Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids

Hao Wu, Xing-Yao Huang, Meng-Xu Sun, Yue Wang, Hang-Yu Zhou, Ying Tian, Beijia He, Kai Li, Li De-Yu, Ai-Ping Wu, Hongmei Wang () and Cheng-Feng Qin ()
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Hao Wu: Chinese Academy of Sciences
Xing-Yao Huang: Academy of Military Medical Sciences
Meng-Xu Sun: Academy of Military Medical Sciences
Yue Wang: Chinese Academy of Sciences
Hang-Yu Zhou: Chinese Academy of Medical Sciences & Peking Union Medical College
Ying Tian: Academy of Military Medical Sciences
Beijia He: Chinese Academy of Sciences
Kai Li: Academy of Military Medical Sciences
Li De-Yu: Academy of Military Medical Sciences
Ai-Ping Wu: Chinese Academy of Medical Sciences & Peking Union Medical College
Hongmei Wang: Chinese Academy of Sciences
Cheng-Feng Qin: Academy of Military Medical Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Zika virus (ZIKV) infection during pregnancy threatens pregnancy and fetal health. However, the infectivity and pathological effects of ZIKV on placental trophoblast progenitor cells in early human embryos remain largely unknown. Here, using human trophoblast stem cells (hTSCs), we demonstrated that hTSCs were permissive to ZIKV infection, and resistance to ZIKV increased with hTSC differentiation. Combining gene knockout and transcriptome analysis, we demonstrated that the intrinsic expression of AXL and TIM-1, and the absence of potent interferon (IFN)-stimulated genes (ISGs) and IFNs contributed to the high sensitivity of hTSCs to ZIKV. Furthermore, using our newly developed hTSC-derived trophoblast organoid (hTSC-organoid), we demonstrated that ZIKV infection disrupted the structure of mature hTSC-organoids and inhibited syncytialization. Single-cell RNA sequencing (scRNA-seq) further demonstrated that ZIKV infection of hTSC-organoids disrupted the stemness of hTSCs and the proliferation of cytotrophoblast cells (CTBs) and probably led to a preeclampsia (PE) phenotype. Overall, our results clearly demonstrate that hTSCs represent the major target cells of ZIKV, and a reduced syncytialization may result from ZIKV infection of early developing placenta. These findings deepen our understanding of the characteristics and consequences of ZIKV infection of hTSCs in early human embryos.

Date: 2023
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DOI: 10.1038/s41467-023-41158-0

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