Session: 501. Hematopoietic Stem and Progenitor Biology: Poster III
Hematology Disease Topics & Pathways:
HSCs, Biological Processes, Cell Lineage, hematopoiesis
To test this hypothesis, we comprehensively profiled human HSPC cell states from human fetal hematopoiesis through adulthood using single cell RNA sequencing (scRNAseq). We obtained CD34+ HSPCs from 14 different human donors covering a range of ages from first and second trimester fetal liver, umbilical cord blood, and pediatric and adult bone marrow. We obtained high quality sequencing data on a total of 38,873 individual HSPCs after filtering out apoptotic cells, hepatocytes, stromal cells, and endothelial cells. We then identified differentially expressed genes and performed dimensionality reduction and uniform manifold approximation and projection followed by Louvain clustering to identify 32 distinct cell types encompassing primitive stem and multipotent progenitor cells as well as committed progenitors in the myeloid, erythroid and lymphoid lineages. We found age-specific alterations in hematopoietic differentiation trajectories, particularly in the myeloid lineages. Additionally, we discovered an HSC, emerging in mid-gestation and diminishing at birth, with a characteristic immunophenotype and megakaryocyte (Meg) differentiation bias. Differential gene expression analysis of the Meg-biased fetal HSC identified increased expression of the MYB transcription factor relative to other HSCs, potentially illuminating a mechanistic role for MYB in driving megakaryocyte-erythroid progenitor (MEP) differentiation of fetal HSCs, that is distinct from the role of MYB in conferring erythroid differentiation bias at the MEP stage itself. Finally, we used this atlas of human developmental hematopoiesis to map lineage commitment and progenitor states in leukemia, highlighting the translational applicability of this resource.
In summary, we have compiled the first comprehensive atlas of HSPCs across human development and aging. This resource allowed us to identify age-specific differentiation trajectories in human hematopoiesis and enabled identification of a Meg-biased fetal-specific HSC. Our research reveals novel mechanisms of maturation and aging of the human hematopoietic system, uncovers transient HSPC states and differentiation trajectories, and establishes a framework for interrogating the differentiation and maturation states of human leukemias that can likely be applied to other blood diseases. As a resource, we expect that this atlas will broadly impact the study of human hematopoietic development and aging, developmental immunology, and the pathophysiology of age-biased blood diseases.
Disclosures: No relevant conflicts of interest to declare.
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