![]() We identify a HSC source population with high expression of CD201 and Sca-1, from which increasingly committed HSCs emerge. Here, we measure and integrate extensive data on HSC differentiation, proliferation, and molecular heterogeneity, all obtained under physiological conditions, to address these fundamental questions. These questions are intimately linked with another controversy that has arisen in the context of the recent HSC fate mapping studies, suggesting steady but infrequent input from HSCs to hematopoiesis 2, 11, 12 or more active contribution 13, 14, 15. These findings raise the questions of the developmental relationships of distinct HSC and progenitor subpopulations in native hematopoiesis and, importantly, how distinct lineage pathways are regulated under physiological conditions to match the demand in mature cells (Fig. Among them are HSCs producing only megakaryocyte progenitors (MkPs) independent of multipotent progenitors (MPPs) 7, 9, 10. Recent in vivo barcoding studies of HSCs in native hematopoiesis have revealed HSC clones with different lineage output 5, 6, 7, 8, which appear to resemble those seen after HSC transplantation 9, 10. The production rate of mature cells from HSCs is massively enhanced after transplantation compared to physiological conditions 2, 3, and it remains unknown whether lineage differentiation pathways also differ between the two settings 4. In particular, numerous HSC transplantation studies have described, to varying degrees, lineage fate biases of HSCs (reviewed in ref. 1) are a heterogeneous population with regard to proliferative activity, lineage fate and repopulation capacity after transplantation. Immunophenotypic HSCs (lineage – Sca-1 + CD117 + (LSK) CD48 −/lo CD150 + Supplementary Fig. In sum, we provide a blueprint for mapping physiological differentiation fluxes from HSCs and decipher two functionally distinct pathways of native thrombopoiesis. Enhanced thrombopoietin signaling differentially accelerates the short pathway, enabling a rapid response to increasing demand. Thrombopoiesis is the sum of two pathways that make comparable contributions in steady state, a long route via multipotent progenitors and CD48 hi megakaryocyte progenitors (MkPs), and a short route from HSCs to developmentally distinct CD48 −/lo MkPs. Downstream, HSCs either retain high Sca-1 expression and the ability to generate lymphocytes, or irreversibly reduce Sca-1 level and enter into erythro-myelopoiesis or thrombopoiesis. ![]() We find that lineages begin to split when cells leave the tip HSC population, marked by high Sca-1 and CD201 expression. Here, we chart native lineage pathways emanating from HSCs and define their physiological regulation by computationally integrating experimental approaches for fate mapping, mitotic tracking, and single-cell RNA sequencing. Hematopoietic stem cells (HSCs) produce highly diverse cell lineages. ![]()
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