ROCK inhibition suppresses host blastomere-mediated elimination and enhances trophoblast stem cell contribution in mouse chimeras

Trophoblast stem cells (TSCs) play a crucial role in modeling the complex dynamics of maternal-fetal morphogenesis and placental development. However, their utility is hindered by low contribution rates in embryonic chimeras. Here, we reveal that during the 8-cell mouse embryo aggregation, host blastomeres selectively eliminate donor TSCs through an actin-dependent, phagocytic-like process and degrade them via lysosomal pathways, acting as a developmental quality-control mechanism. Notably, modulating cytoskeletal dynamics via Rho/ROCK pathway inhibition markedly suppresses this host-mediated clearance, enhancing donor TSC retention and contribution to extraembryonic tissues in pre- and post-implantation chimeras without compromising embryonic viability. Overall, our findings identify host blastomere-mediated elimination as an early barrier to TSC chimerism and establish transient ROCK inhibition as a strategy for improving TSC contribution during placental development.