Abstract
High-throughput single-cell methods have uncovered substantial heterogeneity in the pool of hematopoietic stem and progenitor cells (HSPCs), but how much instruction is inherited by offspring from their heterogeneous ancestors remains unanswered. Using a method that enables simultaneous determination of common ancestor, division number, and differentiation status of a large collection of single cells, our data revealed that murine cells that derived from a common ancestor had significant similarities in their division progression and differentiation outcomes. Although each family diversifies, the overall collection of cell types observed is composed of homogeneous families. Heterogeneity between families could be explained, in part, by differences in ancestral expression of cell surface markers. Our analyses demonstrate that fate decisions of cells are largely inherited from ancestor cells, indicating the importance of common ancestor effects. These results may have ramifications for bone marrow transplantation and leukemia, where substantial heterogeneity in HSPC behavior is observed.
Highlights
The hematopoietic system has long since served as a reference model for stem cell biology, with understanding garnered from the study of hematopoietic stem cells (HSCs) successfully transferred to the clinic
Each family diversifies to some extent, the overall collection of cell types observed in a population is largely composed of homogeneous families from heterogeneous ancestors
Defining a family as all descendants from a marked ancestor cell, the experimental method employed here is based on the observation that by labeling cells with distinct combinations of division diluting dyes, such as 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) and CellTrace Violet (CTV), through the use of flow cytometry it is possible to simultaneously determine each cell’s family membership, generation, and phenotype [23, 24] (Figure 1)
Summary
The hematopoietic system has long since served as a reference model for stem cell biology, with understanding garnered from the study of hematopoietic stem cells (HSCs) successfully transferred to the clinic. In order to maintain blood cell production, rare self-renewing HSCs produce differentiated cells called multi-potent progenitors (MPPs), which proliferate and differentiate through an amplifying cascade of increasingly committed progenitors, resulting in all mature blood cell types. Underpinning this traditional model, which was mostly uncovered through murine studies, is the assumption that the HSC pool is maintained through a process of asymmetric division that results in one HSC and one MPP, while MPPs form a transient cell type that cannot persist indefinitely and must differentiate. These findings questioned the necessity for HSCs to undergo asymmetric division, but they queried the explicit link between division and differentiation
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