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Interferon hyperactivity impairs cardiogenesis in Down syndrome via downregulation of canonical Wnt signaling

Congwu Chi1,2,3, Walter E Knight1,4, Andrew S Riching1,4

  • 1Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA.

Iscience
|June 26, 2023
PubMed

Insights

Children with Down syndrome (DS) often have congenital heart defects (CHDs). This study found that increased interferon signaling due to chromosome 21 changes disrupts heart development in DS, but normalizing this signaling can restore normal heart formation.

Area of Science:

  • Genetics
  • Developmental Biology
  • Stem Cell Biology

Background:

  • Congenital heart defects (CHDs) are common in children with Down syndrome (DS), but the molecular mechanisms remain unclear.
  • Down syndrome is caused by trisomy of chromosome 21, leading to altered gene dosage.
  • Understanding these mechanisms is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the molecular pathways linking trisomy 21 to cardiogenic dysregulation in Down syndrome.
  • To identify the role of interferon (IFN) signaling and Wnt pathway in DS-related heart defects.
  • To explore therapeutic strategies for correcting cardiac abnormalities in DS.

Main Methods:

  • Utilized human-induced pluripotent stem cells (iPSCs) from individuals with DS and CHDs, and healthy controls.
  • Employed the Dp(16)1Yey/+ (Dp16) mouse model for in vivo studies.
  • Differentiated iPSCs into cardiac cells to assess cardiogenesis.
  • Analyzed interferon and Wnt signaling pathways.
  • Investigated genetic and pharmacological interventions to modulate IFN signaling.

Main Results:

  • Trisomy 21 upregulates interferon (IFN) signaling pathways.
  • Increased IFN signaling leads to downregulation of the canonical WNT pathway.
  • This aberrant signaling impairs cardiac differentiation and cardiogenesis in DS models (in vitro and in vivo).
  • Normalization of IFN signaling restored Wnt pathway activity and rescued cardiac defects.

Conclusions:

  • Downregulation of canonical Wnt signaling, driven by increased IFN signaling due to trisomy 21, is a key mechanism causing cardiogenic dysregulation in Down syndrome.
  • Modulating interferon signaling presents a potential therapeutic approach for treating congenital heart defects in individuals with DS.
  • This research offers novel insights into the pathogenesis of DS-associated heart abnormalities.
Keywords:
Cell biologyDevelopmental biologyStem cells researchTranscriptomics

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