UC Santa Cruz

Hematopoiesis is the process through which hematopoietic stem cells (HSCs) produce all mature and immune cells in the blood. This thesis focuses on three aspects of hematopoiesis research: methods for studying hematopoiesis, the effects of environmental exposures of fetal hematopoiesis, and epigenetic changes influencing hematopoiesis during aging.The first part of this thesis delves into the historical and ongoing significance of the spleen colony-forming unit assay, a pioneering in vivo functional assay to elucidate bone marrow cell functions. Then, the focus shifts to overcoming the limitations of traditional host conditioning methods, introducing innovative mouse models for selective ablations of all hematopoietic cells or HSCs specifically. These models offer non-irradiation alternative for studying HSC function, engraftment ability, and differentiation pathways. Together, these chapters contribute to advancing our understanding of HSC identity and functions. The second part of this thesis investigates the impact of environmental toxic compounds on hematopoiesis and immune function. We specifically reviewed the effects of nicotine on HSCs and other blood cells. Then, we investigated the effects of in utero nicotine exposure on the establishment of the hematopoietic system and we determined its long-term consequences. These chapters collectively offer insights into the perturbations of normal hematopoiesis by environmental exposures during development. The last part of this thesis focuses on unraveling the dynamics of HSC differentiation and lineage fate decisions, with an emphasis on platelet differentiation. First, we reviewed evidence suggesting the existence of a non-canonical platelet differentiation pathway from HSCs, predominantly primarily observed during inflammation. Then, we investigated how epigenetic lineage priming drives differentiation of HSCs into the five mature lineages by maintaining chromatin accessibility at lineage-specific regulatory regions. Finally, we investigated how epigenetic priming of the Nuclear Protein 1 (Nupr1) gene in aged HSCs drives non-canonical platelet differentiation, offering a comprehensive understanding of the intricate processes governing aging hematopoiesis. Ultimately, the studies presented here promise advance in our comprehension of hematopoiesis and open avenues for innovative approaches in regenerative medicine and therapeutic interventions.