The endo-lysosomal system drives lumen formation in a human epiblast model

Epiblast lumen formation is a critical step that occurs during human embryo implantation. It begins with the apicosome, an apical compartment partly derived from endocytosed material. However, how the endo-lysosomal system contributes to apicosome formation and later lumen development remains unclear. Using a human pluripotent stem cell-derived model of epiblast formation, we show that apicosome formation is accompanied by transient expansion of early endosomes, late endosomes, and lysosomes, as well as the formation of hybrid compartments with features of both early and late endo-lysosomal stages. These changes depend on the RAB GTPases RAB35 and RAB7, which are required for proper apicosome formation and lumen morphology of the human epiblast model. Our findings identify RAB35- and RAB7-dependent endo-lysosomal remodeling as a key mechanism driving apical membrane morphogenesis during human epiblast development. Rengarajan et al. identify RAB35- and RAB7-regulated endo-lysosomal dynamics as important drivers of the formation of the apicosome and lumen formation in a model of human epiblast formation. This study presents new insights into peri-implantation human embryo morphogenesis.