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Nicotinamide Riboside Promotes the Proliferation of Endogenous Neural Stem Cells to Repair Spinal Cord Injury

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Abstract

Activation of endogenous neural stem cells (NSC) is one of the most potential measures for neural repair after spinal cord injury. However, methods for regulating neural stem cell behavior are still limited. Here, we investigated the effects of nicotinamide riboside promoting the proliferation of endogenous neural stem cells to repair spinal cord injury. Nicotinamide riboside promotes the proliferation of endogenous neural stem cells and regulates their differentiation into neurons. In addition, nicotinamide riboside significantly restored lower limb motor dysfunction caused by spinal cord injury. Nicotinamide riboside plays its role in promoting the proliferation of neural stem cells by activating the Wnt signaling pathway through the LGR5 gene. Knockdown of the LGR5 gene by lentivirus eliminates the effect of nicotinamide riboside on the proliferation of endogenous neural stem cells. In addition, administration of Wnt pathway inhibitors also eliminated the proliferative effect of nicotinamide riboside. Collectively, these findings demonstrate that nicotinamide promotes the proliferation of neural stem cells by targeting the LGR5 gene to activate the Wnt pathway, which provides a new way to repair spinal cord injury.

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References

  1. Fan, B., et al. (2018). Microenvironment imbalance of spinal cord injury. Cell Transplantation, 27(6), 853–866.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Mathieu, P., et al. (2010). The more you have, the less you get: The functional role of inflammation on neuronal differentiation of endogenous and transplanted neural stem cells in the adult brain. Journal of Neurochemistry, 112(6), 1368–1385.

    Article  CAS  PubMed  Google Scholar 

  3. Chen, X., et al. (2018). Peroxynitrite enhances self-renewal, proliferation and neuronal differentiation of neural stem/progenitor cells through activating HIF-1alpha and Wnt/beta-catenin signaling pathway. Free Radical Biology and Medicine, 117, 158–167.

    Article  PubMed  Google Scholar 

  4. Gage, F. H. (2000). Mammalian neural stem cells. Science, 287(5457), 1433–1438.

    Article  CAS  PubMed  Google Scholar 

  5. Liu, X., et al. (2021). Arid1a regulates neural stem/progenitor cell proliferation and differentiation during cortical development. Cell Proliferation, 54(11), e13124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Canto, C., Menzies, K. J., & Auwerx, J. (2015). NAD(+) metabolism and the control of energy homeostasis: A balancing act between mitochondria and the nucleus. Cell Metabolism, 22(1), 31–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Imai, S., & Guarente, L. (2014). NAD+ and sirtuins in aging and disease. Trends in Cell Biology, 24(8), 464–471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Verdin, E. (2015). NAD(+) in aging, metabolism, and neurodegeneration. Science, 350(6265), 1208–1213.

    Article  CAS  PubMed  Google Scholar 

  9. Remie, C. M. E., et al. (2020). Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. The American Journal of Clinical Nutrition, 112(2), 413–426.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Li, D. J., et al. (2021). NAD(+)-boosting therapy alleviates nonalcoholic fatty liver disease via stimulating a novel exerkine Fndc5/irisin. Theranostics, 11(9), 4381–4402.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hou, Y., Wei, Y., Lautrup, S., Yang, B., Wang, Y., Cordonnier, S., Mattson, M. P., Croteau, D. L., & Bohr, V. A. (2021). NAD(+) supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING. Proceedings of the National Academy of Sciences of the United States of America, 118(37), e2011226118.

  12. Bieganowski, P., & Brenner, C. (2004). Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-handler independent route to NAD+ in fungi and humans. Cell, 117(4), 495–502.

    Article  CAS  PubMed  Google Scholar 

  13. Belenky, P., et al. (2007). Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell, 129(3), 473–484.

    Article  CAS  PubMed  Google Scholar 

  14. Hara, S., et al. (2012). A further study on chromosome minimization by protoplast fusion in aspergillus oryzae. Molecular Genetics and Genomics, 287(2), 177–187.

    Article  CAS  PubMed  Google Scholar 

  15. Tanaka, T., & Nabeshima, Y. (2007). Nampt/PBEF/Visfatin: A new player in beta cell physiology and in metabolic diseases? Cell Metabolism, 6(5), 341–343.

    Article  CAS  PubMed  Google Scholar 

  16. Gao, J., et al. (2021). Wnt/beta-catenin signaling in neural stem cell homeostasis and neurological diseases. Neuroscientist, 27(1), 58–72.

