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An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging

Nature Aging (2024)Cite this article

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Abstract

How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.

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Fig. 1: CD38 is required to support HSC proliferation at young age.
Fig. 2: CD38 regulates Ca2+ signaling and mitochondrial activity on HSC proliferation.
Fig. 3: CD38 inactivation prevents HSC aging.
Fig. 4: 78c treatment reverses HSC aging.

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Data availability

Sequencing data are deposited to the Gene Expression Omnibus under accession no. GSE268310. All data supporting the findings are available from the corresponding author. Source data are provided with this paper.

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Acknowledgements

This study was supported by National Institutes of Health grant nos. R01AG082105, R01DK 117481, R01AG063404 and R01AG 063389 to D.C., no. R01 AA029124 to C.J., nos. R01 AG26094, R01 AG58812 and R01 CA233790 to E.N.C.; the Glenn Foundation for Medical Research via the Paul F. Glenn Laboratories for the Biology of Aging at the Mayo Clinic (E.N.C.); the National Institute of Food and Agriculture to D.C.; the Dr. and Mrs. James C.Y. Soong Fellowship (W.-C.M.); the Taiwan Government for Study Abroad Scholarship (W.-C.M.); the QB3 Frontiers in Medical Research Fellowship (W.-C.M.); the ITO Scholarship (A.M.); and the JASSO Graduate Scholarship for Degree Seeking Students (A.M.).

Author information

Authors and Affiliations

  1. Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA

    Zehan Song, Wei-Chieh Mu, Yufan Feng, Chih-Ling Wang, Yifei Wang, Marine Barthez, Ayane Maruichi, Jiayue Guo, Fanghan Yang & Danica Chen

  2. Metabolic Biology Graduate Program, University of California, Berkeley, CA, USA

    Zehan Song, Yifei Wang & Danica Chen

  3. Department of Biological Chemistry, University of California, Irvine, CA, USA

    Sang Hee Park & Cholsoon Jang

  4. Endocrinology Graduate Program, University of California, Berkeley, CA, USA

    Wei-Chieh Mu, Ayane Maruichi, Fanghan Yang & Danica Chen

  5. Cancer Research Laboratory, University of California, Berkeley, CA, USA

    Anita Wong Lin & Kartoosh Heydari

  6. Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Jacksonville, FL, USA

    Claudia C. S. Chini & Eduardo N. Chini

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Contributions

D.C. conceived the study. Z.S., Y.F., C.-L.W., Y.W., M.B., A.M., J.G. and F.Y. characterized the CD38 KO mice, CD38-overexpressing mice, CD38hi versus CD38lo HSC comparison, and young and old HSC comparison. S.H.P. and C.J. performed the metabolomics studies. W.-C.M. and Z.S. characterized the MCU KO mice. A.W.L. and K.H. assisted with cell sorting. C.C.S.C. and E.N.C. provided the CD38 KO mice and advised on CD38. D.C. wrote the manuscript with contributions from all authors.

Corresponding author

Correspondence to Danica Chen.

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Competing interests

E.N.C. holds a patent on the use of CD38 inhibitors for metabolic diseases that is licensed by Elysium Health. E.N.C. is a consultant for TeneoBio, Calico, Mitobridge and Cytokinetics. E.N.C. is on the advisory board of Eolo Pharma. E.N.C. owns stocks in TeneoBio. Research in the Chini laboratory has been conducted in compliance with the Mayo Clinic conflict of interest policies. The other authors declare no competing interests.

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Nature Aging thanks Nicola Vannini and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 CD38 is not required for HSC maintenance under homeostatic condition at young age.

a-i. Comparison of 3-month-old WT and CD38 KO mice. A. Gating strategy for HSCs. Enriched HSCs: Lin−c-Kit+Sca1+. Highly enriched HSCs: Lin−c-Kit+Sca1+CD150+CD48−. B, C. The number of enriched (p = 0.4210) (B) and highly enriched (p = 0.4955) (C) HSCs in the bone marrow were analyzed via flow cytometry. n = 6. D, E. Ki-67 (p = 0.2928) (D) and 7-AAD (p = 0.2349) (E) staining of HSCs were analyzed via flow cytometry. n = 6. F. Lineage differentiation in the peripheral blood was analyzed via flow cytometry. MNCs, mononuclear cells (p = 0.4013). n = 5 and 6. G, H. Complete blood count analyses (G, p = 0.4174; H, p = 0.1768). n = 6. I. Bone marrow cellularity normalized by body weight (p = 0.0718). n = 6 and 5. Data are presented as mean values +/- SE. ns: p > 0.05. One-sided student’s t test.

