Genetically edited human placental organoids cast new light on the role of ACE2
Abstract ACE2 expression is altered in pregnancy disorders and ACE2 gene variants are associated with several major pregnancy complications including small-for-gestational-age, fetal growth restriction and preeclampsia. This study utilised gene-editing to generate both ACE2 knockout and ACE2 rs20741...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07400-x |
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| author | Anya L. Arthurs Bianca Dietrich Martin Knöfler Caleb J. Lushington Paul Q. Thomas Fatwa Adikusuma Jessica M. Williamson Susan Babikha Tyla Damhuis Tanja Jankovic-Karasoulos Melanie D. Smith Kirsty G. Pringle Claire T. Roberts |
| author_facet | Anya L. Arthurs Bianca Dietrich Martin Knöfler Caleb J. Lushington Paul Q. Thomas Fatwa Adikusuma Jessica M. Williamson Susan Babikha Tyla Damhuis Tanja Jankovic-Karasoulos Melanie D. Smith Kirsty G. Pringle Claire T. Roberts |
| author_sort | Anya L. Arthurs |
| collection | DOAJ |
| description | Abstract ACE2 expression is altered in pregnancy disorders and ACE2 gene variants are associated with several major pregnancy complications including small-for-gestational-age, fetal growth restriction and preeclampsia. This study utilised gene-editing to generate both ACE2 knockout and ACE2 rs2074192 placental organoids, facilitating mechanistic studies into the role of ACE2 in placental development, and the effect of fetal carriage of ACE2 rs2074192 CC, CT and TT genotypes. Parameters of cell and organoid growth were measured, together with qPCR, Western Blotting, and ELISA assessments, in all groups from both organoid models. Here, we report that ACE2 knockout results in delayed placental cell growth and increased cell death. ACE2 knockout organoids had lower ACE protein expression, reduced organoid diameters and asymmetrical growth. Placental organoids with the ACE2 rs2074192 TT genotype had significantly higher expression of ACE2 mRNA and ACE2 protein with elevated ACE2:ACE expression ratio and no change in ACE protein. Despite increased expression of ACE2 protein, ACE2 enzyme activity was significantly decreased in ACE2 rs2074192 TT placental organoids. TT organoids also had reduced diameters and asymmetrical growth. Our research provides a new molecular understanding of the role of ACE2 in placental development, with potential implications for pregnancy in the carriage of the ACE2 rs2074192 gene variant. |
| format | Article |
| id | doaj-art-8186fd352de0461c88a6d4aa2248d54e |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-8186fd352de0461c88a6d4aa2248d54e2025-02-09T12:56:51ZengNature Publishing GroupCell Death and Disease2041-48892025-02-0116111210.1038/s41419-025-07400-xGenetically edited human placental organoids cast new light on the role of ACE2Anya L. Arthurs0Bianca Dietrich1Martin Knöfler2Caleb J. Lushington3Paul Q. Thomas4Fatwa Adikusuma5Jessica M. Williamson6Susan Babikha7Tyla Damhuis8Tanja Jankovic-Karasoulos9Melanie D. Smith10Kirsty G. Pringle11Claire T. Roberts12Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research InstitutePlacental Development Group, Medical University of ViennaPlacental Development Group, Medical University of ViennaSchool of Biomedicine and Robinson Research Institute, University of AdelaideSchool of Biomedicine and Robinson Research Institute, University of AdelaideSchool of Biomedicine and Robinson Research Institute, University of AdelaideFlinders University, College of Medicine and Public Health, Flinders Health and Medical Research InstituteFlinders University, College of Medicine and Public Health, Flinders Health and Medical Research InstituteFlinders University, College of Medicine and Public Health, Flinders Health and Medical Research InstituteFlinders University, College of Medicine and Public Health, Flinders Health and Medical Research InstituteFlinders University, College of Medicine and Public Health, Flinders Health and Medical Research InstituteSchool of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of NewcastleFlinders University, College of Medicine and Public Health, Flinders Health and Medical Research InstituteAbstract ACE2 expression is altered in pregnancy disorders and ACE2 gene variants are associated with several major pregnancy complications including small-for-gestational-age, fetal growth restriction and preeclampsia. This study utilised gene-editing to generate both ACE2 knockout and ACE2 rs2074192 placental organoids, facilitating mechanistic studies into the role of ACE2 in placental development, and the effect of fetal carriage of ACE2 rs2074192 CC, CT and TT genotypes. Parameters of cell and organoid growth were measured, together with qPCR, Western Blotting, and ELISA assessments, in all groups from both organoid models. Here, we report that ACE2 knockout results in delayed placental cell growth and increased cell death. ACE2 knockout organoids had lower ACE protein expression, reduced organoid diameters and asymmetrical growth. Placental organoids with the ACE2 rs2074192 TT genotype had significantly higher expression of ACE2 mRNA and ACE2 protein with elevated ACE2:ACE expression ratio and no change in ACE protein. Despite increased expression of ACE2 protein, ACE2 enzyme activity was significantly decreased in ACE2 rs2074192 TT placental organoids. TT organoids also had reduced diameters and asymmetrical growth. Our research provides a new molecular understanding of the role of ACE2 in placental development, with potential implications for pregnancy in the carriage of the ACE2 rs2074192 gene variant.https://doi.org/10.1038/s41419-025-07400-x |
| spellingShingle | Anya L. Arthurs Bianca Dietrich Martin Knöfler Caleb J. Lushington Paul Q. Thomas Fatwa Adikusuma Jessica M. Williamson Susan Babikha Tyla Damhuis Tanja Jankovic-Karasoulos Melanie D. Smith Kirsty G. Pringle Claire T. Roberts Genetically edited human placental organoids cast new light on the role of ACE2 Cell Death and Disease |
| title | Genetically edited human placental organoids cast new light on the role of ACE2 |
| title_full | Genetically edited human placental organoids cast new light on the role of ACE2 |
| title_fullStr | Genetically edited human placental organoids cast new light on the role of ACE2 |
| title_full_unstemmed | Genetically edited human placental organoids cast new light on the role of ACE2 |
| title_short | Genetically edited human placental organoids cast new light on the role of ACE2 |
| title_sort | genetically edited human placental organoids cast new light on the role of ace2 |
| url | https://doi.org/10.1038/s41419-025-07400-x |
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