UC Irvine

The question of the developmental origins of hematopoietic stem cells (HSCs) is an actively investigated topic in the hematopoiesis field. It is an important subject to address because of its potential impact on identifying and treating the root cause of hematopoietic disorders and diseases. It had been found that LYVE1, which is most commonly known as a lymphatic vessel marker, identifies a population of blood vessel endothelial cells in the embryo and hematopoietic cells in the adult mouse (Pham et al. 2010). Over the course of my dissertation research, we sought to determine the contribution of LYVE1-derived cells to the adult (definitive) HSC population. We utilized a lineage tracing system and identified that LYVE1 marks definitive hemogenic endothelium— a subset of endothelial cells that gives rise to hematopoietic cells early in development— in the yolk sac and the AGM. We found that these LYVE1-derived pre-HSCs take longer to mature than their non-LYVE1-derived counterparts and need to receive maturation signals from the intra-embryonic environment in order to become fully functional. These LYVE1-derived cells persist to adulthood and contribute to approximately a third of the adult murine HSC pool. During the course of these studies, we also found the importance of utilizing different reporter systems in order to validate the phenotypes identified using Cre-Lox recombination systems. Overall, the findings in these studies indicate that there are multiple pools of HSCs (Lyve1-derived and not) and that each pool has a unique origin. The heterogeneity of the HSC pool should be considered when differentiating these cells from iPSCs for both research and clinical translational purposes. It should also be something that is considered during the treatment of different hematopoietic disorders, as there may be a healthy and diseased pool of HSCs that corresponds with their developmental origins.