BMP7-Loaded Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Ameliorate Liver Fibrosis by Targeting Activated Hepatic Stellate Cells
Dan Zhu,1 Zongbin Sun,1 Jiayun Wei,2 Yulin Zhang,2 Wenjing An,2 Yan Lin,1 Xun Li1– 3 1First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China; 2Gansu Province Key Laboratory of Biotherapy and Regenerative Medicine, First Hospital of Lanzhou University, Lanzhou Univers...
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| Format: | Article |
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Dove Medical Press
2024-04-01
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| Series: | International Journal of Nanomedicine |
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| Online Access: | https://www.dovepress.com/bmp7-loaded-human-umbilical-cord-mesenchymal-stem-cell-derived-small-e-peer-reviewed-fulltext-article-IJN |
| _version_ | 1797213858202386432 |
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| author | Zhu D Sun Z Wei J Zhang Y An W Lin Y Li X |
| author_facet | Zhu D Sun Z Wei J Zhang Y An W Lin Y Li X |
| author_sort | Zhu D |
| collection | DOAJ |
| description | Dan Zhu,1 Zongbin Sun,1 Jiayun Wei,2 Yulin Zhang,2 Wenjing An,2 Yan Lin,1 Xun Li1– 3 1First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China; 2Gansu Province Key Laboratory of Biotherapy and Regenerative Medicine, First Hospital of Lanzhou University, Lanzhou University, Lanzhou, People’s Republic of China; 3General Surgery Department, First Hospital of Lanzhou University, Lanzhou University, Lanzhou, People’s Republic of ChinaCorrespondence: Xun Li, First Hospital of Lanzhou University, 1st West Donggang Road, Chengguan District, Lanzhou, Gansu Province, 730000, People’s Republic of China, Tel +86-931-8356056, Fax +86-931-8629797, Email lxdr21@126.comPurpose: Human umbilical cord mesenchymal stem cell (hucMSC)-derived small extracellular vesicles (sEVs) are natural nanocarriers with promising potential in treating liver fibrosis and have widespread applications in the fields of nanomedicine and regenerative medicine. However, the therapeutic efficacy of natural hucMSC-sEVs is currently limited owing to their non-specific distribution in vivo and partial removal by mononuclear macrophages following systemic delivery. Thus, the therapeutic efficacy can be improved through the development of engineered hucMSC-sEVs capable to overcome these limitations.Patients and Methods: To improve the anti-liver fibrosis efficacy of hucMSC-sEVs, we genetically engineered hucMSC-sEVs to overexpress the anti-fibrotic gene bone morphogenic protein 7 (BMP7) in parental cells. This was achieved using lentiviral transfection, following which BMP7-loaded hucMSC-sEVs were isolated through ultracentrifugation. First, the liver fibrosis was induced in C57BL/6J mice by intraperitoneal injection of 50% carbon tetrachloride (CCL4) twice a week for 8 weeks. These mice were subsequently treated with BMP7+sEVs via tail vein injection, and the anti-liver fibrosis effect of BMP7+sEVs was validated using small animal in vivo imaging, immunohistochemistry (IHC), tissue immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Finally, cell function studies were performed to confirm the in vivo results.Results: Liver imaging and liver histopathology confirmed that the engineered hucMSC-sEVs could reach the liver of mice and aggregate around activated hepatic stellate cells (aHSCs) with a significantly stronger anti-liver fibrosis effect of BMP7-loaded hucMSC-sEVs compared to those of blank or negative control-transfected hucMSC-sEVs. In vitro, BMP7-loaded hucMSC-sEVs promoted the phenotypic reversal of aHSCs and inhibited their proliferation to enhance the anti-fibrotic effects.Conclusion: These engineered BMP7-loaded hucMSC-sEVs offer a novel and promising strategy for the clinical treatment of liver fibrosis. Keywords: hucMSCs, sEVs, aHSCs, nanocarrier, BMP7 |
| first_indexed | 2024-04-24T11:04:57Z |
| format | Article |
| id | doaj.art-22f801b1ca954baa99e266fa615e88e3 |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-04-24T11:04:57Z |
