Non -genetic heritability of cell division shapes human hematopoiesis

Cell dynamics need to be controlled to ensure the specification and maintenance of the hematopoietic stem and progenitor compartment (HSPCs). However, the relationship between the defining parameters (division, differentiation, and death) are not totally understood, especially in human. Recent studies showed that cell fate is clonally inherited in mice but whether this is true for division is currently unknown. Here, using a combination of single-cell fate mapping, live cell imaging, and single-cell transcriptomic, we describe the cell division dynamics of normal and pathological human HSPCs. We observe that most progenitors give rise to kinships where cells divide the same number of times, as well as display homogeneity in cell fate. These clonal features of division and differentiation are cell-intrinsic and inherited through multiple generations. We observe conserved transcriptional programs associated with specific fates within cell kinships. Finally, we demonstrate that the clonal division property is disrupted in the context of acute myeloid leukemia: cells from the same kinship divide in a more erratic and discordant way, a property independent of the genetic background. The clonal division property is partially restored by therapeutic agents, suggesting that it may be playing a role in leukemia physiopathology. Together this data demonstrates that differentiation and division are inherited by individual kinship in healthy human hematopoiesis and that these properties are perturbed in human leukemic HSPC. Cell dynamics need to be controlled to ensure the specification and maintenance of the hematopoietic stem and progenitor compartment (HSPCs). However, the relationship between the defining parameters (division, differentiation, and death) are not totally understood, especially in human. Recent studies showed that cell fate is clonally inherited in mice but whether this is true for division is currently unknown. Here, using a combination of single-cell fate mapping, live cell imaging, and single-cell transcriptomic, we describe the cell division dynamics of normal and pathological human HSPCs. We observe that most progenitors give rise to kinships where cells divide the same number of times, as well as display homogeneity in cell fate. These clonal features of division and differentiation are cell-intrinsic and inherited through multiple generations. We observe conserved transcriptional programs associated with specific fates within cell kinships. Finally, we demonstrate that the clonal division property is disrupted in the context of acute myeloid leukemia: cells from the same kinship divide in a more erratic and discordant way, a property independent of the genetic background. The clonal division property is partially restored by therapeutic agents, suggesting that it may be playing a role in leukemia physiopathology. Together this data demonstrates that differentiation and division are inherited by individual kinship in healthy human hematopoiesis and that these properties are perturbed in human leukemic HSPC.