Spatiotemporal and genetic cell lineage tracing of endodermal organogenesis at single-cell resolution [Smart-seq3-RNA-seq-add]

During early mammalian development, the endoderm layer undergoes complex patterning to form the foundations of the respiratory and digestive systems. This intricate process, guided by a series of cell fate decisions, remains only partially understood. Our research introduces a pioneering genetic tracing code across 14 distinct endodermal regions by developing a group of mouse strains. By integrating high-throughput and high-precision single-cell RNA sequencing with sophisticated imaging techniques across various mouse models, we comprehensively resolve the spatiotemporal and genetic lineage differentiation processes of the endoderm at a single-cell resolution. Our findings reveal a previously unrecognized multipotentiality within early endodermal regions for differentiation into diverse organ primordia. Furthermore, this research illuminates the complex and underestimated phenomenon of multiple origins in the development of endodermal organs, prompting a reevaluation of differentiation models for these organs. This work not only advances our understanding of developmental biology, but also has significant implications for regenerative medicine and the development of organoid models, providing new insights into the intricate mechanisms that guide organogenesis.