Engineered EVs from LncEEF1G - overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cells
Abstract Fibrosis is a disease that negatively affects liver regeneration, resulting in severe complications after liver surgery. However, there is still no clinically effective treatment for promoting fibrotic liver regeneration because the underlying hepatocellular mechanism remains poorly underst...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-03-01
|
| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-025-01413-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850153889395900416 |
|---|---|
| author | Jiebin Zhang Xiaotong Qiu Yunguo Lei Haitian Chen Dongwei Wu Tingting Wang Xin Sui Jiaqi Xiao Chenhao Jiang Huayao Zhang Yasong Liu Xiaoquan Liu Yingcai Zhang Xu Che Ye Lin Jia Yao Zihao Pan Rong Li Jun Zheng |
| author_facet | Jiebin Zhang Xiaotong Qiu Yunguo Lei Haitian Chen Dongwei Wu Tingting Wang Xin Sui Jiaqi Xiao Chenhao Jiang Huayao Zhang Yasong Liu Xiaoquan Liu Yingcai Zhang Xu Che Ye Lin Jia Yao Zihao Pan Rong Li Jun Zheng |
| author_sort | Jiebin Zhang |
| collection | DOAJ |
| description | Abstract Fibrosis is a disease that negatively affects liver regeneration, resulting in severe complications after liver surgery. However, there is still no clinically effective treatment for promoting fibrotic liver regeneration because the underlying hepatocellular mechanism remains poorly understood. Through microRNA microarrays combined with the application of AAV6, we found that high expression of miR-181a-5p in activated hepatic stellate cells (HSCs) suppressed the expression of hepatic growth factor (HGF) and partially contributed to impaired regeneration potential in mice with hepatic fibrosis that had undergone two-thirds partial hepatectomy. As nanotherapeutics, mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) have been verified as effective treatments for liver regeneration. Here we observe that MSC-EVs can also promote fibrotic liver regeneration via enriched lncEEF1G, which acts as a competing endogenous RNA to directly sponge miR-181a-5p, leading to the upregulated expression of HGF in HSCs. Finally, engineered MSC-EVs with high expression of lncEEF1G (lncEEF1GOE-EVs) were constructed, suggesting greater potential for this model. In summary, our findings indicate that lncEEF1GOE-EVs have a nanotherapeutic effect on promoting regeneration of fibrotic livers by modulating the miR-181a-5p/HGF pathway in HSCs, which highlights the potential of extracellular vesicle engineering technology for patients with hepatic fibrosis who have undergone hepatic surgery. Engineered mesenchymal stem cells that overexpress lncEEF1G can secrete extracellular vesicles that are rich in lncEEF1G (lncEEF1GOE-EVs). Upon injection of lncEEF1GOE-EVs into a fibrotic 70% partial hepatectomy mouse model, lncEEF1G competitively binds to miR-181a-5p in hepatic stellate cells, preventing the interaction between miR-181a-5p and the messenger RNA of hepatocyte growth factor. This consequently leads to an increase in the secretion of hepatocyte growth factor and the promotion of hepatocyte proliferation. |
| format | Article |
| id | doaj-art-a4feb24b92a44f6ab49c5d3a99a94ea1 |
| institution | OA Journals |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-a4feb24b92a44f6ab49c5d3a99a94ea12025-08-20T02:25:36ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-03-0157358460010.1038/s12276-025-01413-4Engineered EVs from LncEEF1G - overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cellsJiebin Zhang0Xiaotong Qiu1Yunguo Lei2Haitian Chen3Dongwei Wu4Tingting Wang5Xin Sui6Jiaqi Xiao7Chenhao Jiang8Huayao Zhang9Yasong Liu10Xiaoquan Liu11Yingcai Zhang12Xu Che13Ye Lin14Jia Yao15Zihao Pan16Rong Li17Jun Zheng18Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation MedicineDepartment of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation MedicineDepartment of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation MedicineDepartment of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation MedicineDepartment of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation MedicineDepartment of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation MedicineSurgical ICU, the Third Affiliated Hospital of Sun Yat-sen UniversityDepartment of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation MedicineDepartment of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation MedicineShaoguan Maternal and Child Health HospitalDepartment of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation MedicineDepartment of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen UniversityDepartment of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation MedicineDepartment of Hepatobiliary and Pancreatic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation MedicineDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityGuangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen UniversityDepartment of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation MedicineAbstract Fibrosis is a disease that negatively affects liver regeneration, resulting in severe complications after liver surgery. However, there is still no clinically effective treatment for promoting fibrotic liver regeneration because the underlying hepatocellular mechanism remains poorly understood. Through microRNA microarrays combined with the application of AAV6, we found that high expression of miR-181a-5p in activated hepatic stellate cells (HSCs) suppressed the expression of hepatic growth factor (HGF) and partially contributed to impaired regeneration potential in mice with hepatic fibrosis that had undergone two-thirds partial hepatectomy. As nanotherapeutics, mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) have been verified as effective treatments for liver regeneration. Here we observe that MSC-EVs can also promote fibrotic liver regeneration via enriched lncEEF1G, which acts as a competing endogenous RNA to directly sponge miR-181a-5p, leading to the upregulated expression of HGF in HSCs. Finally, engineered MSC-EVs with high expression of lncEEF1G (lncEEF1GOE-EVs) were constructed, suggesting greater potential for this model. In summary, our findings indicate that lncEEF1GOE-EVs have a nanotherapeutic effect on promoting regeneration of fibrotic livers by modulating the miR-181a-5p/HGF pathway in HSCs, which highlights the potential of extracellular vesicle engineering technology for patients with hepatic fibrosis who have undergone hepatic surgery. Engineered mesenchymal stem cells that overexpress lncEEF1G can secrete extracellular vesicles that are rich in lncEEF1G (lncEEF1GOE-EVs). Upon injection of lncEEF1GOE-EVs into a fibrotic 70% partial hepatectomy mouse model, lncEEF1G competitively binds to miR-181a-5p in hepatic stellate cells, preventing the interaction between miR-181a-5p and the messenger RNA of hepatocyte growth factor. This consequently leads to an increase in the secretion of hepatocyte growth factor and the promotion of hepatocyte proliferation.https://doi.org/10.1038/s12276-025-01413-4 |
| spellingShingle | Jiebin Zhang Xiaotong Qiu Yunguo Lei Haitian Chen Dongwei Wu Tingting Wang Xin Sui Jiaqi Xiao Chenhao Jiang Huayao Zhang Yasong Liu Xiaoquan Liu Yingcai Zhang Xu Che Ye Lin Jia Yao Zihao Pan Rong Li Jun Zheng Engineered EVs from LncEEF1G - overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cells Experimental and Molecular Medicine |
| title | Engineered EVs from LncEEF1G - overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cells |
| title_full | Engineered EVs from LncEEF1G - overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cells |
| title_fullStr | Engineered EVs from LncEEF1G - overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cells |
| title_full_unstemmed | Engineered EVs from LncEEF1G - overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cells |
| title_short | Engineered EVs from LncEEF1G - overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cells |
| title_sort | engineered evs from lnceef1g overexpressing mscs promote fibrotic liver regeneration by upregulating hgf release from hepatic stellate cells |
| url | https://doi.org/10.1038/s12276-025-01413-4 |
| work_keys_str_mv | AT jiebinzhang engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT xiaotongqiu engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT yunguolei engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT haitianchen engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT dongweiwu engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT tingtingwang engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT xinsui engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT jiaqixiao engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT chenhaojiang engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT huayaozhang engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT yasongliu engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT xiaoquanliu engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT yingcaizhang engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT xuche engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT yelin engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT jiayao engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT zihaopan engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT rongli engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells AT junzheng engineeredevsfromlnceef1goverexpressingmscspromotefibroticliverregenerationbyupregulatinghgfreleasefromhepaticstellatecells |