Interferon hyperactivity impairs cardiogenesis in Down syndrome via downregulation of canonical Wnt signaling.
Interferon hyperactivity impairs cardiogenesis in Down syndrome via downregulation of canonical Wnt signaling.
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DOI：
10.1016/j.isci.2023.107012
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发表时间：
2023-07-21
期刊：
影响因子：
5.8
通讯作者：
Song, Kunhua
中科院分区：
文献类型：
--
作者：
Chi, Congwu;Knight, Walter E.;Riching, Andrew S.;Zhang, Zhen;Tatavosian, Roubina;Zhuang, Yonghua;Moldovan, Radu;Rachubinski, Angela L.;Gao, Dexiang;Xu, Hongyan;Espinosa, Joaquin M.;Song, Kunhua
先天性心脏缺陷（CHDs）在患有唐氏综合症（DS）的儿童中很常见，由21号染色体三体引起。然而，人们对其潜在机制知之甚少。本研究利用基于人诱导多能干细胞（iPSC）的模型和DS的Dp(16)1Yey/+ (Dp16)小鼠模型，我们发现21号染色体上干扰素（IFN）受体（IFNRs）基因剂量增加的下游典型Wnt信号下调是DS心源性失调的一个致病因素。我们将来自DS和CHDs个体以及健康整倍体对照的人类iPSCs分化为心脏细胞。我们观察到T21上调IFN信号，下调典型WNT通路，并损害心脏分化。此外，IFN信号的遗传和药理学正常化恢复了正常的WNT信号，并在体外和体内修复了DS的心脏发生缺陷。我们的发现提供了对退行性椎体滑移异常心脏发生机制的深入了解，最终有助于制定治疗策略。干扰素信号在唐氏综合征心脏发生过程中过度激活典型Wnt信号在唐氏综合征心脏发生过程中下调干扰素过度活跃通过下调Wnt通路损害心脏发生细胞生物学；干细胞研究；发育生物学;转录组
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. Interferon signaling is hyperactivated during cardiogenesis in Down syndrome Canonical Wnt signaling is downregulated during cardiogenesis in Down syndrome Interferon hyperactivity impairs cardiogenesis by downregulating the Wnt pathway Cell biology; Stem cells research; Developmental biology; Transcriptomics
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