing a promising therapeutic target for enhancing hepatic repair. |
| title | LECT2 promotes liver regeneration across developmental stages by activating the ADAM10-NOTCH signaling pathway. |
| topic | Liver Regeneration Animals ADAM10 Protein Mice Signal Transduction Receptors, Notch Hepatectomy Amyloid Precursor Protein Secretases Intercellular Signaling Peptides and Proteins Humans Liver Membrane Proteins Hepatocytes Cell Proliferation Male Mice, Inbred C57BL |
| url | https://pubmed.ncbi.nlm.nih.gov/41811354/ |