The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance

Abstract

Graphical AbstractHighlights d Vitamin B3 analogs improve hematopoietic stem cell (HSC) and progenitor function d Nicotinamide riboside (NR) increases mitochondrial recycling in HSCs d In vitro NR exposure induces asymmetric mitochondrial distribution in dividing HSCs d NR dietary supplementation improves survival after HSC transplantation in mice SUMMARYIt 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.

Ca2+-Activated Mitochondrial Biogenesis and Functions Improve Stem Cell Fate in Rg3-Treated Human Mesenchymal Stem Cells

“…Recent advances have shown that adequate mitochondrial function in stem cells is essential to maintain proliferation and differentiation abilities [2,3]. Inhibition of mitochondrial fatty acid oxidation or impaired clearance of dysfunctional mitochondria deteriorates stem cell function and fate [15,16]. Here, we demonstrated that upregulated mitochondrial biogenesis and respiratory capacity by ginsenosides Previous reports on mitochondrial actions of Rg3 or ginseng extracts in myoblast cells are consistent with our ndings in stem cells [14,17].…”

The crosstalk of NAD, ROS and autophagy in cellular health and ageing

“…Additionally, evidence from NAD ? supplementation studies in cell culture and in animal models suggests that boosting NAD levels is sufficient to not only improve mitochondrial function, but also stimulate SIRT-dependent mitochondrial recycling via increased TFEB-and FoxO-dependent expression of autophagy/mitophagy genes and PTMs of autophagy proteins, and thus promote clearance of dysfunctional organelles and protein aggregates (Fang et al 2019(Fang et al , 2016Hou et al 2018;Schöndorf et al 2018;Vannini et al 2019;Zhang et al 2016b). Altogether, this 'silver bullet' approach might serve as an intervention to the vicious cycle of damage and NAD depletion and thus not only combat the depletion itself, but also support resolution of the underlying stresses and promote long-term cellular health.…”

Ca2+-activated mitochondrial biogenesis and functions improve stem cell fate in Rg3-treated human mesenchymal stem cells

“…Recent advances have shown that adequate mitochondrial function in stem cells is essential to maintain proliferation and differentiation abilities [2,3]. Inhibition of mitochondrial fatty acid oxidation or impaired clearance of dysfunctional mitochondria deteriorates stem cell function and fate [15,16]. Here, we demonstrated that upregulated mitochondrial biogenesis and respiratory capacity by ginsenosides Rg3 are related to improved stem cell fates, including increased proliferation, reduced senescence, and facilitated osteogenic differentiation of human BMSCs.…”