In situ fate mapping identifies the neonatal origin of platelet-biased hematopoietic stem cells [Native Developmental Atlas]

Hematopoietic stem cells (HSCs) display heritable and deterministic gene regulatory states associated with functional heterogeneity. However how these biased fate programs change through development remains poorly understood. Here, using single-cell lineage tracing, we map the function and state of thousands of individual mouse HSCs spanning from the earliest mature fetal stages until young adults. We identify a burst of platelet- and myeloid-biased HSCs during the first postnatal week. Fetal HSCs retain a fetal-like program even after 4 months in the recipient bone marrow, suggesting that the adult HSC program is epigenetically configured early after birth. Creating a single-cell atlas of mouse perinatal HSCs, we identify a transient HSC state with hallmarks of Epithelial-Mesenchymal Transition (EMT), mTOR complex 1 activity, and cholesterol synthesis (SREBP targets). Tracing the rare cells that traverse this transient state, we reveal the neonatal origin of long-term platelet/myeloid-biased HSCs in both native and transplantation hematopoiesis. Transient treatment with mTORC1 inhibitor rapamycin during the first postnatal week suffices to reduce the platelet-biased adult HSC programming, without affecting total HSC numbers. In sum, we reveal a late developmental origin for platelet-biased HSCs, with important implications for hematopoietic aging.