Abstract P1161: Interferon Hyperactivity Impairs Cardiogenesis In Down Syndrome Via Downregulation Of Canonical Wnt Signaling

• Published in: Circulation research 2023-08, Vol.133 (Suppl_1)
• Main Authors: Song, Kunhua, Chi, Congwu
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.133.suppl_1.P1161

Abstract only Congenital heart defects (CHDs) are very frequent in children with Down syndrome (DS), the genetic condition caused by trisomy of chromosome 21 (T21). Despite significant efforts, the mechanisms by which T21 causes susceptibility to CHDs remain largely unknown. Here, using a combination of a human induced pluripotent stem cell (iPSC)-based model and the Dp(16)1Yey/+ (Dp16) mouse model of DS, we identified downregulation of canonical Wnt signaling downstream of increased dosage of interferon (IFN) receptors (IFNRs) genes on chromosome 21 as a causative factor of CHDs in DS. We differentiated human iPSCs derived from individuals with DS and CHDs (DS/CHD iPSCs), and euploid controls into cardiac cells. We observed that T21 upregulates IFN signaling, downregulates the canonical WNT pathway, and impairs cardiac differentiation. Furthermore, genetic and pharmacological normalization of IFN signaling restored canonical WNT signaling and rescued defects in cardiac differentiation of DS/CHD iPSCs. To define the role of IFN signaling in CHDs in vivo , we genetically and pharmacologically normalized the activity of IFN signaling in the Dp16 mouse model of DS. Normalization of the activity of IFN signaling prevented heart malformations in Dp16 embryos. In addition, treatment with an inhibitor of Janus kinases, which act downstream of IFNRs, normalized canonical Wnt signaling and ameliorated CHDs in Dp16 embryos. Our findings provide new insights into mechanisms underlying CHDs in DS, ultimately aiding the development of novel therapeutic strategies.