Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis
Liver fibrosis generates fibrotic foci with abundant activated hepatic stellate cells and excessive collagen deposition juxtaposed with healthy regions. Targeted delivery of antifibrotic therapeutics to hepatic stellate cells (HSCs) might improve treatment outcomes and reduce adverse effects on heal...
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| Format: | Article |
| Language: | en_US |
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Mary Ann Liebert
2013
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| Online Access: | http://hdl.handle.net/1721.1/80395 https://orcid.org/0000-0002-0339-3685 https://orcid.org/0000-0003-4698-6488 |
| _version_ | 1826199643162148864 |
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| author | Narmada, Balakrishnan Chakrapani Kang, Yuzhan Venkatraman, Lakshmi Peng, Qiwen Sakban, Rashidah Binte Nugraha, Bramasta Jiang, Xuan Bunte, Ralph M. So, Peter T.C. Tucker-Kellogg, Lisa Mao, Hai-Quan Yu, Hanry |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Narmada, Balakrishnan Chakrapani Kang, Yuzhan Venkatraman, Lakshmi Peng, Qiwen Sakban, Rashidah Binte Nugraha, Bramasta Jiang, Xuan Bunte, Ralph M. So, Peter T.C. Tucker-Kellogg, Lisa Mao, Hai-Quan Yu, Hanry |
| author_sort | Narmada, Balakrishnan Chakrapani |
| collection | MIT |
| description | Liver fibrosis generates fibrotic foci with abundant activated hepatic stellate cells and excessive collagen deposition juxtaposed with healthy regions. Targeted delivery of antifibrotic therapeutics to hepatic stellate cells (HSCs) might improve treatment outcomes and reduce adverse effects on healthy tissue. We delivered the hepatocyte growth factor (HGF) gene specifically to activated hepatic stellate cells in fibrotic liver using vitamin A–coupled liposomes by retrograde intrabiliary infusion to bypass capillarized hepatic sinusoids. The antifibrotic effects of DsRed2-HGF vector encapsulated within vitamin A–coupled liposomes were validated by decreases in fibrotic markers in vitro. Fibrotic cultures transfected with the targeted transgene showed a significant decrease in fibrotic markers such as transforming growth factor-β1. In rats, dimethylnitrosamine-induced liver fibrosis is manifested by an increase in collagen deposition and severe defenestration of sinusoidal endothelial cells. The HSC-targeted transgene, administered via retrograde intrabiliary infusion in fibrotic rats, successfully reduced liver fibrosis markers alpha-smooth muscle actin and collagen, accompanied by an increase in the expression of DsRed2-HGF near the fibrotic foci. Thus, targeted delivery of HGF gene to hepatic stellate cells increased the transgene expression at the fibrotic foci and strongly enhanced its antifibrotic effects. |
| first_indexed | 2024-09-23T11:23:31Z |
| format | Article |
| id | mit-1721.1/80395 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:23:31Z |
| publishDate | 2013 |
| publisher | Mary Ann Liebert |
| record_format | dspace |
| spelling | mit-1721.1/803952022-09-27T19:12:51Z Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis Narmada, Balakrishnan Chakrapani Kang, Yuzhan Venkatraman, Lakshmi Peng, Qiwen Sakban, Rashidah Binte Nugraha, Bramasta Jiang, Xuan Bunte, Ralph M. So, Peter T.C. Tucker-Kellogg, Lisa Mao, Hai-Quan Yu, Hanry Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Mechanical Engineering So, Peter T. C. Yu, Hanry Liver fibrosis generates fibrotic foci with abundant activated hepatic stellate cells and excessive collagen deposition juxtaposed with healthy regions. Targeted delivery of antifibrotic therapeutics to hepatic stellate cells (HSCs) might improve treatment outcomes and reduce adverse effects on healthy tissue. We delivered the hepatocyte growth factor (HGF) gene specifically to activated hepatic stellate cells in fibrotic liver using vitamin A–coupled liposomes by retrograde intrabiliary infusion to bypass capillarized hepatic sinusoids. The antifibrotic effects of DsRed2-HGF vector encapsulated within vitamin A–coupled liposomes were validated by decreases in fibrotic markers in vitro. Fibrotic cultures transfected with the targeted transgene showed a significant decrease in fibrotic markers such as transforming growth factor-β1. In rats, dimethylnitrosamine-induced liver fibrosis is manifested by an increase in collagen deposition and severe defenestration of sinusoidal endothelial cells. The HSC-targeted transgene, administered via retrograde intrabiliary infusion in fibrotic rats, successfully reduced liver fibrosis markers alpha-smooth muscle actin and collagen, accompanied by an increase in the expression of DsRed2-HGF near the fibrotic foci. Thus, targeted delivery of HGF gene to hepatic stellate cells increased the transgene expression at the fibrotic foci and strongly enhanced its antifibrotic effects. Singapore-MIT Alliance Computational and Systems Biology Flagship Project (Grant C-382-641-001-091) 2013-09-11T16:31:32Z 2013-09-11T16:31:32Z 2013-03 2013-03 Article http://purl.org/eprint/type/JournalArticle 1043-0342 1557-7422 http://hdl.handle.net/1721.1/80395 Narmada, Balakrishnan Chakrapani, Yuzhan Kang, Lakshmi Venkatraman, Qiwen Peng, Rashidah Binte Sakban, Bramasta Nugraha, Xuan Jiang, et al. “Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis.” Human Gene Therapy 24, no. 5 (May 2013): 508-519. © 2013 Mary Ann Liebert, Inc. https://orcid.org/0000-0002-0339-3685 https://orcid.org/0000-0003-4698-6488 en_US http://dx.doi.org/10.1089/hum.2012.158 Human Gene Therapy Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Mary Ann Liebert Mary Ann Leibert |
| spellingShingle | Narmada, Balakrishnan Chakrapani Kang, Yuzhan Venkatraman, Lakshmi Peng, Qiwen Sakban, Rashidah Binte Nugraha, Bramasta Jiang, Xuan Bunte, Ralph M. So, Peter T.C. Tucker-Kellogg, Lisa Mao, Hai-Quan Yu, Hanry Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis |
| title | Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis |
| title_full | Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis |
| title_fullStr | Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis |
| title_full_unstemmed | Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis |
| title_short | Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis |
| title_sort | hepatic stellate cell targeted delivery of hepatocyte growth factor transgene via bile duct infusion enhances its expression at fibrotic foci to regress dimethylnitrosamine induced liver fibrosis |
| url | http://hdl.handle.net/1721.1/80395 https://orcid.org/0000-0002-0339-3685 https://orcid.org/0000-0003-4698-6488 |
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