    Article  CAS  PubMed  Google Scholar 

  17. Austin, S. H. L., Rigo, P., Paun, O., Harris, L., Guillemot, F., & Urbán, N. (2021). Wnt/β-catenin signalling is dispensable for adult neural stem cell homeostasis and activation. Development, 148(20), dev199629. https://doi.org/10.1242/dev.199629

  18. Nusse, R., & Varmus, H. E. (1982). Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, 31(1), 99–109.

    Article  CAS  PubMed  Google Scholar 

  19. Zhu, L., et al. (2009). Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature, 457(7229), 603–607.

    Article  CAS  PubMed  Google Scholar 

  20. Barker, N., et al. (2009). Crypt stem cells as the cells-of-origin of intestinal cancer. Nature, 457(7229), 608–611.

    Article  CAS  PubMed  Google Scholar 

  21. Jaks, V., et al. (2008). Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nature Genetics, 40(11), 1291–1299.

    Article  CAS  PubMed  Google Scholar 

  22. Barker, N., et al. (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature, 449(7165), 1003–1007.

    Article  CAS  PubMed  Google Scholar 

  23. Choi, Y. J., et al. (2016). Expression of leucine-rich repeat-containing G-protein coupled receptor 5 and CD44: Potential implications for gastric Cancer stem cell marker. Journal of Cancer Prevention, 21(4), 279–287.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Takahashi, H., et al. (2011). Significance of Lgr5(+ve) cancer stem cells in the colon and rectum. Annals of Surgical Oncology, 18(4), 1166–1174.

    Article  PubMed  Google Scholar 

  25. Wang, D., et al. (2014). Knockdown of LGR5 suppresses the proliferation of glioma cells in vitro and in vivo. Oncology Reports, 31(1), 41–49.

    Article  PubMed  Google Scholar 

  26. Chen, X., et al. (2014). LGR5 is required for the maintenance of spheroid-derived colon cancer stem cells. International Journal of Molecular Medicine, 34(1), 35–42.

    Article  PubMed  PubMed Central  Google Scholar 

  27. **, H. Q., et al. (2014). Leucine-rich repeat-containing G-protein-coupled receptor 5 is associated with invasion, metastasis, and could be a potential therapeutic target in human gastric cancer. British Journal of Cancer, 110(8), 2011–2020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang, J., et al. (2018). LGR5, a novel functional glioma stem cell marker, promotes EMT by activating the Wnt/beta-catenin pathway and predicts poor survival of glioma patients. Journal of Experimental & Clinical Cancer Research, 37(1), 225.

    Article  Google Scholar 

  29. Leung, C., Tan, S. H., & Barker, N. (2018). Recent advances in Lgr5(+) stem cell research. Trends in Cell Biology, 28(5), 380–391.

    Article  CAS  PubMed  Google Scholar 

  30. Petin, K., et al. (2019). NAD metabolites interfere with proliferation and functional properties of THP-1 cells. Innate Immunity, 25(5), 280–293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gazanion, E., et al. (2011). The Leishmania nicotinamidase is essential for NAD+ production and parasite proliferation. Molecular Microbiology, 82(1), 21–38.

    Article  CAS  PubMed  Google Scholar 

  32. Brown, K. D., et al. (2014). Activation of SIRT3 by the NAD(+) precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metabolism, 20(6), 1059–1068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sirichoat, A., et al. (2020). Melatonin attenuates 5-fluorouracil-induced spatial memory and hippocampal neurogenesis impairment in adult rats. Life Sciences, 248, 117468.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang, S., et al. (2023). Dexmedetomidine attenuates sleep deprivation-induced inhibition of hippocampal neurogenesis via VEGF-VEGFR2 signaling and inhibits neuroinflammation. Biomedicine & Pharmacotherapy, 165, 115085.

    Article  CAS  Google Scholar 

  35. Vieira, G. C., et al. (2015). LGR5 regulates pro-survival MEK/ERK and proliferative Wnt/beta-catenin signalling in neuroblastoma. Oncotarget, 6(37), 40053–40067.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Wang, Y., et al. (2017). beta-catenin-mediated YAP signaling promotes human glioma growth. Journal of Experimental & Clinical Cancer Research, 36(1), 136.

    Article  Google Scholar 

  37. Lim, J. H., Chun, Y. S., & Park, J. W. (2008). Hypoxia-inducible factor-1alpha obstructs a Wnt signaling pathway by inhibiting the hARD1-mediated activation of beta-catenin. Cancer Research, 68(13), 5177–5184.

    Article  CAS  PubMed  Google Scholar 

  38. Stenudd, M., Sabelstrom, H., & Frisen, J. (2015). Role of endogenous neural stem cells in spinal cord injury and repair. JAMA Neurology, 72(2), 235–237.

    Article  PubMed  Google Scholar 

  39. Brousse, B., et al. (2021). Endogenous neural stem cells modulate microglia and protect against demyelination. Stem Cell Reports, 16(7), 1792–1804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang, Y., et al. (2021). Small molecules combined with collagen hydrogel direct neurogenesis and migration of neural stem cells after spinal cord injury. Biomaterials, 269, 120479.

    Article  CAS  PubMed  Google Scholar 

  41. Matsubara, S., Matsuda, T., & Nakashima, K. (2021). Regulation of adult mammalian neural stem cells and neurogenesis by cell extrinsic and intrinsic factors. Cells, 10(5), 1145.

  42. Elhassan, Y. S., et al. (2019). Nicotinamide riboside augments the aged human skeletal muscle NAD(+) metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Reports, 28(7), 1717–1728.e6.

