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

doi:10.1016/j.isci.2023.107012

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

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

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.

Original language	English (US)
Article number	107012
Journal	iScience
Volume	26
Issue number	7
DOIs	https://doi.org/10.1016/j.isci.2023.107012
State	Published - Jul 21 2023
Externally published	Yes

Keywords

Cell biology
Developmental biology
Stem cells research
Transcriptomics

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2023.107012

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title = "Interferon hyperactivity impairs cardiogenesis in Down syndrome via downregulation of canonical Wnt signaling",

abstract = "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.",

keywords = "Cell biology, Developmental biology, Stem cells research, Transcriptomics",

author = "Congwu Chi and Knight, {Walter E.} and Riching, {Andrew S.} and Zhen Zhang and Roubina Tatavosian and Yonghua Zhuang and Radu Moldovan and Rachubinski, {Angela L.} and Dexiang Gao and Hongyan Xu and Espinosa, {Joaquin M.} and Kunhua Song",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = jul,

day = "21",

doi = "10.1016/j.isci.2023.107012",

language = "English (US)",

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T1 - Interferon hyperactivity impairs cardiogenesis in Down syndrome via downregulation of canonical Wnt signaling

AU - Chi, Congwu

AU - Knight, Walter E.

AU - Riching, Andrew S.

AU - Zhang, Zhen

AU - Tatavosian, Roubina

AU - Zhuang, Yonghua

AU - Moldovan, Radu

AU - Rachubinski, Angela L.

AU - Gao, Dexiang

AU - Xu, Hongyan

AU - Espinosa, Joaquin M.

AU - Song, Kunhua

PY - 2023/7/21

Y1 - 2023/7/21

N2 - 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.

AB - 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.

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KW - Developmental biology

KW - Stem cells research

KW - Transcriptomics

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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