Zygotes and early blastomeres possess totipotency, which represents the highest level of developmental potency. While capturing totipotent stem cells in vitro with functionalities comparable to those of totipotent embryos in vivo remains challenging, our lab achieved a breakthrough in 2021 by stably culturing mouse totipotent blastomere-like cells (mTBLC) using splicing inhibition (Shen et al., 2021). Building upon this success, we extended our strategy to successfully culture human totipotent blastomere-like cells (hTBLC) derived from hESCs and iPSCs (Li et al., 2024). In addition, using the mTBLC-based system, we developed an in vitro model simulating early embryonic development, from ZGA to post-implantation stages (Peng et al., 2025).