Capture of Post-Pluripotency Human Neuromesodermal and Neural Tube Axial Stem Cell States

The capture of pluripotent and adult tissue stem cells has transformed biomedicine, yet stable stem cell states between these developmental extremes have remained elusive. Here, we capture two human axial stem cell (AxSC) states corresponding to neuromesodermal and derivative neural tube progenitors. These states maintain telomere length without teratoma formation, and neuromesodermal AxSCs were recaptured from human embryonic tail buds. Mechanistically, genome-wide knockout screening and multiomics analyses revealed capture-associated acquisition of a stemness regulatory network with Trithorax-Polycomb dual functionality. Integration with genome-wide DNA methylation analysis identified a novel HOX timer driven by time-grouped DNA demethylation of target genes. Additionally, stage-specific glycolytic/OXPHOS remodeling in AxSCs was linked to bioenergetic pathways and histone acetylation dynamics. Finally, we captured mouse AxSCs that contribute to chimeras and exhibit an evolutionary divergent neuromesodermal-neural combined state. AxSCs are authentic post pluripotent stem cells for upscalable interrogation of development, with potential for regenerative medicine and drug discovery.