Abstract
Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain homeostasis. With aging, the frequency of polar HSCs decreases. Cell polarity in HSCs is controlled by the activity of the small RhoGTPase cell division control protein 42 (Cdc42). Here we demonstrate—using a comprehensive set of paired daughter cell analyses that include single-cell 3D confocal imaging, single-cell transplants, single-cell RNA-seq, and single-cell transposase-accessible chromatin sequencing (ATAC-seq)—that the outcome of HSC divisions is strongly linked to the polarity status before mitosis, which is in turn determined by the level of the activity Cdc42 in stem cells. Aged apolar HSCs undergo preferentially self-renewing symmetric divisions, resulting in daughter stem cells with reduced regenerative capacity and lymphoid potential, while young polar HSCs undergo preferentially asymmetric divisions. Mathematical modeling in combination with experimental data implies a mechanistic role of the asymmetric sorting of Cdc42 in determining the potential of daughter cells via epigenetic mechanisms. Therefore, molecules that control HSC polarity might serve as modulators of the mode of stem cell division regulating the potential of daughter cells.
Highlights
Hematopoietic homeostasis depends on the ability of hematopoietic stem cells (HSCs) to balance symmetric and asymmetric divisions over an organism’s lifespan
We demonstrate—using a comprehensive set of paired daughter cell analyses that include single-cell 3D confocal imaging, single-cell transplants, single-cell RNA-seq, and single-cell transposase-accessible chromatin sequencing (ATAC-seq)—that the outcome of HSC divisions is strongly linked to the polarity status before mitosis, which is in turn determined by the level of the activity cell division control protein 42 (Cdc42) in stem cells
Aged HSCs displayed a symmetric distribution of both Cdc42 and H4K16ac in daughter cells, and inhibition of Cdc42 activity in aged HSCs increased the frequency of asymmetric divisions among aged HSCs
Summary
Hematopoietic homeostasis depends on the ability of hematopoietic stem cells (HSCs) to balance symmetric and asymmetric divisions over an organism’s lifespan. Asymmetric divisions allow one daughter cell to differentiate while the other retains its stem cell potential. The asymmetric or symmetric distribution of cellular components to daughter cells during mitosis is thought to determine their fate. This concept has been proposed as a way of controlling the size of the HSC pool [9]. The mechanisms that control the mode and outcome of HSC divisions with respect to the potential and function of daughter cells remain incompletely understood
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