Defects in placental syncytiotrophoblast cells are a common cause of developmental heart disease

Bethany N. Radford, Xiang Zhao, Tali Glazer, Malcolm Eaton, Danielle Blackwell, Shuhiba Mohammad, Lucas Daniel Lo Vercio, Jay Devine, Tali Shalom-Barak, Benedikt Hallgrimsson, James C. Cross, Henry M. Sucov, Yaacov Barak, Wendy Dean () and Myriam Hemberger ()
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Bethany N. Radford: University of Calgary
Xiang Zhao: University of Calgary
Tali Glazer: University of Calgary
Malcolm Eaton: University of Calgary
Danielle Blackwell: University of Calgary
Shuhiba Mohammad: University of Calgary
Lucas Daniel Lo Vercio: University of Calgary
Jay Devine: University of Calgary
Tali Shalom-Barak: University of Pittsburgh
Benedikt Hallgrimsson: University of Calgary
James C. Cross: University of Calgary
Henry M. Sucov: Medical University of South Carolina
Yaacov Barak: University of Pittsburgh
Wendy Dean: University of Calgary
Myriam Hemberger: University of Calgary

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Placental abnormalities have been sporadically implicated as a source of developmental heart defects. Yet it remains unknown how often the placenta is at the root of congenital heart defects (CHDs), and what the cellular mechanisms are that underpin this connection. Here, we selected three mouse mutant lines, Atp11a, Smg9 and Ssr2, that presented with placental and heart defects in a recent phenotyping screen, resulting in embryonic lethality. To dissect phenotype causality, we generated embryo- and trophoblast-specific conditional knockouts for each of these lines. This was facilitated by the establishment of a new transgenic mouse, Sox2-Flp, that enables the efficient generation of trophoblast-specific conditional knockouts. We demonstrate a strictly trophoblast-driven cause of the CHD and embryonic lethality in one of the three lines (Atp11a) and a significant contribution of the placenta to the embryonic phenotypes in another line (Smg9). Importantly, our data reveal defects in the maternal blood-facing syncytiotrophoblast layer as a shared pathology in placentally induced CHD models. This study highlights the placenta as a significant source of developmental heart disorders, insights that will transform our understanding of the vast number of unexplained congenital heart defects.

Date: 2023
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DOI: 10.1038/s41467-023-36740-5

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