The evolution of hematopoietic models through a clonal lens

Hematopoiesis is a tightly regulated process through which a small pool of stem cells sustains the lifelong production of all blood cell types in response to physiological demand. Understanding how this process is controlled and how hematopoietic stem cells commit to specific lineages is essential to understand blood and immune health and to treat their disorders. In this review, we examine the major conceptual frameworks that have been proposed to describe hematopoiesis and the underlying data that informed them, ranging from the classical discrete hierarchy to the continuous model, the punctuated continuum, and the multitrack model. Evidence from clonal lineage-tracing studies in mouse, nonhuman primates, and humans supports the idea that lineage fate is largely predetermined rather than stochastically acquired, and we highlight the importance of clonal multiomics approaches for identifying the molecular predictors of fate. We then discuss the computational models that have been developed to study hematopoietic development. Finally, we outline key challenges, including resolving native hematopoiesis in vivo, in both mouse and humans, and identifying the molecular programs that encode fate trajectories and how they are altered in disease. Looking at the hematopoietic process through a clonal lens is paramount to find the molecular signatures that truly can predict fate.