Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids
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 demonstr...
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| Format: | Article |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41158-0 |
| _version_ | 1797558418234408960 |
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| author | Hao Wu Xing-Yao Huang Meng-Xu Sun Yue Wang Hang-Yu Zhou Ying Tian Beijia He Kai Li De-Yu Li Ai-Ping Wu Hongmei Wang Cheng-Feng Qin |
| author_facet | Hao Wu Xing-Yao Huang Meng-Xu Sun Yue Wang Hang-Yu Zhou Ying Tian Beijia He Kai Li De-Yu Li Ai-Ping Wu Hongmei Wang Cheng-Feng Qin |
| author_sort | Hao Wu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:30:11Z |
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| id | doaj.art-efe6d64e4a4b45bbb403854f342c4115 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:30:11Z |
| publishDate | 2023-09-01 |
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| series | Nature Communications |
| spelling | doaj.art-efe6d64e4a4b45bbb403854f342c41152023-11-20T10:03:13ZengNature PortfolioNature Communications2041-17232023-09-0114111610.1038/s41467-023-41158-0Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoidsHao Wu0Xing-Yao Huang1Meng-Xu Sun2Yue Wang3Hang-Yu Zhou4Ying Tian5Beijia He6Kai Li7De-Yu Li8Ai-Ping Wu9Hongmei Wang10Cheng-Feng Qin11State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical SciencesState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical SciencesState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical SciencesState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical SciencesState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical SciencesState Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical SciencesAbstract 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.https://doi.org/10.1038/s41467-023-41158-0 |
| spellingShingle | Hao Wu Xing-Yao Huang Meng-Xu Sun Yue Wang Hang-Yu Zhou Ying Tian Beijia He Kai Li De-Yu Li Ai-Ping Wu Hongmei Wang Cheng-Feng Qin Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids Nature Communications |
| title | Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids |
| title_full | Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids |
| title_fullStr | Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids |
| title_full_unstemmed | Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids |
| title_short | Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids |
| title_sort | zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids |
| url | https://doi.org/10.1038/s41467-023-41158-0 |
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