Stem Cell-Niche Interactions in the Establishment of Hematopoietic Stem Cell Heterogeneity

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ABSTRACT Within the blood there is abundant diversity among hematopoietic stem cells (HSCs) in lineage contribution, proliferation, stimuli response, and surface markers. While HSC heterogeneity has been observed during embryonic development, it is unclear how it is generated. My goal is to understand how clonal diversity in HSCs is specified. Hematopoietic stem and progenitor cells (HSPCs) form from budding endothelial cells in the aorta-gonad-mesonephros (AGM), and temporarily colonize the fetal liver in mammals or the caudal hematopoietic tissue (CHT) in zebrafish, before homing to the adult niche in bone or kidney marrow, respectively. HSC subtype behaviors can be found as early as fetal-liver stage and are remarkably stable, with lineage-biases maintained even after serial transplantation. This is suggestive of a model in which early events in development establish intrinsic clonal behavior in HSCs that persists throughout the life of the animal. I hypothesize that signals in the AGM and CHT establish long-lasting clonal differences in emerging and nascent HSCs. This project aims to define the role of embryonic microenvironments in establishing HSC clonal lineage skews and to investigate candidate cellular and genetic effectors of HSC clonal behavior. To accomplish this, I have established a novel method for rapid enrichment of rare embryonic cells, a technical hurdle that has previously hindered efforts to measure these rare developmental events in a high-throughput manner. Experiments outlined in Aim 1 will 1) identify transcriptional diversity in nascent HSPCs to determine when subtypes are established in stem cell induction and 2) test candidate pathways implicated in establishing HSC subtypes. Aim 2 will specifically interrogate the role of primitive macrophages in regulating the nascent HSC pool by identifying and perturbing molecular changes induced after cell-cell interactions in the CHT.