iPSC-derived type IV collagen α5-expressing kidney organoids model Alport syndrome
Abstract Alport syndrome (AS) is a hereditary glomerulonephritis caused by COL4A3, COL4A4 or COL4A5 gene mutations and characterized by abnormalities of glomerular basement membranes (GBMs). Due to a lack of curative treatments, the condition proceeds to end-stage renal disease even in adolescents....
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05203-4 |
| _version_ | 1827708986670972928 |
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| author | Ryuichiro Hirayama Kosuke Toyohara Kei Watanabe Takeya Otsuki Toshikazu Araoka Shin-Ichi Mae Tomoko Horinouchi Tomohiko Yamamura Keisuke Okita Akitsu Hotta Kazumoto Iijima Kandai Nozu Kenji Osafune |
| author_facet | Ryuichiro Hirayama Kosuke Toyohara Kei Watanabe Takeya Otsuki Toshikazu Araoka Shin-Ichi Mae Tomoko Horinouchi Tomohiko Yamamura Keisuke Okita Akitsu Hotta Kazumoto Iijima Kandai Nozu Kenji Osafune |
| author_sort | Ryuichiro Hirayama |
| collection | DOAJ |
| description | Abstract Alport syndrome (AS) is a hereditary glomerulonephritis caused by COL4A3, COL4A4 or COL4A5 gene mutations and characterized by abnormalities of glomerular basement membranes (GBMs). Due to a lack of curative treatments, the condition proceeds to end-stage renal disease even in adolescents. Hampering drug discovery is the absence of effective in vitro methods for testing the restoration of normal GBMs. Here, we aimed to develop kidney organoid models from AS patient iPSCs for this purpose. We established iPSC-derived collagen α5(IV)-expressing kidney organoids and confirmed that kidney organoids from COL4A5 mutation-corrected iPSCs restore collagen α5(IV) protein expression. Importantly, our model recapitulates the differences in collagen composition between iPSC-derived kidney organoids from mild and severe AS cases. Furthermore, we demonstrate that a chemical chaperone, 4-phenyl butyric acid, has the potential to correct GBM abnormalities in kidney organoids showing mild AS phenotypes. This iPSC-derived kidney organoid model will contribute to drug discovery for AS. |
| first_indexed | 2024-03-10T17:14:33Z |
| format | Article |
| id | doaj.art-d35615f2c8824439a7a88aa52196dc4a |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-10T17:14:33Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-d35615f2c8824439a7a88aa52196dc4a2023-11-20T10:33:44ZengNature PortfolioCommunications Biology2399-36422023-09-016111110.1038/s42003-023-05203-4iPSC-derived type IV collagen α5-expressing kidney organoids model Alport syndromeRyuichiro Hirayama0Kosuke Toyohara1Kei Watanabe2Takeya Otsuki3Toshikazu Araoka4Shin-Ichi Mae5Tomoko Horinouchi6Tomohiko Yamamura7Keisuke Okita8Akitsu Hotta9Kazumoto Iijima10Kandai Nozu11Kenji Osafune12Center for iPS Cell Research and Application (CiRA), Kyoto UniversityCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityDepartment of Pediatrics, Kobe University Graduate School of MedicineDepartment of Pediatrics, Kobe University Graduate School of MedicineCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityDepartment of Pediatrics, Kobe University Graduate School of MedicineDepartment of Pediatrics, Kobe University Graduate School of MedicineCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityAbstract Alport syndrome (AS) is a hereditary glomerulonephritis caused by COL4A3, COL4A4 or COL4A5 gene mutations and characterized by abnormalities of glomerular basement membranes (GBMs). Due to a lack of curative treatments, the condition proceeds to end-stage renal disease even in adolescents. Hampering drug discovery is the absence of effective in vitro methods for testing the restoration of normal GBMs. Here, we aimed to develop kidney organoid models from AS patient iPSCs for this purpose. We established iPSC-derived collagen α5(IV)-expressing kidney organoids and confirmed that kidney organoids from COL4A5 mutation-corrected iPSCs restore collagen α5(IV) protein expression. Importantly, our model recapitulates the differences in collagen composition between iPSC-derived kidney organoids from mild and severe AS cases. Furthermore, we demonstrate that a chemical chaperone, 4-phenyl butyric acid, has the potential to correct GBM abnormalities in kidney organoids showing mild AS phenotypes. This iPSC-derived kidney organoid model will contribute to drug discovery for AS.https://doi.org/10.1038/s42003-023-05203-4 |
| spellingShingle | Ryuichiro Hirayama Kosuke Toyohara Kei Watanabe Takeya Otsuki Toshikazu Araoka Shin-Ichi Mae Tomoko Horinouchi Tomohiko Yamamura Keisuke Okita Akitsu Hotta Kazumoto Iijima Kandai Nozu Kenji Osafune iPSC-derived type IV collagen α5-expressing kidney organoids model Alport syndrome Communications Biology |
| title | iPSC-derived type IV collagen α5-expressing kidney organoids model Alport syndrome |
| title_full | iPSC-derived type IV collagen α5-expressing kidney organoids model Alport syndrome |
| title_fullStr | iPSC-derived type IV collagen α5-expressing kidney organoids model Alport syndrome |
| title_full_unstemmed | iPSC-derived type IV collagen α5-expressing kidney organoids model Alport syndrome |
| title_short | iPSC-derived type IV collagen α5-expressing kidney organoids model Alport syndrome |
| title_sort | ipsc derived type iv collagen α5 expressing kidney organoids model alport syndrome |
| url | https://doi.org/10.1038/s42003-023-05203-4 |
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