Inhibition of Wnt activity improves peri-implantation development of somatic cell nuclear transfer embryos

Yanhe Li; Caihong Zheng; Yingdong Liu; Jincan He; Qiang Zhang; Yalin Zhang; Xiaochen Kou; Yanhong Zhao; Kuisheng Liu; Dandan Bai; Yanping Jia; Xiaoxiao Han; Yifan Sheng; Jiqing Yin; Hong Wang; Shuai Gao; Wenqiang Liu; Shaorong Gao

doi:10.1093/nsr/nwad173

Inhibition of Wnt activity improves peri-implantation development of somatic cell nuclear transfer embryos

Natl Sci Rev. 2023 Aug 16;10(9):nwad173. doi: 10.1093/nsr/nwad173. eCollection 2023 Sep.

Authors

Yanhe Li¹, Caihong Zheng², Yingdong Liu¹, Jincan He¹, Qiang Zhang³, Yalin Zhang¹, Xiaochen Kou¹, Yanhong Zhao¹, Kuisheng Liu¹, Dandan Bai¹, Yanping Jia¹, Xiaoxiao Han¹, Yifan Sheng¹, Jiqing Yin¹, Hong Wang¹, Shuai Gao³, Wenqiang Liu¹, Shaorong Gao¹

Affiliations

¹ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
² CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China.
³ Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.

Abstract

Somatic cell nuclear transfer (SCNT) can reprogram differentiated somatic cells into totipotency. Although pre-implantation development of SCNT embryos has greatly improved, most SCNT blastocysts are still arrested at the peri-implantation stage, and the underlying mechanism remains elusive. Here, we develop a 3D in vitro culture system for SCNT peri-implantation embryos and discover that persistent Wnt signals block the naïve-to-primed pluripotency transition of epiblasts with aberrant H3K27me3 occupancy, which in turn leads to defects in epiblast transformation events and subsequent implantation failure. Strikingly, manipulating Wnt signals can attenuate the pluripotency transition and H3K27me3 deposition defects in epiblasts and achieve up to a 9-fold increase in cloning efficiency. Finally, single-cell RNA-seq analysis reveals that Wnt inhibition markedly enhances the lineage developmental trajectories of SCNT blastocysts during peri-implantation development. Overall, these findings reveal diminished potentials of SCNT blastocysts for lineage specification and validate a critical peri-implantation barrier for SCNT embryos.

Keywords: SCNT; Wnt; epiblast; epigenetic barrier; implantation; naïve pluripotency; primed pluripotency; reprogramming; single-cell RNA-seq.