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Cited by 22Sirtuins and Resveratrol in MedicineHematopoietic Stem Cell TransplantationBiochemical and Molecular Research

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NAD+ augmentation with nicotinamide riboside improves lymphoid potential of Atm−/− and old mice HSCs

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Zong, Le, Tanaka-Yano, Mayuri, Park, Bongsoo, Yanai, Hagai, Turhan, Ferda T., Croteau, Deborah L., Tian, Jane, Fang, Evandro F., Bohr, Vilhelm A., Beerman, Isabel·2021·npj Aging and Mechanisms of Disease
DOI 10.1038/s41514-021-00078-3PMC PMC8455618
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Abstract

NAD + supplementation has significant benefits in compromised settings, acting largely through improved mitochondrial function and DNA repair. Elevating NAD + to physiological levels has been shown to improve the function of some adult stem cells, with implications that these changes will lead to sustained improvement of the tissue or system. Here, we examined the effect of elevating NAD + levels in models with reduced hematopoietic stem cell (HSC) potential, ATM-deficient and aged WT mice, and showed that supplementation of nicotinamide riboside (NR), a NAD + precursor, improved lymphoid lineage potential during supplementation. In aged mice, this improved lymphoid potential was maintained in competitive transplants and was associated with transcriptional repression of myeloid gene signatures in stem and lineage-committed progenitor cells after NR treatment. However, the altered transcriptional priming of the stem cells toward lymphoid lineages was not sustained in the aged mice after NR removal. These data characterize significant alterations to the lineage potential of functionally compromised HSCs after short-term exposure to NR treatment.

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Crossref · 10.1038/s41514-021-00078-3

