The role of mitochondria in hematopoietic stem cell self-renewal

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Abstract Hematopoietic stem cells (HSC) sustain the production of all blood and immune cells throughout life by differentiating into all blood lineages and regenerate long-lived HSC, ie self-renew. However, although HSC have high regenerative potential, the actual capacity of ‘self-renewal’, ie regenerating a daughter cell that has identical properties’ is limited. It is known that HSC progressively lose regenerative potential with divisional history. A clear understanding of the mechanism responsible for HSC functional decline under homeostatic conditions is still lacking. This lack of knowledge has hampered our ability to maintain HSC functions through divisions. The overall goal of this grant application is to understand which physiological mechanisms get triggered in HSCs with replication, which reduce the activity of the HSC pool. We have discovered that once HSCs get activated, mitochondria irreversibly remodel and do not return to homeostatic conditions. HSCs accumulate dysfunctional mitochondria due to a progressive decline in mitochondrial quality control mechanisms, including reduced mitochondrial turnover and dynamism such that HSCs carry mitochondria have that are different in shape and functions. Mechanistically, HSC lose mitochondrial fission activity [ie, loss of the fission regulator Drp1 activity], which causes a decrease in HSC regenerative potential. We hypothesize that HSC mitochondrial remodeling drives HSC functional decline under homeostatic conditions. The main objectives of this proposal are to understand the contribution and mechanisms of how changes in the quality of mitochondria determine HSC functions. Aim1 will further investigate how a change in mitochondrial dynamism and turnover alter HSC functions. We will examine mitochondria remodeling with HSC replication and the impact it has on HSC functions; mechanistically determine which molecular pathways drive mitochondrial defects and HSC attrition; determine the role of mitochondria in human HSC in physiologically relevant models. Aim2 will investigate mechanisms responsible for the loss of mitochondrial quality controls in HSCs with a focus on cardiolipin. We will examine the role of cardiolipin as causal factor of mitochondrial dysfunctions in HSCs. We will test therapeutic potentials for lipid supplementation in ameliorating HSC functions in vivo. The proposed studies provide a unique opportunity to examine the specific contribution of abnormal mitochondrial functions to HSC functional decline with divisions under homeostatic conditions. It will investigate the novel concept that HSCs accumulate dysfunctional mitochondria to drive their functional decline under homeostatic conditions, perhaps as a mean of HSC internal biological clock, which may lead to the identification of novel approaches for pharmacological intervention to maintain HSC functions through divisions.