Genetically edited human placental organoids cast new light on the role of ACE2

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dc.contributor.authorArthurs, A.L.
dc.contributor.authorDietrich, B.
dc.contributor.authorKnöfler, M.
dc.contributor.authorLushington, C.J.
dc.contributor.authorThomas, P.Q.
dc.contributor.authorAdikusuma, F.
dc.contributor.authorWilliamson, J.M.
dc.contributor.authorBabikha, S.
dc.contributor.authorDamhuis, T.
dc.contributor.authorJankovic-Karasoulos, T.
dc.contributor.authorSmith, M.D.
dc.contributor.authorPringle, K.G.
dc.contributor.authorRoberts, C.T.
dc.date.issued2025
dc.descriptionPublished online: 07 February 2025
dc.description.abstractACE2 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.
dc.description.statementofresponsibilityAnya 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 and Claire T. Roberts
dc.identifier.citationCell Death and Disease, 2025; 16(1):78-1-78-12
dc.identifier.doi10.1038/s41419-025-07400-x
dc.identifier.issn2041-4889
dc.identifier.issn2041-4889
dc.identifier.orcidArthurs, A.L. [0000-0002-4382-0610]
dc.identifier.orcidLushington, C.J. [0000-0001-7131-972X]
dc.identifier.orcidAdikusuma, F. [0000-0003-2163-0514]
dc.identifier.orcidJankovic-Karasoulos, T. [0000-0003-4293-359X]
dc.identifier.orcidSmith, M.D. [0000-0001-7016-8245]
dc.identifier.orcidRoberts, C.T. [0000-0002-9250-2192]
dc.identifier.urihttps://hdl.handle.net/2440/144436
dc.language.isoen
dc.publisherSpringer Nature
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1174971
dc.rights© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
dc.source.urihttps://doi.org/10.1038/s41419-025-07400-x
dc.subjectAngiotensin-Converting Enzyme 2
dc.subject.meshAngiotensin-Converting Enzyme 2
dc.subject.meshFemale
dc.subject.meshGene Editing
dc.subject.meshGenotype
dc.subject.meshHumans
dc.subject.meshOrganoids
dc.subject.meshPeptidyl-Dipeptidase A
dc.subject.meshPlacenta
dc.subject.meshPregnancy
dc.titleGenetically edited human placental organoids cast new light on the role of ACE2
dc.typeJournal article
pubs.publication-statusPublished

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