Efficient engraftment and viral transduction of human hepatocytes in an FRG rat liver humanization model
Abstract Humanized liver rodent models, in which the host liver parenchyma is repopulated by human hepatocytes, have been increasingly used for drug development and disease research. Unlike the leading humanized liver mouse model in which Fumarylacetoacetate Hydrolase (Fah), Recombination Activating...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-18119-6 |
| _version_ | 1817999218274467840 |
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| author | Marisa Carbonaro Jeffrey Lee Evangelos Pefanis Mathieu Desclaux Kehui Wang Alexander Pennington Hui Huang Alejo Mujica Jose Rojas Roxanne Ally Daniel Kennedy Michael Brown Vitaliy Rogulin Sven Moller-Tank Leah Sabin Brian Zambrowicz Gavin Thurston Zhe Li |
| author_facet | Marisa Carbonaro Jeffrey Lee Evangelos Pefanis Mathieu Desclaux Kehui Wang Alexander Pennington Hui Huang Alejo Mujica Jose Rojas Roxanne Ally Daniel Kennedy Michael Brown Vitaliy Rogulin Sven Moller-Tank Leah Sabin Brian Zambrowicz Gavin Thurston Zhe Li |
| author_sort | Marisa Carbonaro |
| collection | DOAJ |
| description | Abstract Humanized liver rodent models, in which the host liver parenchyma is repopulated by human hepatocytes, have been increasingly used for drug development and disease research. Unlike the leading humanized liver mouse model in which Fumarylacetoacetate Hydrolase (Fah), Recombination Activating Gene (Rag)-2 and Interleukin-2 Receptor Gamma (Il2rg) genes were inactivated simultaneously, generation of similar recipient rats has been challenging. Here, using Velocigene and 1-cell-embryo-targeting technologies, we generated a rat model deficient in Fah, Rag1/2 and Il2rg genes, similar to humanized liver mice. These rats were efficiently engrafted with Fah-expressing hepatocytes from rat, mouse and human. Humanized liver rats expressed human albumin and complement proteins in serum and showed a normal liver zonation pattern. Further, approaches were developed for gene delivery through viral transduction of human hepatocytes either in vivo, or in vitro prior to engraftment, providing a novel platform to study liver disease and hepatocyte-targeted therapies. |
| first_indexed | 2024-04-14T03:05:29Z |
| format | Article |
| id | doaj.art-f36f9f2973d74161ab4380d6be2edfb7 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-14T03:05:29Z |
| publishDate | 2022-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-f36f9f2973d74161ab4380d6be2edfb72022-12-22T02:15:45ZengNature PortfolioScientific Reports2045-23222022-08-0112111110.1038/s41598-022-18119-6Efficient engraftment and viral transduction of human hepatocytes in an FRG rat liver humanization modelMarisa Carbonaro0Jeffrey Lee1Evangelos Pefanis2Mathieu Desclaux3Kehui Wang4Alexander Pennington5Hui Huang6Alejo Mujica7Jose Rojas8Roxanne Ally9Daniel Kennedy10Michael Brown11Vitaliy Rogulin12Sven Moller-Tank13Leah Sabin14Brian Zambrowicz15Gavin Thurston16Zhe Li17Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Regeneron Pharmaceuticals, Inc.Abstract Humanized liver rodent models, in which the host liver parenchyma is repopulated by human hepatocytes, have been increasingly used for drug development and disease research. Unlike the leading humanized liver mouse model in which Fumarylacetoacetate Hydrolase (Fah), Recombination Activating Gene (Rag)-2 and Interleukin-2 Receptor Gamma (Il2rg) genes were inactivated simultaneously, generation of similar recipient rats has been challenging. Here, using Velocigene and 1-cell-embryo-targeting technologies, we generated a rat model deficient in Fah, Rag1/2 and Il2rg genes, similar to humanized liver mice. These rats were efficiently engrafted with Fah-expressing hepatocytes from rat, mouse and human. Humanized liver rats expressed human albumin and complement proteins in serum and showed a normal liver zonation pattern. Further, approaches were developed for gene delivery through viral transduction of human hepatocytes either in vivo, or in vitro prior to engraftment, providing a novel platform to study liver disease and hepatocyte-targeted therapies.https://doi.org/10.1038/s41598-022-18119-6 |
| spellingShingle | Marisa Carbonaro Jeffrey Lee Evangelos Pefanis Mathieu Desclaux Kehui Wang Alexander Pennington Hui Huang Alejo Mujica Jose Rojas Roxanne Ally Daniel Kennedy Michael Brown Vitaliy Rogulin Sven Moller-Tank Leah Sabin Brian Zambrowicz Gavin Thurston Zhe Li Efficient engraftment and viral transduction of human hepatocytes in an FRG rat liver humanization model Scientific Reports |
| title | Efficient engraftment and viral transduction of human hepatocytes in an FRG rat liver humanization model |
| title_full | Efficient engraftment and viral transduction of human hepatocytes in an FRG rat liver humanization model |
| title_fullStr | Efficient engraftment and viral transduction of human hepatocytes in an FRG rat liver humanization model |
| title_full_unstemmed | Efficient engraftment and viral transduction of human hepatocytes in an FRG rat liver humanization model |
| title_short | Efficient engraftment and viral transduction of human hepatocytes in an FRG rat liver humanization model |
| title_sort | efficient engraftment and viral transduction of human hepatocytes in an frg rat liver humanization model |
| url | https://doi.org/10.1038/s41598-022-18119-6 |
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