The NAD-booster nicotinamide riboside potently stimulates hematopoiesis through increased mitochondrial clearance

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, establishes a novel link between HSC mitochondrial stress, mitophagy and stem cell fate decision, and unveils the potential of NR to improve recovery of patients suffering from hematological failure including post-chemo/radiotherapy.

近期研究表明，线粒体活性升高所反映的氧化磷酸化增强，加之线粒体应激反应受损，会严重损害造血干细胞（hematopoietic stem cell, HSC）的再生能力。本研究发现，提升烟酰胺腺嘌呤二核苷酸（NAD+）水平的试剂烟酰胺核糖（Nicotinamide Riboside, NR）可通过增强线粒体清除，降低造血干细胞内的线粒体活性，进而促进造血干细胞的不对称分裂。对小鼠进行NR膳食补充后，其祖细胞池显著扩大且未伴随造血干细胞耗竭，同时可使小鼠在致死性辐射与限制性造血干细胞移植后的存活率提升80%，并加速血液系统恢复。在免疫缺陷小鼠模型中，NR可促进hCD34+祖细胞生成人类白细胞。本研究首次证实了提升NAD+水平的策略对最原始的血液干细胞具有积极作用，建立了造血干细胞线粒体应激、线粒体自噬与干细胞命运决定之间的全新关联，并揭示了NR可用于改善包括放化疗后血液系统衰竭在内的各类血液疾病患者的机体恢复潜力。