Johan Auwerx, Carlos Canto Alvarez, George Coukos, Bart Deplancke, Martin Ehrbar, Sonja Giger, Mukul Girotra, Vasco Ledebur de Antas de Campos, Matthias Lütolf, Olaia Maria Naveiras Torres-Quiroga, Gennady Nikitin, Aurélien Laurent Jean-Charles Oggier, Eija Riitta Pirinen, Simone Ragusa, Pernille Yde Rainer, Joanna Ratajczak, Shanti Rojas-Sutterlin, Pedro Romero, Dongryeol Ryu, Federico Sizzano, Loïc Tauzin, Vincent Trachsel, Josefine Catharina Pedersen Tratwal, Nicola Vannini, Yannick Lionel Yersin
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.
CELL PRESS2019