- Sequential TPRX1 then HERVL activation defines ordered trajectory yielding TPRX1+HERVL+ 8CLCs transcriptionally resembling the in vivo 8-cell embryo.
- Single-cell transcriptomics and time-resolved flow cytometry reveal a continuous transition from primed hPSCs through a TPRX1 positive intermediate to HERVL positive 8CLC state.
- CRISPRi and RNA-directed perturbations indicate HERVL elements and HERVL-derived RNA functionally contribute to 8CLC transition; locus-dependent mechanisms remain unresolved.
Cell Rep. 2026 Oct 17;45(11):118163. doi: 10.1016/j.celrep.2026.118163. Online ahead of print.
ABSTRACT
The in vitro induction of 8-cell-like cells (8CLCs) from human pluripotent stem cells (hPSCs) provides a model to study the regulatory principles of totipotency and zygotic genome activation (ZGA). However, the cellular dynamics underlying 8CLC emergence remain poorly understood. Here, we generate a TPRX1-EGFP/HERVL-tdTomato dual-reporter hPSC line to resolve the stepwise acquisition of totipotent-like identity. We show that 8CLC induction follows an ordered trajectory in which TPRX1 activation precedes the emergence of TPRX1+HERVL+ cells, which most closely resemble the in vivo 8-cell embryo transcriptionally. Single-cell transcriptomics and time-resolved flow cytometry further define a continuous transition from the primed state through a TPRX1+ intermediate to the HERVL+ 8CLC state. CRISPRi and RNA-directed perturbations support functional contributions of HERVL elements and HERVL-derived RNA to this transition, while potential locus-dependent mechanisms remain unresolved. Together, these findings establish sequential TPRX1 and HERVL activation as a defining feature of human 8CLC induction.
PMID:42893511 | DOI:10.1016/j.celrep.2026.118163
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