It has been recently shown that increased oxidative phosphorylation, as reflected by increased mitochondrial activity, together with impairment of the mitochondrial stress response, can severely compromise hematopoietic stem cell (HSC) regeneration. Here we show that the NAD+-boosting agent nicotinamide riboside (NR) reduces mitochondrial activity within HSCs through increased mitochondrial clearance, leading to increased asymmetric HSC divisions. NR dietary supplementation results in a significantly enlarged pool of progenitors, without concurrent HSC exhaustion, improves survival by 80%, and accelerates blood recovery after murine lethal irradiation and limiting-HSC transplantation. In immune-deficient mice, NR increased the production of human leucocytes from hCD34+ progenitors. Our work demonstrates for the first time a positive effect of NAD+-boosting strategies on the most primitive blood stem cells, establishing a link between HSC mitochondrial stress, mitophagy, and stem-cell fate decision, and unveiling the potential of NR to improve recovery of patients suffering from hematological failure including post chemo- and radiotherapy.
Keywords: HSC; UPRmt; aplastic anemia; asymmetric stem cell division; autophagy; bone marrow aplasia; bone marrow failure; bone marrow transplantation; chemotherapy; hematopoietic stem cell; hematopoietic stem cell transplantation; human CD34+ progenitors; immune thrombocytopenia; long-term hematopoietic stem cell; mitochondria; mitochondrial clearance; mitochondrial recycling; mitonuclear protein imbalance; mitophagy; myelodysplasia; myelodysplastic syndrome; radiotherapy; unfolded protein response mitochondria.
Copyright © 2019. Published by Elsevier Inc.