Volume 35, No 10, Oct 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 10, October 2025: 719-734

ORIGINAL ARTICLES

Establishment of human gastrulating stem cells with the capacity of stable differentiation into multiple gastrulating cell types

Mingqian Huang^1,† , Mengqi Chen^1,† , Gege Yuan^1,† , Yiqiang Cui^1,† , Bin Shen¹ , Zhaode Liu¹ , Bohang Zhang¹ , Junqing Chen¹ , Dingdong Chen¹ , Shuangshuang Qiu¹ , Yichun Zhang¹ , Li Liu^1,2 , Lianju Qin³ , Yunfei Zhu¹ , Jiayin Liu³ , Hao Zhang^1,* , Jun Wu^4,5,6,* , Yan Yuan^1,* , Jiahao Sha^7,*

¹State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu, China
²The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
³State Key Laboratory of Reproductive Medicine and Offspring Health, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
⁴Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
⁵Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
⁶Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
⁷State Key Laboratory of Reproductive Medicine and Offspring Health, Women’s Hospital of Nanjing Medical University, Nanjing Women and Children’s Healthcare Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
^†These authors contributed equally: Mingqian Huang, Mengqi Chen, Gege Yuan, Yiqiang Cui
Correspondence: Hao Zhang(haozhang@njmu.edu.cn)Jun Wu(jun2.wu@utsouthwestern.edu)Yan Yuan(yuanyan@njmu.edu.cn)Jiahao Sha(shajh@njmu.edu.cn)

Pluripotent stem cells (PSCs) have been derived from various species, but most culture systems stabilize only a single PSC type. By contrast, epiblast cells in vivo exist along a continuum and interact dynamically with both embryonic and extraembryonic cells, interactions missing in standard PSC cultures. This absence limits the self-organizing potential of PSCs and leads to disorganized tissue formation in teratomas. To address this, we developed a unified culture system that supports the stable differentiation of epiblast-like cells into multiple key human gastrulating cell types, collectively called human gastrulating stem cells (hGaSCs). hGaSCs, composed of endoderm-like, mesoderm-like, ectoderm-like, amnion ectoderm-like, and primordial germ cell-like cells, maintain a stable balance during long-term culture. In 3D culture, hGaSCs self-assemble into gastruloid-like structures (hGaSC-gastruloids) that model aspects of a Carnegie Stage 7 human embryo, including gastrulation and germ layer specification. Using hGaSC-gastruloids, we modeled the effects of valproic acid (VPA) on human gastrulation and uncovered molecular pathways underlying VPA-induced malformations. When transplanted into the seminiferous tubules, hGaSCs formed embryo-like structures, progressing through fetal tissue and organ development, unlike the disorganized growth seen in teratomas. In conclusion, hGaSCs provide a versatile platform to study human gastrulation, early organogenesis, developmental defects, and drug teratogenicity, with promising applications in tissue and organ generation from cultured stem cells.

https://doi.org/10.1038/s41422-025-01146-z

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