Modeling early gastrulation in human blastoids with DNA methylation patterns of natural blastocysts

Han Xie; Chenrui An; Bing Bai; Jiajia Luo; Nianqin Sun; Baiquan Ci; Long Jin; Peiting Mo; Yawen Lu; Ke Zhong; Yang Yu; Tao Tan; Rong Li; Yong Fan

doi:10.1016/j.stem.2024.12.010

Modeling early gastrulation in human blastoids with DNA methylation patterns of natural blastocysts

Cell Stem Cell. 2025 Jan 7:S1934-5909(24)00450-8. doi: 10.1016/j.stem.2024.12.010. Online ahead of print.

Authors

Han Xie¹, Chenrui An¹, Bing Bai², Jiajia Luo¹, Nianqin Sun², Baiquan Ci², Long Jin¹, Peiting Mo¹, Yawen Lu¹, Ke Zhong¹, Yang Yu³, Tao Tan⁴, Rong Li⁵, Yong Fan⁶

Affiliations

¹ Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
² State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, Yunnan, China.
³ Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China. Electronic address: [email protected].
⁴ State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, Yunnan, China. Electronic address: [email protected].
⁵ Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China. Electronic address: [email protected].
⁶ Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China. Electronic address: [email protected].

PMID: 39814012
DOI: 10.1016/j.stem.2024.12.010

Abstract

Blastoids are a promising model for studying early human embryogenesis, but current models have limitations in post-implantation development and lack comprehensive epigenetic assessments, especially regarding genomic imprinting. These issues can lead to failures in accurately modeling early embryonic development. In this study, we developed a high-fidelity blastoid model using 4 chemicals + leukemia inhibitory factor (LIF) (4CL) naive human pluripotent stem cells (hPSCs) (4CL blastoids). 4CL blastoids closely resemble human blastocysts in morphology and transcriptional profiles, exhibiting similar DNA methylation and gene imprinting patterns. By extending the 3D culture to 14 days, these blastoids mimic early gastrulation, demonstrating the specification and migration of cells. They also show the transcriptional signature of hemogenic angioblast (HAB) cells at Carnegie stage 6 (CS6). This model bridges pre- and post-implantation stages, offering valuable insights into early tissue formation and human development.

Keywords: DNA methylation; blastoids; early gastrulation; naive human pluripotent stem cells.