Human adult hematopoietic stem cells through aging, inflammation and clonal selection

About This Grant

A. Project Summary: Hematopoiesis is the process where a self-renewing, multipotent hematopoietic stem cell (HSC) produces all the differentiated cells in the blood system. Careful regulation of hematopoiesis by HSCs is required to meet the evolving demands of the body throughout life. To maintain lifelong hematopoiesis, HSCs must retain their ability to self-renew, i.e. to divide without differentiating, and their multipotency, which is their ability to differentiate into all blood cells. However, aging HSCs often develop reduced self-renewal capacity and myeloid biased differentiation potential which may lead to immune deficiencies and other blood disorders. Aging HSCs can also acquire mutations, expand, and produce clonally restricted blood cells through a process called clonal hematopoiesis (CH), which has been associated with an increased risk of developing cardiovascular disease and cancer. The clonal HSCs that produce CH (CH-HSCs) are also functionally heterogeneous as individual CH-HSCs have variable impairment in blood cell production. Additionally, emerging evidence has shown that inflammation can further modify HSC and CH-HSC function. Overall, these observations suggest that aging HSCs become increasingly heterogeneous in humans, and the associated impact of this heterogeneity on hematopoiesis is largely unknown. Our understanding of HSC biology has primarily been driven by important observations made in mice. However, it is unclear if aging human adult HSCs mirror the same functional changes as mice. A key limitation in understanding how human adult HSCs maintain homeostatic hematopoiesis is our in-ability to purify and study specific sub-populations within the human HSC pool. This limitation has led to several important questions. For instance, are there myeloid biased HSCs that expand in older humans, and can they be depleted to restore balanced hematopoiesis as observed in mice? How exactly do aging HSCs become clonally restricted and deregulated under the external pressure of inflammation? Do CH- HSCs express unique biomolecular features that distinguish them from healthy HSCs? To address these questions, this proposal will investigate the cellular heterogeneity of aging adult human HSCs with the hypothesis that there are unique features associated with clonal HSC expansion during aging which can be exploited therapeutically. Guided by strong preliminary data and new state-of-the-art single cell methods, the central hypothesis will be tested by pursuing three specific aims. The first aim will investigate human adult HSC heterogeneity through aging. The second aim will investigate how inflammation impairs aging HSC function and whether inhibiting DAPK1 can mitigate these effects. The third aim will study the role of DAPK1 on HSC function and fitness. This contribution will be significant because it will ultimately uncover important information on HSC heterogeneity as it relates to human health and disease and evaluate a novel target for treating hematologic disorders of the elderly. These results can be used to optimize HSC directed translational research, disease monitoring and therapeutic development.