Interferon hyperactivity impairs cardiogenesis in Down syndrome via downregulation of canonical Wnt signaling
Congwu Chi,
Walter E. Knight,
Andrew S. Riching,
Zhen Zhang,
Roubina Tatavosian,
Yonghua Zhuang,
Radu Moldovan,
Angela L. Rachubinski,
Dexiang Gao,
Hongyan Xu,
Joaquin M. Espinosa,
Kunhua Song
Affiliations
Congwu Chi
Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA; Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA
Walter E. Knight
Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA; Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA
Andrew S. Riching
Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA; Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA
Zhen Zhang
Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA
Roubina Tatavosian
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA
Yonghua Zhuang
Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA
Radu Moldovan
Department of Pharmacology, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA
Angela L. Rachubinski
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA
Dexiang Gao
Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA
Hongyan Xu
Department of Population Health Sciences, Medical College of Georgia, Augusta University; Augusta, GA 30912, USA
Joaquin M. Espinosa
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA
Kunhua Song
Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA; Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA; Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA; Corresponding author
Summary: Congenital heart defects (CHDs) are frequent in children with Down syndrome (DS), caused by trisomy of chromosome 21. However, the underlying mechanisms are poorly understood. Here, using 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 cardiogenic dysregulation in DS. We differentiated human iPSCs derived from individuals with DS and CHDs, and healthy 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 cardiogenesis in DS in vitro and in vivo. Our findings provide insights into mechanisms underlying abnormal cardiogenesis in DS, ultimately aiding the development of therapeutic strategies.
