Laboratory of Regenerative Hematopoiesis, Swiss Institute for Experimental Cancer Research (ISREC) & Institute of Bioengineering (IBI), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland.
Laboratory of Regenerative Hematopoiesis, Swiss Institute for Experimental Cancer Research (ISREC) & Institute of Bioengineering (IBI), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Cell Stem Cell. 2019 Mar 7;24(3):405-418.e7. doi: 10.1016/j.stem.2019.02.012.
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.
最近有研究表明，增加氧化磷酸化（反映为线粒体活性增加），同时损害线粒体应激反应，会严重损害造血干细胞（HSC）的再生。在这里，我们表明，NAD 增强剂烟酰胺核糖（NR）通过增加线粒体清除来降低 HSCs 内的线粒体活性，导致不对称 HSC 分裂增加。NR 的饮食补充会导致祖细胞的数量显著增加，而不会同时耗尽 HSC，从而将存活率提高 80%，并加速小鼠致死性辐射和限制 HSC 移植后的血液恢复。在免疫缺陷小鼠中，NR 增加了来自 hCD34+祖细胞的人类白细胞的产生。我们的工作首次证明了 NAD 增强策略对最原始的血液干细胞有积极影响，建立了 HSC 线粒体应激、线粒体自噬和干细胞命运决定之间的联系，并揭示了 NR 改善包括化疗和放疗后血液衰竭患者恢复的潜力。
