Molecular regulation of native hematopoiesis

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SUMMARY Decades of work have established a paradigm for hematopoietic regeneration and maintenance based on the activity of multipotent hematopoietic stem cells (HSCs) at its apex. Our understanding of the fundamental properties of HSCs and progenitor populations has been historically based on notions derived from transplantation assays. Data over the last few years, however, have challenged the most fundamental aspects of models based on these studies, and have raised biological questions that are of direct clinical relevance in the hematology field. Additionally, it is now clear that intrinsic heterogeneity exists among seemingly pure populations of HSCs and downstream progenitors. How the functionally distinct behavior of these stem/progenitor cells is molecularly regulated and how individual clone size is controlled over time represent important biological questions relevant to our understanding of normal and diseased hematopoiesis. Over the past five years, my lab has developed novel single cell-based lineage tracing systems to study hematopoietic biology in the non-transplanted individual, which we refer to as native hematopoiesis. With these tools, we have shown that important biological differences exist between the source of hematopoietic cells and their outcomes when comparing transplantation versus native blood physiology. More recently, we have coupled lineage output readouts with molecular measurements at the single cell level, allowing us to identify transcriptional features of stem/progenitor cells that carry distinct functional outcomes. In this renewal application, we aim to utilize these high-resolution lineage-tracing tools to further characterize drivers of functional HSC heterogeneity and aging in native hematopoiesis. First, we will functionally and molecularly characterize a novel transcriptional regulator of the native HSC state, which we have identified using our singe cell screens. Second, we will utilize a combination of single cell lineage tracing, transcriptomics, and epigenomics to understand the molecular changes and clonal fluctuations that occur during the aging process in the mouse. Third, we will adapt our single cell molecular tracing strategies to characterize human hematopoiesis in a surrogate native state, and to identify potential novel regulators of human HSC behavior. Our comprehensive and interdisciplinary studies will shed led on the cellular and molecular mechanisms driving hematopoiesis in situ. Moreover, these studies will inform efforts to enhance hematopoietic regeneration and prevent pre-malignant clonal hematopoiesis.