Haematopoietic stem cell fitness mechanisms

Haematopoietic stem cells (HSCs) are important for human health and clinical therapy. A heterogenous pool of HSCs sustain blood production through life by balancing self-renewal and multilineage differentiation. Aging is associated with a decline in the function of the HSC pool and haematopoietic perturbations. Additionally, aging correlates with clonal haematopoiesis, driven by the accumulation of genetic mutations in this long-lived cell population that can lead to altered cell function and ultimately to leukemic transformation. Alongside their natural role in sustaining haematopoiesis, healthy HSCs are also used clinically for their regenerative capacity in stem cell transplantation, where they reconstitute the entire adult blood system and can cure a range of blood disorders. Within these contexts, the term fitness is regularly used but often poorly defined. In this perspective, we summarise two distinct types of HSC fitness, clonal fitness and stem cell fitness. We go on to introduce mechanisms known to shape each and discuss the therapeutic implications for modulating HSC fitness mechanisms. TEASER ABSTRACT: This Perspective discusses two types of hematopoietic stem cell fitness, clonal fitness and stem cell fitness, and summarise mechanisms known to shape each and their therapeutic implications.