| publishDate | 2024-04-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-22f801b1ca954baa99e266fa615e88e32024-04-11T18:05:51ZengDove Medical PressInternational Journal of Nanomedicine1178-20132024-04-01Volume 193475349591887BMP7-Loaded Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Ameliorate Liver Fibrosis by Targeting Activated Hepatic Stellate CellsZhu DSun ZWei JZhang YAn WLin YLi XDan Zhu,1 Zongbin Sun,1 Jiayun Wei,2 Yulin Zhang,2 Wenjing An,2 Yan Lin,1 Xun Li1– 3 1First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China; 2Gansu Province Key Laboratory of Biotherapy and Regenerative Medicine, First Hospital of Lanzhou University, Lanzhou University, Lanzhou, People’s Republic of China; 3General Surgery Department, First Hospital of Lanzhou University, Lanzhou University, Lanzhou, People’s Republic of ChinaCorrespondence: Xun Li, First Hospital of Lanzhou University, 1st West Donggang Road, Chengguan District, Lanzhou, Gansu Province, 730000, People’s Republic of China, Tel +86-931-8356056, Fax +86-931-8629797, Email lxdr21@126.comPurpose: Human umbilical cord mesenchymal stem cell (hucMSC)-derived small extracellular vesicles (sEVs) are natural nanocarriers with promising potential in treating liver fibrosis and have widespread applications in the fields of nanomedicine and regenerative medicine. However, the therapeutic efficacy of natural hucMSC-sEVs is currently limited owing to their non-specific distribution in vivo and partial removal by mononuclear macrophages following systemic delivery. Thus, the therapeutic efficacy can be improved through the development of engineered hucMSC-sEVs capable to overcome these limitations.Patients and Methods: To improve the anti-liver fibrosis efficacy of hucMSC-sEVs, we genetically engineered hucMSC-sEVs to overexpress the anti-fibrotic gene bone morphogenic protein 7 (BMP7) in parental cells. This was achieved using lentiviral transfection, following which BMP7-loaded hucMSC-sEVs were isolated through ultracentrifugation. First, the liver fibrosis was induced in C57BL/6J mice by intraperitoneal injection of 50% carbon tetrachloride (CCL4) twice a week for 8 weeks. These mice were subsequently treated with BMP7+sEVs via tail vein injection, and the anti-liver fibrosis effect of BMP7+sEVs was validated using small animal in vivo imaging, immunohistochemistry (IHC), tissue immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Finally, cell function studies were performed to confirm the in vivo results.Results: Liver imaging and liver histopathology confirmed that the engineered hucMSC-sEVs could reach the liver of mice and aggregate around activated hepatic stellate cells (aHSCs) with a significantly stronger anti-liver fibrosis effect of BMP7-loaded hucMSC-sEVs compared to those of blank or negative control-transfected hucMSC-sEVs. In vitro, BMP7-loaded hucMSC-sEVs promoted the phenotypic reversal of aHSCs and inhibited their proliferation to enhance the anti-fibrotic effects.Conclusion: These engineered BMP7-loaded hucMSC-sEVs offer a novel and promising strategy for the clinical treatment of liver fibrosis. Keywords: hucMSCs, sEVs, aHSCs, nanocarrier, BMP7https://www.dovepress.com/bmp7-loaded-human-umbilical-cord-mesenchymal-stem-cell-derived-small-e-peer-reviewed-fulltext-article-IJNhucmscssevsahscsnanocarrierbmp7 |
| spellingShingle | Zhu D Sun Z Wei J Zhang Y An W Lin Y Li X BMP7-Loaded Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Ameliorate Liver Fibrosis by Targeting Activated Hepatic Stellate Cells International Journal of Nanomedicine hucmscs sevs ahscs nanocarrier bmp7 |
| title | BMP7-Loaded Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Ameliorate Liver Fibrosis by Targeting Activated Hepatic Stellate Cells |
| title_full | BMP7-Loaded Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Ameliorate Liver Fibrosis by Targeting Activated Hepatic Stellate Cells |
| title_fullStr | BMP7-Loaded Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Ameliorate Liver Fibrosis by Targeting Activated Hepatic Stellate Cells |
| title_full_unstemmed | BMP7-Loaded Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Ameliorate Liver Fibrosis by Targeting Activated Hepatic Stellate Cells |
| title_short | BMP7-Loaded Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Ameliorate Liver Fibrosis by Targeting Activated Hepatic Stellate Cells |
| title_sort | bmp7 loaded human umbilical cord mesenchymal stem cell derived small extracellular vesicles ameliorate liver fibrosis by targeting activated hepatic stellate cells |
| topic | hucmscs sevs ahscs nanocarrier bmp7 |
| url | https://www.dovepress.com/bmp7-loaded-human-umbilical-cord-mesenchymal-stem-cell-derived-small-e-peer-reviewed-fulltext-article-IJN |
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