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Lineage tracing models reveal novel fate determinants for hematopoietic stem and progenitor cells


Hematopoietic stem cells (HSC) must constantly replenish the blood system by making billions of new cells every day. This high demand for new cells has led to a tightly controlled series of intrinsic and extrinsic signals which enable HSC to balance the need for self-renewal and differentiation. The purpose of this thesis is to explore the myriad signals that regulate the choice between differentiation and self-renewal in HSC and their immediate progeny, multipotent progenitors (MPP). First I describe a novel lineage tracing mouse model that streamlines previously complex flow cytometry staining panels into a single color reporter. This model can now be used for microscopy or flow cytometry analyses to interrogate HSC location and their niche in situ. Additionally, I present evidence for the role of the spleen as a microenvironment particularly important for MPP differentiation. Loss of the spleen leads to significantly lowered red blood cell production after transplantation by MPP but not HSC, which indicates that these cell types have different sensitivities to the signals produced there. Finally, I characterized a novel subset of fetal HSC and showed that it is lymphoid biased at a molecular level. This project also generated an RNA sequencing library that can be mined for future characterization of these fetal HSC. Together this work has given us insight into the signals and microenvironments that lead to HSC differentiation in situ, after transplantation, and during fetal development.

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