Deciphering signaling mechanisms and developmental dynamics in extraembryonic mesoderm specification from hESCs
Abstract Extraembryonic mesoderm (ExM) is crucial for human development, yet its specification is poorly understood. Human embryonic stem cell (hESC)-based models, including embryoids and differentiated derivatives, are emerging as promising tools for studying ExM development. Despite this, the sign...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59491-x |
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| author | Baohua Niu Da Wang Yingjie Hu Yundi Wang Gaohui Shi Zhongying Chen Lifeng Xiang Chi Zhang Xuesong Wei Ruize Kong Hongzhi Cai Weizhi Ji Yu Yin Tianqing Li Zongyong Ai |
| author_facet | Baohua Niu Da Wang Yingjie Hu Yundi Wang Gaohui Shi Zhongying Chen Lifeng Xiang Chi Zhang Xuesong Wei Ruize Kong Hongzhi Cai Weizhi Ji Yu Yin Tianqing Li Zongyong Ai |
| author_sort | Baohua Niu |
| collection | DOAJ |
| description | Abstract Extraembryonic mesoderm (ExM) is crucial for human development, yet its specification is poorly understood. Human embryonic stem cell (hESC)-based models, including embryoids and differentiated derivatives, are emerging as promising tools for studying ExM development. Despite this, the signaling mechanisms and developmental dynamics that underlie ExM specification from hESCs remain challenging to study. Here, we report that the modulation of BMP, WNT, and Nodal signaling pathways can rapidly (4-5 days) and efficiently ( ~90%) induce the differentiation of both naive and primed hESCs into ExM-like cells (ExMs). We reveal that ExM specification from hESCs predominantly proceeds through intermediates exhibiting a primitive streak (PS)-like gene expression pattern and delineate the regulatory roles of WNT and Nodal signaling in this process. Furthermore, we find that the initial pluripotent state governs hESC-based ExM specification by influencing signal response, cellular composition, developmental progression, and transcriptional characteristics of the resulting ExMs. Our study provides promising models for dissecting human ExM development and sheds light on the signaling principles, developmental dynamics, and influences of pluripotency states underlying ExM specification from hESCs. |
| format | Article |
| id | doaj-art-09f89752e0bf446c8d7b6d2f2adde5dd |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-09f89752e0bf446c8d7b6d2f2adde5dd2025-08-20T01:53:23ZengNature PortfolioNature Communications2041-17232025-05-0116112010.1038/s41467-025-59491-xDeciphering signaling mechanisms and developmental dynamics in extraembryonic mesoderm specification from hESCsBaohua Niu0Da Wang1Yingjie Hu2Yundi Wang3Gaohui Shi4Zhongying Chen5Lifeng Xiang6Chi Zhang7Xuesong Wei8Ruize Kong9Hongzhi Cai10Weizhi Ji11Yu Yin12Tianqing Li13Zongyong Ai14State Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and TechnologyState Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and TechnologyState Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and TechnologyState Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and TechnologyState Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and TechnologyUltrasound Department, The Third People’s Hospital of Yunnan ProvinceDepartment of Reproductive Medicine, The First People’s Hospital of Yunnan ProvinceState Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and TechnologyState Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and TechnologyDepartment of Reproductive Medicine, The First People’s Hospital of Yunnan ProvinceState Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and TechnologyState Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and TechnologyState Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and TechnologyState Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and TechnologyState Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and TechnologyAbstract Extraembryonic mesoderm (ExM) is crucial for human development, yet its specification is poorly understood. Human embryonic stem cell (hESC)-based models, including embryoids and differentiated derivatives, are emerging as promising tools for studying ExM development. Despite this, the signaling mechanisms and developmental dynamics that underlie ExM specification from hESCs remain challenging to study. Here, we report that the modulation of BMP, WNT, and Nodal signaling pathways can rapidly (4-5 days) and efficiently ( ~90%) induce the differentiation of both naive and primed hESCs into ExM-like cells (ExMs). We reveal that ExM specification from hESCs predominantly proceeds through intermediates exhibiting a primitive streak (PS)-like gene expression pattern and delineate the regulatory roles of WNT and Nodal signaling in this process. Furthermore, we find that the initial pluripotent state governs hESC-based ExM specification by influencing signal response, cellular composition, developmental progression, and transcriptional characteristics of the resulting ExMs. Our study provides promising models for dissecting human ExM development and sheds light on the signaling principles, developmental dynamics, and influences of pluripotency states underlying ExM specification from hESCs.https://doi.org/10.1038/s41467-025-59491-x |
| spellingShingle | Baohua Niu Da Wang Yingjie Hu Yundi Wang Gaohui Shi Zhongying Chen Lifeng Xiang Chi Zhang Xuesong Wei Ruize Kong Hongzhi Cai Weizhi Ji Yu Yin Tianqing Li Zongyong Ai Deciphering signaling mechanisms and developmental dynamics in extraembryonic mesoderm specification from hESCs Nature Communications |
| title | Deciphering signaling mechanisms and developmental dynamics in extraembryonic mesoderm specification from hESCs |
| title_full | Deciphering signaling mechanisms and developmental dynamics in extraembryonic mesoderm specification from hESCs |
| title_fullStr | Deciphering signaling mechanisms and developmental dynamics in extraembryonic mesoderm specification from hESCs |
| title_full_unstemmed | Deciphering signaling mechanisms and developmental dynamics in extraembryonic mesoderm specification from hESCs |
| title_short | Deciphering signaling mechanisms and developmental dynamics in extraembryonic mesoderm specification from hESCs |
| title_sort | deciphering signaling mechanisms and developmental dynamics in extraembryonic mesoderm specification from hescs |
| url | https://doi.org/10.1038/s41467-025-59491-x |
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