S136 REPROGRAMMING HEMATOPOIETIC STEM CELL FUNCTION VIA MODULATION OF MITOCHONDRIAL ACTIVITY

Abstract

Background:Hematopoietic stem cells (HSCs) are a small group of cells that ensure a steady production of all mature blood cells throughout an organism's lifetime. HSCs mediate this process by giving rise to progenitors that in turn produce terminally differentiated mature blood cell lineages via several rounds of cell division and well‐orchestrated differentiation steps. Cellular metabolism has emerged as a crucial regulator guiding this complex process. Especially, HSCs differ from their committed progeny by relying primarily on anaerobic glycolysis rather than mitochondrial oxidative phosphorylation for energy production. This distinct metabolic state protects the HSCs from cellular damage inflicted by reactive oxygen species (ROS) in active mitochondria. However, whether this change in the metabolic program is the cause or a consequence of the unique function of HSCs remains unknown.Aims:Having previously shown that mitochondrial activity can be used as a reliable readout for HSC fate, here we asked if modulation of mitochondrial activity results in enhancement of HSC function.Methods:We used in vitro mitochondrial activity and in vivo long‐term blood reconstitution assays as readouts of murine and human HSC functionality.Results:We previously demonstrated that modulation of mitochondrial metabolism in murine and human HSCs, by chemical uncouplers of the electron transport chain or via NAD+ boosting agent Nicotinamide Riboside (NR), results in better long‐term blood production in serially transplanted mice (Vannini N∗, Girotra M∗. et al., Nature Communication 2016 and, Vannini et al., Cell Stem Cell, in press). Here we proceeded to carry out a screen, using mitochondrial activity as readout, to identify metabolic modulators that enhance HSC function. We found two novel candidates, a natural compound and a vitamin precursor, that modulate mitochondrial activity in both mouse and human HSCs, and resulted in enhanced HSC function post bone‐marrow transplantation. Interestingly, we found that these candidates mediate their effects partially by inducing mitophagy, supporting recent studies highlighting the role of mitophagy as a key driver of HSC function. Moreover, our preliminary analysis reveals that they mediate similar effects in aged human HSCs, making them ideal candidates to revert age‐associated myeloid bias in human patients.Summary/Conclusion:Our data establishes a causal relationship between mitochondrial metabolism and HSC function via mitophagy. It also provides a valuable tool to identify optimal ex vivo conditions for HSC expansion, to improve the outcome for patients suffering from bone marrow insufficiency and to restore the functionality of the immune system in aged individuals.