Source data

Extended Data Fig. 2 CD38 regulates Ca2+ signaling and mitochondrial activity upon HSC proliferation.

a. HSCs isolated from 3-month-old WT and CD38 KO mice were cultured in the presence of PVA for 7 days. Total cell number was counted by hemocytometer (p = 0.0026). n = 9. b. Flow cytometry analyses of Ki-67 staining of HSCs isolated from 3-month-old WT and CD38 KO mice 16 hours post pIpC treatment (p = 0.0229). n = 6. c. HSCs isolated from 3-month-old CD38 KO mice were transduced with lentivirus overexpressing CD38 or control lentivirus and were used as donors in competitive transplantation. The percentage of total donor-derived cells in the peripheral blood of the recipients was analyzed by flow cytometry (4 weeks p = 0.0652; 8 weeks p = 0.0059; 12 weeks p = 0.0085; 16 weeks p = 0.0260). n = 12. d-n. Noncompetitive transplantation was performed using bone marrow cells from 3-month-old WT and CD38 KO mice as donors. Donor-derived enriched HSCs from the recipient mice were compared. d, e. Relative abundances of metabolites were measured by LC-MS (D, p = 0.0273; E, p = 0.0105). n = 6 and 7(D). n = 10 (E). f. ATP levels (p = 0.0007). n = 4. g-n. Representative histograms and quantification for Fluo-4 (p = 0.0357) (G, H), Rhod-2 (p = 0.0291) (I, J), TMRM (p = 0.0389) (K, L), and ROS (p = 0.0367) (M, N) staining analyzed via flow cytometry. n = 6 and 5 (G, H). n = 5 and 6 (I, J), n = 6 (K, L), n = 5 (M, N). Data are presented as mean values +/- SE. *: p < 0.05. **: p < 0.01. ***: p < 0.001. One-sided student’s t test.

Source data

Extended Data Fig. 3 CD38 regulates Ca2+ signaling and mitochondrial activity upon HSC proliferation.

a–c. Flow cytometry analyses of Rhod-2 (p = 0.0049) (A), TMRM (p = 0.0400) (B), ROS (p = 0.0497) (C) staining of HSCs isolated from 3-month-old WT and CD38 KO mice 16 hours post pIpC treatment. n = 5 and 6 (A, C). n = 5 (B). d. Gating strategy. e, f. Flow cytometry analyses of TMRM (p = 0.0265) (E) and ROS (p = 0.0137) (F) staining of CD38high and CD38low HSCs isolated from 3-month-old WT mice cultured for 18 hours in the presence of cytokines. n = 6 and 5 (E). n = 6 (F). Data are presented as mean values +/- SE. *: p < 0.05. **: p < 0.01. One-sided student’s t test.

Source data

Extended Data Fig. 4 Effect of CD38 on Ca2+ signaling and mitochondrial activity under homeostatic condition.

a-h. Comparison of enriched HSCs derived from 3-month-old WT and CD38 KO mice. A, B. Representative histograms (A) and quantification (p = 0.3041) (B) for Fluo-4 staining analyzed via flow cytometry. MFI, mean fluorescence intensity. n = 6. c, d. Representative histograms (C) and quantification (D) for Rhod-2 staining analyzed via flow cytometry (p = 0.2955). n = 6. e, f. Representative histograms (E) and quantification (F) for ROS staining analyzed via flow cytometry (p = 0.3350). n = 6. g, h. Representative histograms (G) and quantification (H) for TMRM staining analyzed via flow cytometry (p = 0.1819). n = 6. Data are presented as mean values +/- SE. ns: p > 0.05. One-sided student’s t test.

Source data

Extended Data Fig. 5 MCU is not required for HSC maintenance under homeostatic condition at young age.

a-d. Comparison of 7-month-old WT and MCU KO mice. A. HSC number in the bone marrow analyzed via flow cytometry (p = 0.2488). n = 6. B. 7-AAD staining of HSCs analyzed via flow cytometry (p = 0.2157). n = 6. C. Lineage differentiation in the peripheral blood analyzed via flow cytometry. MNCs, mononuclear cells (p = 0.2453). n = 10 and 11. D. Bone marrow cellularity normalized by body weight (p = 0.1160). n = 6. Data are presented as mean values +/- SE. ns: p > 0.05. One-sided student’s t test.

Source data

Extended Data Fig. 6 MCU is required to support HSC proliferation.

a, b. Competitive transplantation using HSCs isolated from 7-month-old WT and MCU KO mice as donors. The percentage of donor-derived HSCs in the bone marrow of the recipients (p = 0.0267) (A) and the percentage of donor-derived cells in the peripheral blood of the recipients (4 weeks p = 0.0425; 8 weeks p = 0.0101; 12 weeks p = 0.0142; 16 weeks p = 0.0090) (B) were quantified by flow cytometry. n = 6 (A). n = 14 (B). c-g. Enriched HSCs isolated from 3-month-old WT and MCU KO mice were cultured in the presence of cytokines. BrdU incorporation (p = 0.0477) (C), 7-AAD (p = 0.0984) (D), Rhod-2 (p = 0.0031) (E), TMRM (p = 0.0445) (F), and ROS (p = 0.0278) (G) staining of HSCs were analyzed by flow cytometry. n = 6 (C, D). n = 5 (E-G). Data are presented as mean values +/- SE. *: p < 0.05. **: p < 0.01. ns: p > 0.05. One-sided student’s t test.

