Towards Understanding Molecular Mechanisms of Human Hematopoietic Stem Cells' Quiescence

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SUMMARY/ABSTRACT Hematopoietic stem cells (HSCs) produce all blood lineages and replenish blood in response to loss or injury throughout life. HSCs like most adult stem cells, are mainly quiescent. Quiescence is proposed to protect HSCs from replicative and metabolic stress that would otherwise impact health and longevity, thereby enabling them to maintain tissue homeostasis and allowing for the repair of defective/damaged tissue during their lifetime. Progress in HSC-based therapies is partly hindered by lack of reliable approaches to modulate HSC quiescence and activity. Thus, understanding the core molecular mechanisms of HSC quiescence is fundamental for improving HSC health and longevity and has major translational implications for the clinic. By applying a new approach based on mitochondrial membrane potential (MMP), we identified the most dormant subsets of both human and mouse HSCs. Using this approach, we recently discovered that lysosomal activity is pivotal for the maintenance of mouse HSC quiescence. Our findings suggest that lysosomes dynamically regulate the hematopoietic stem cell switch between quiescent and active states. Here, we propose to investigate lysosomal function and the effects of modulation of lysosomal activity on the potency of human HSCs. These studies are likely to provide means towards extending the availability of human HSCs. Overall, translation of our findings to human HSCs will build the foundation towards advancing cell therapy.