9-cis-Retinoic Acid Improves Disease Modelling in iPSC-Derived Liver Organoids
Liver fibrosis majorly impacts global health, necessitating the development of in vitro models to study disease mechanisms and develop drug therapies. Relevant models should at least include hepatocytes and hepatic stellate cells (HSCs) and ideally use three-dimensional cultures to mimic in vivo con...
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MDPI AG
2025-06-01
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| author | Mina Kazemzadeh Dastjerd Vincent Merens Ayla Smout Rebeca De Wolf Christophe Chesné Catherine Verfaillie Stefaan Verhulst Leo A. van Grunsven |
| author_facet | Mina Kazemzadeh Dastjerd Vincent Merens Ayla Smout Rebeca De Wolf Christophe Chesné Catherine Verfaillie Stefaan Verhulst Leo A. van Grunsven |
| author_sort | Mina Kazemzadeh Dastjerd |
| collection | DOAJ |
| description | Liver fibrosis majorly impacts global health, necessitating the development of in vitro models to study disease mechanisms and develop drug therapies. Relevant models should at least include hepatocytes and hepatic stellate cells (HSCs) and ideally use three-dimensional cultures to mimic in vivo conditions. Induced pluripotent stem cells (iPSCs) allow for patient-specific liver modelling, but current models based on iPSC-derived hepatocytes (iHepatocytes) and HSCs (iHSCs) still lack key functions. We developed organoids of iHepatocytes and iHSCs and compared them to HepaRG and primary HSC organoids. RNA sequencing analysis comparison of these cultures identified a potential role for the transcription factor RXRA in hepatocyte differentiation and HSC quiescence. Treating cells with the RXRA ligand 9-cis-retinoic acid (9CRA) promoted iHepatocyte metabolism and iHSC quiescence. In organoids, 9CRA enhanced fibrotic response to TGF-β and acetaminophen, highlighting its potential for refining iPSC-based liver fibrosis models to more faithfully replicate human drug-induced liver injury and fibrotic conditions. |
| format | Article |
| id | doaj-art-50bfb628e3cd4cefb40b7c5646cf494c |
| institution | OA Journals |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-50bfb628e3cd4cefb40b7c5646cf494c2025-08-20T02:35:59ZengMDPI AGCells2073-44092025-06-01141398310.3390/cells141309839-cis-Retinoic Acid Improves Disease Modelling in iPSC-Derived Liver OrganoidsMina Kazemzadeh Dastjerd0Vincent Merens1Ayla Smout2Rebeca De Wolf3Christophe Chesné4Catherine Verfaillie5Stefaan Verhulst6Leo A. van Grunsven7Liver Cell Biology Research Group, Vrije Universiteit Brussel, 1090 Brussel, BelgiumLiver Cell Biology Research Group, Vrije Universiteit Brussel, 1090 Brussel, BelgiumLiver Cell Biology Research Group, Vrije Universiteit Brussel, 1090 Brussel, BelgiumLiver Cell Biology Research Group, Vrije Universiteit Brussel, 1090 Brussel, BelgiumBiopredic International SARL, Parc de la Bretech, 35760 Saint Grégoire, FranceStamcelinstituut Leuven, KU Leuven, 3000 Leuven, BelgiumLiver Cell Biology Research Group, Vrije Universiteit Brussel, 1090 Brussel, BelgiumLiver Cell Biology Research Group, Vrije Universiteit Brussel, 1090 Brussel, BelgiumLiver fibrosis majorly impacts global health, necessitating the development of in vitro models to study disease mechanisms and develop drug therapies. Relevant models should at least include hepatocytes and hepatic stellate cells (HSCs) and ideally use three-dimensional cultures to mimic in vivo conditions. Induced pluripotent stem cells (iPSCs) allow for patient-specific liver modelling, but current models based on iPSC-derived hepatocytes (iHepatocytes) and HSCs (iHSCs) still lack key functions. We developed organoids of iHepatocytes and iHSCs and compared them to HepaRG and primary HSC organoids. RNA sequencing analysis comparison of these cultures identified a potential role for the transcription factor RXRA in hepatocyte differentiation and HSC quiescence. Treating cells with the RXRA ligand 9-cis-retinoic acid (9CRA) promoted iHepatocyte metabolism and iHSC quiescence. In organoids, 9CRA enhanced fibrotic response to TGF-β and acetaminophen, highlighting its potential for refining iPSC-based liver fibrosis models to more faithfully replicate human drug-induced liver injury and fibrotic conditions.https://www.mdpi.com/2073-4409/14/13/983liver fibrosisDILIhepatic stellate cell activationhepatocytesdrug metabolismiPSC |
| spellingShingle | Mina Kazemzadeh Dastjerd Vincent Merens Ayla Smout Rebeca De Wolf Christophe Chesné Catherine Verfaillie Stefaan Verhulst Leo A. van Grunsven 9-cis-Retinoic Acid Improves Disease Modelling in iPSC-Derived Liver Organoids Cells liver fibrosis DILI hepatic stellate cell activation hepatocytes drug metabolism iPSC |
| title | 9-cis-Retinoic Acid Improves Disease Modelling in iPSC-Derived Liver Organoids |
| title_full | 9-cis-Retinoic Acid Improves Disease Modelling in iPSC-Derived Liver Organoids |
| title_fullStr | 9-cis-Retinoic Acid Improves Disease Modelling in iPSC-Derived Liver Organoids |
| title_full_unstemmed | 9-cis-Retinoic Acid Improves Disease Modelling in iPSC-Derived Liver Organoids |
| title_short | 9-cis-Retinoic Acid Improves Disease Modelling in iPSC-Derived Liver Organoids |
| title_sort | 9 cis retinoic acid improves disease modelling in ipsc derived liver organoids |
| topic | liver fibrosis DILI hepatic stellate cell activation hepatocytes drug metabolism iPSC |
| url | https://www.mdpi.com/2073-4409/14/13/983 |
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