Source data

Extended Data Fig. 7 CD38 regulates HSC function via Ca2+ signaling and mitochondrial activity.

a-d. HSCs from 3-month-old WT and CD38 KO mice were treated with or without MCU shRNA for 48 hours in culture in the presence of cytokines before flow cytometry analyses of Rhod2 staining (Ctrl, p = 0.0239; MCU shRNA, p = 0.4907) (A), TMRM staining (Ctrl, p = 0.0334; MCU shRNA, p = 0.0720) (B), HSC number (Ctrl, p = 0.0002; MCU shRNA, p = 0.2252) (C), and colony forming assay (Ctrl, p = 0.0250; MCU shRNA, p = 0.2180) (D). n = 3. Data are presented as mean values +/- SE. *: p < 0.05. ***: p < 0.001. ns: p > 0.05. One-sided student’s t test.

Source data

Extended Data Fig. 8 CD38 is upregulated in HSCs during aging.

a. Schematic illustration of the NAD+ metabolic pathways. b-g. Comparison of HSCs isolated from young (3 months old) and old (24 months old) WT mice. B. Quantitative real-time PCR analyses of NAD+ metabolic enzymes (PARP1, p = 0.4431; NAMPT, p = 0.1517; NAPRT, p = 0.1546; NMNAT3, p = 0.3542; QPRT, p = 0.0419; CD38, p = 0.0010). n = 6 and 7 (CD38). n = 3 and 4 (other enzymes). C, D. Representative histograms (C) and quantification (D) for CD38 staining analyzed via flow cytometry (p = 0.0472). n = 4. E-G. Flow cytometry analyses of Fluo-4 (p = 0.0269) (E), TMRM (p = 0.0005) (F), and ROS (p = 0.0001) (G) staining. n = 5. Data are presented as mean values +/- SE. *: p < 0.05. **: p < 0.01. ***: p < 0.001. ns: p > 0.05. One-sided student’s t test.

Source data

Extended Data Fig. 9 CD38 inactivation prevents HSC aging.

a-h. Comparison of HSCs isolated from 24-month-old WT and CD38 KO mice. A, B. RNA-sequencing analyses of enriched HSCs. Volcano plot summarizing the differentially expressed genes (Red: upregulated in CD38 KO. Blue: downregulated in CD38 KO. P adj<0.1. Benjamini-Hochberg procedure). Genes related to ribosomal proteins are labeled (A). Gene ontology analysis for the biological functions of differentially expressed genes (B). n = 2. C, D. Flow cytometry analyses of TMRM (p = 0.0076) (C) and ROS (p = 0.0058) (D) staining. n = 10 (C). n = 10 and 12 (D). E. Quantitative real-time PCR analysis of HSP60 (p = 0.0022). n = 3. F-H. Staining for 7-AAD (p = 0.0029) (F), activated caspase 1 (p = 0.0254) (G), and Ki-67 (p = 0.1974) (H) were analyzed by flow cytometry. n = 6 (F). n = 6 and 5 (G). n = 5 and 6 (H). Data are presented as mean values +/- SE. *: p < 0.05. **: p < 0.01. ns: p > 0.05. One-sided student’s t test.

Source data

Extended Data Fig. 10 MCU inactivation prevents HSC aging.

a-e. Comparison of 24-month-old WT and MCU KO mice. A, B. Complete blood count analyses (A, p = 0.0190; B, p = 0.0122). n = 8. C. Bone marrow cellularity normalized by body weight (p = 0.0181). n = 7 and 8. D, E. Competitive transplantation using HSCs isolated from 24-month-old WT and MCU KO mice as donors. The percentage of donor-derived cells in the peripheral blood of the recipients (4 weeks p = 0.0419; 8 weeks p = 0.0001; 12 weeks p = 0.0023; 16 weeks p = 0.0010) (D) and donor-derived lineage differentiation in the peripheral blood of the recipients (p = 0.0002) (E) were determined by flow cytometry. n = 12 and 9. f. A working model. CD38 catalyzes synthesis of Ca2+ second messengers from NAD+. At young age, CD38 is required for HSC proliferation through activating Ca2+ signaling and mitochondrial metabolism. NAD+ metabolism is required for activating sirtuins and suppressing mitochondrial stress. The balanced NAD+ metabolism and Ca2+ signaling ensure sufficient mitochondrial activation and adequate mitochondrial stress resistance. At old age, CD38 is upregulated, tipping the balance toward increased Ca2+ signaling and decreased NAD+ metabolism, and leading to uncontrolled mitochondrial activation and stress. Data are presented as mean values +/- SE. *: p < 0.05. **: p < 0.01. ***: p < 0.001. One-sided student’s t test.

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Supplementary information

Reporting Summary

Supplementary Tables 1–3

Differentially expressed genes for RNA sequencing analyses of enriched HSCs isolated from 3-month-old WT and CD38 KO mice cultured in the presence of cytokines (Supplementary Table 1), under homeostatic conditions (Supplementary Table 2) or from 24-month-old WT and CD38 KO mice under homeostatic conditions (Supplementary Table 3). The Benjamini–Hochberg procedure.

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Song, Z., Park, S.H., Mu, WC. et al. An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging. Nat Aging (2024). https://doi.org/10.1038/s43587-024-00670-8

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  • DOI: https://doi.org/10.1038/s43587-024-00670-8

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