UC Santa Cruz

Hematopoiesis is the process by which all blood and immune cells are generated by hematopoietic stem cells (HSCs). As stem cells, HSCs can both self-renew and differentiate, and it is this regenerative capacity that is harnessed in the clinic to treat a multitude of hematologic malignancies. However, HSC reconstitution capacity is dynamic throughout life, specifically with regards to tissue-resident immune cells. Unlike circulating immune cells that are continuously generated from HSCs, many tissue-resident immune cells are of fetal origin and poorly generated from adult HSCs. Therefore, to improve the clinical utility of HSCs, it is essential to understand how tissue-resident immune cells are generated. Using lineage tracing, gene knock-out models and transplantation assays, we assessed the roles of Flk2 and IL7Rα in HSC tissue-resident immune cell reconstitution capacity. These studies uncovered an essential role of IL7Rα in tissue-resident lymphoid (TLC) development and generation and a more specific, temporal role in tissue-resident macrophage (TrMac) development. To further understand the epigenetic underpinnings of HSC regenerative capacity, we assessed chromatin accessibility in HSCs throughout life and discovered unique chromatin architecture that dictates age-specific functional differences. Together, this body of work identifies both cellular and molecular mechanisms of HSC reconstitution potential that may be targeted to ultimately improve HSC-based therapies.