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Figures

Fig. 1 NR treatment increases lymphoid-progenitor cell frequencies in Atm−/− bone marrow. a–c Frequency analysis of early progenitor compartments in NR-treated (NR) or untreated bone marrow from Atm+/+ (WT) or Atm−/− (ATM) mice (2–3 months). CLP common lymphoid progenitors (Lin−IL-7Rα+Flk2+), LSK lineage−Sca1+c-Kit+, HSC Lin−c-Kit+Sca1−CD34−Flk2−. d Composition of the LSK compartment. e Frequencies of lineage-biased subsets of HSCs defined by Slamf1(CD150) expression. Data are represented as mean ± SEM. n: 4–6. Kruskal–Wallis test for a–c, two-way ANOVA for d and e. q value (Kruskal–Wallis test) or p value (two-way ANOVA): <0.05*, <0.01**, <0.001***.
Fig. 1 NR treatment increases lymphoid-progenitor cell frequencies in Atm−/− bone marrow. a–c Frequency analysis of early progenitor compartments in NR-treated (NR) or untreated bone marrow from Atm+/+ (WT) or Atm−/− (ATM) mice (2–3 months). CLP common lymphoid progenitors (Lin−IL-7Rα+Flk2+), LSK lineage−Sca1+c-Kit+, HSC Lin−c-Kit+Sca1−CD34−Flk2−. d Composition of the LSK compartment. e Frequencies of lineage-biased subsets of HSCs defined by Slamf1(CD150) expression. Data are represented as mean ± SEM. n: 4–6. Kruskal–Wallis test for a–c, two-way ANOVA for d and e. q value (Kruskal–Wallis test) or p value (two-way ANOVA): <0.05*, <0.01**, <0.001***.CC BY · PubMed Central
Fig. 2 NR treatment improves the lymphoid potential of HSCs from aged mice. a, b Frequency analysis of early progenitor compartments in NR-treated (NR) or untreated bone marrow from young (Y-WT, 3–4 months) or aged (O-WT, 24–29 months) mice (n = 4–10). c Peripheral blood chimerism generated from 200 purified HSCs against 2 × 105 competitor cells every 4 weeks for 4 months (n = 10). d Lineage composition of donor derived peripheral blood 4 months post transplant (n = 10). Data are represented as mean ± SEM. Kruskal–Wallis test for a and b, two-way ANOVA for c and d: <0.05*, <0.01**, <0.001***.
Fig. 2 NR treatment improves the lymphoid potential of HSCs from aged mice. a, b Frequency analysis of early progenitor compartments in NR-treated (NR) or untreated bone marrow from young (Y-WT, 3–4 months) or aged (O-WT, 24–29 months) mice (n = 4–10). c Peripheral blood chimerism generated from 200 purified HSCs against 2 × 105 competitor cells every 4 weeks for 4 months (n = 10). d Lineage composition of donor derived peripheral blood 4 months post transplant (n = 10). Data are represented as mean ± SEM. Kruskal–Wallis test for a and b, two-way ANOVA for c and d: <0.05*, <0.01**, <0.001***.CC BY · PubMed Central
Fig. 3 NR treatment reduces inflammation in old WT mice. a Complete blood cell count data from four experimental groups shows differences in neutrophils (n = 4–17). b Composition of Mac1+ cells from peripheral blood (n = 4–17). c Serum cytokine levels from young, old, and NR-treated old mice were evaluated with LEGENDplexTM mouse inflammation panel (n = 6–7). d B220+ cells derived ex vivo from HSCs and CLPs. Data are represented as mean ± SEM. Kruskal–Wallis test for a, c, and d, two-way ANOVA for b. q value (Kruskal–Wallis test) or p value (two-way ANOVA): <0.05*, <0.01**, <0.001***.
Fig. 3 NR treatment reduces inflammation in old WT mice. a Complete blood cell count data from four experimental groups shows differences in neutrophils (n = 4–17). b Composition of Mac1+ cells from peripheral blood (n = 4–17). c Serum cytokine levels from young, old, and NR-treated old mice were evaluated with LEGENDplexTM mouse inflammation panel (n = 6–7). d B220+ cells derived ex vivo from HSCs and CLPs. Data are represented as mean ± SEM. Kruskal–Wallis test for a, c, and d, two-way ANOVA for b. q value (Kruskal–Wallis test) or p value (two-way ANOVA): <0.05*, <0.01**, <0.001***.CC BY · PubMed Central
Fig. 4 NR supplementation leads to transcriptional alteration in aged HSCs, CLPs, and GMPs. a PCA analysis of total RNA-seq transcripts from old WT and NR-treated HSCs (Blue), CLPs (Green), and GMPs (Red). b Heatmap analysis of differentially expressed genes in HSCs, CLPs, and GMPs (O-WT vs O-NR) determined using the following thresholds: expression levels CPM > 3, and p value < 0.01. c Normalized enrichment scores (NES) for gene sets comparing NR and untreated cells. d Quantification of ΔΨm in aged bone marrow populations after NR (with verapamil). e Gene set enrichment analysis (GSEA) for genes belonging GSE37301_CLP_VS_GMP_Down show decreased expression after NR supplementation in all HSC, CLP, and GMP populations.
Fig. 4 NR supplementation leads to transcriptional alteration in aged HSCs, CLPs, and GMPs. a PCA analysis of total RNA-seq transcripts from old WT and NR-treated HSCs (Blue), CLPs (Green), and GMPs (Red). b Heatmap analysis of differentially expressed genes in HSCs, CLPs, and GMPs (O-WT vs O-NR) determined using the following thresholds: expression levels CPM > 3, and p value < 0.01. c Normalized enrichment scores (NES) for gene sets comparing NR and untreated cells. d Quantification of ΔΨm in aged bone marrow populations after NR (with verapamil). e Gene set enrichment analysis (GSEA) for genes belonging GSE37301_CLP_VS_GMP_Down show decreased expression after NR supplementation in all HSC, CLP, and GMP populations.CC BY · PubMed Central
Fig. 5 NR supplementation effects are not sustained upon NR removal. a, b Frequency analysis of early progenitor compartments in old mice after recovery (NR-RC: 2 months of supplement withdrawal) compared to O-WT and O-NR (n = 3–10). c Composition of Mac1+ cells from peripheral blood (n = 3–17). d PCA analysis of total RNA-seq transcripts from old WT (Blue) and old NR-treated HSCs (Green), and old NR-RC HSCs (Orange). e Heatmap analysis of differentially expressed genes in O-NR and after recovery (ONRRC) determined using the following thresholds: expression levels CPM > 3, and p value < 0.01. f Normalized enrichment scores (NES) for gene sets comparing old-WT, old-NR, and old-NRRC HSCs. g CellRadar plot indicating the lineage potential derived from transcriptional changes between old WT and old NR (left: enriched in NR, green/depleted in NR, blue) and between old NR and old-NRRC (right: enriched after NR removal, orange/depleted after NR removal, green). Data are represented as mean ± SEM. Kruskal–Wallis test for a and b, two-way ANOVA for c. q value (Kruskal–Wallis test) or p value (two-way ANOVA): <0.05*, <0.01**, <0.001***.
Fig. 5 NR supplementation effects are not sustained upon NR removal. a, b Frequency analysis of early progenitor compartments in old mice after recovery (NR-RC: 2 months of supplement withdrawal) compared to O-WT and O-NR (n = 3–10). c Composition of Mac1+ cells from peripheral blood (n = 3–17). d PCA analysis of total RNA-seq transcripts from old WT (Blue) and old NR-treated HSCs (Green), and old NR-RC HSCs (Orange). e Heatmap analysis of differentially expressed genes in O-NR and after recovery (ONRRC) determined using the following thresholds: expression levels CPM > 3, and p value < 0.01. f Normalized enrichment scores (NES) for gene sets comparing old-WT, old-NR, and old-NRRC HSCs. g CellRadar plot indicating the lineage potential derived from transcriptional changes between old WT and old NR (left: enriched in NR, green/depleted in NR, blue) and between old NR and old-NRRC (right: enriched after NR removal, orange/depleted after NR removal, green). Data are represented as mean ± SEM. Kruskal–Wallis test for a and b, two-way ANOVA for c. q value (Kruskal–Wallis test) or p value (two-way ANOVA): <0.05*, <0.01**, <0.001***.CC BY · PubMed Central

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Metadata

Authors
Zong, L., Tanaka-Yano, M., Park, B., Yanai, H., Turhan, F. T., Croteau, D. L., Tian, J., Fang, E. F., Bohr, V. A., & Beerman, I.
Affiliations
National Institutes of Health (US)
Corresponding author
Beerman, Isabel
ORCID
Venue
npj Aging and Mechanisms of Disease
Publisher
Springer Science and Business Media LLC
Published
2021-09-21
Volume
7
Issue
1
Pages
25-25
ISSN
2056-3973 (ISSN-L)
DOI
10.1038/s41514-021-00078-3
PMC
PMC8455618
OpenAlex
W3199551479
Cited by
22
References
48
Citations by year
2026: 3 · 2025: 6 · 2024: 1 · 2023: 6 · 2022: 4 · 2021: 2
FWCI
1.79
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Aging and Mechanisms of Disease (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
Funders
  • U.S. Department of Health and Human Services (AG000992)
  • National Natural Science Foundation of China (#81971327)
  • Norges Forskningsråd (#262175)
  • National Institutes of Health
  • Japan Society for the Promotion of Science
  • National Institute on Aging (ZIAAG000992)
Topics
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords
NAD+ supplementation, nicotinamide riboside, hematopoietic stem cells, ATM deficiency, aging, competitive transplantation, DNA repair, mitochondrial function

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