Gastruloid patterning reflects division of labor among biased stem cell clones

Division of labor, whereby individuals specialize in complementary roles to collectively achieve beneficial outcomes, is a recurring phenomenon in economics, ecology, and microbiology. In development, individual cells specialize, but this specialization is thought to arise from instruction by external signaling cues upon otherwise interchangeable progenitors. It is unclear if progenitors exhibit some degree of specialization, and if so, whether that specialization is optimized for developmental outcomes. Using fluorescence-based lineage tracing in combination with spatial transcriptomics, we show that, in the gastruloid model of early development, individual stem cell clones harbored reproducible spatial propensities for anterior or posterior fates that result in a spontaneous division of labor during axial organization. Gastruloids derived from pure clones generated elongated structures less frequently than a polyclonal population, but mixing clones allowed clones to follow their inherent propensity, restoring proper axial elongation. Spatial transcriptomics reveals that pure clones show disrupted gene expression with inappropriate coexpression of anterior and posterior markers, while clone combinations restore proper spatial organization. We further show that propensities are globally utilized: a clone with a particular propensity can adopt different fates depending on what is more optimal for development as a whole. Perturbations to key developmental signaling pathways disrupted this sorting and profiling revealed molecular characteristics of propensity. Proper developmental outcomes may thus emerge from the coordinated action of intrinsically biased clonal populations.