The Evolution of Haematopoietic Models Through a Clonal Lens

Haematopoiesis 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 haematopoietic stem cells (HSCs) commit to specific lineages, is essential to fine tune immune cell production both in vivo and in vitro for cell therapy applications. In this review, we examine the major conceptual frameworks that have been proposed to describe haematopoiesis and the underlying data that informed them, ranging from the classical discrete hierarchy to the continuous model, the punctuated continuum, and the multi-track model. Evidence from clonal lineage-tracing studies in mouse, non-human primates, and humans supports the idea that lineage fate is largely predetermined rather than stochastically acquired, and we highlight the importance of clonal multi-omics approaches for identifying the molecular predictors of fate. We then discuss the computational models that have been developed to study haematopoietic development. Finally, we outline key challenges, including resolving native haematopoiesis 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 haematopoietic process through a clonal lens is paramount to find the molecular signatures that truly can predict fate.