    Article  CAS  PubMed  Google Scholar 

  43. Braidy, N., & Liu, Y. (2020). Can nicotinamide riboside protect against cognitive impairment? Current Opinion in Clinical Nutrition & Metabolic Care, 23(6), 413–420.

    Article  CAS  Google Scholar 

  44. Martens, C. R., et al. (2018). Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nature Communications, 9(1), 1286.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Lan, C., et al. (2021). FAM83A promotes the proliferative and invasive abilities of cervical Cancer cells via epithelial-mesenchymal transition and the Wnt signaling pathway. Journal of Cancer, 12(21), 6320–6329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bejsovec, A. (2013). Wingless/Wnt signaling in Drosophila: The pattern and the pathway. Molecular Reproduction and Development, 80(11), 882–894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hachim, M. Y., et al. (2021). Wnt signaling is deranged in asthmatic bronchial epithelium and fibroblasts. Frontiers in Cell and Developmental Biology, 9, 641404.

    Article  PubMed  PubMed Central  Google Scholar 

  48. English, D., et al. (2013). Neural stem cells-trends and advances. Journal of Cellular Biochemistry, 114(4), 764–772.

    Article  CAS  PubMed  Google Scholar 

  49. Decimo, I., et al. (2012). Neural stem cell niches in health and diseases. Current Pharmaceutical Design, 18(13), 1755–1783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. de Freria, C. M., Van Niekerk, E., Blesch, A., & Lu, P. (2021). Neural stem cells: Promoting axonal regeneration and spinal cord connectivity. Cells, 10(12), 3296.

  51. Vannini, N., et al. (2019). The NAD-booster nicotinamide riboside potently stimulates hematopoiesis through increased mitochondrial clearance. Cell Stem Cell, 24(3), 405–418.e7.

    Article  CAS  PubMed  Google Scholar 

  52. Xu, Y., et al. (2021). Understanding the role of tissue-specific decellularized spinal cord matrix hydrogel for neural stem/progenitor cell microenvironment reconstruction and spinal cord injury. Biomaterials, 268, 120596.

    Article  CAS  PubMed  Google Scholar 

  53. Gao, L., et al. (2018). Stem cell therapy: A promising therapeutic method for intracerebral hemorrhage. Cell Transplantation, 27(12), 1809–1824.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Shao, A., et al. (2019). Crosstalk between stem cell and spinal cord injury: Pathophysiology and treatment strategies. Stem Cell Research & Therapy, 10(1), 238.

    Article  Google Scholar 

  55. Mehmel, M., Jovanovic, N., & Spitz, U. (2020). Nicotinamide riboside-the current state of research and therapeutic uses. Nutrients, 12(6), 1616.

  56. Bogan, K. L., & Brenner, C. (2008). Nicotinic acid, nicotinamide, and nicotinamide riboside: A molecular evaluation of NAD+ precursor vitamins in human nutrition. Annual Review of Nutrition, 28, 115–130.

    Article  CAS  PubMed  Google Scholar 

  57. Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Therapeutic potential of NAD-boosting molecules: The in vivo evidence. Cell Metabolism, 27(3), 529–547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yan, K. S., et al. (2017). Non-equivalence of Wnt and R-spondin ligands during Lgr5(+) intestinal stem-cell self-renewal. Nature, 545(7653), 238–242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ohta, Y., et al. (2022). Cell-matrix interface regulates dormancy in human colon cancer stem cells. Nature, 608(7924), 784–794.

    Article  CAS  PubMed  Google Scholar 

  60. Hsu, S. Y., Liang, S. G., & Hsueh, A. J. (1998). Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Molecular Endocrinology, 12(12), 1830–1845.

    Article  CAS  PubMed  Google Scholar 

  61. Ratajczak, M. Z. (2017). Why are hematopoietic stem cells so 'sexy'? On a search for developmental explanation. Leukemia, 31(8), 1671–1677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Huang, H., et al. (2020). Clinical Neurorestorative therapeutic guidelines for spinal cord injury (IANR/CANR version 2019). Journal of Orthopaedic Translation, 20, 14–24.

    Article  PubMed  Google Scholar 

  63. Sher, F., et al. (2008). Differentiation of neural stem cells into oligodendrocytes: Involvement of the polycomb group protein Ezh2. Stem Cells, 26(11), 2875–2883.

    Article  CAS  PubMed  Google Scholar 

  64. Moghadam, F. H., Sadeghi-Zadeh, M., Alizadeh-Shoorjestan, B., Dehghani-Varnamkhasti, R., Narimani, S., Darabi, L., Esfahani, A. K., & Esfahani, M. H. N. (2018). Isolation and culture of embryonic mouse neural stem cells. Journal of Visualized Experiments, 141, 10.3791/58874. https://doi.org/10.3791/58874

  65. Wang, Y., Wu, W., Wu, X., Sun, Y., Zhang, Y. P., Deng, L. X., Walker, M. J., Qu, W., Chen, C., Liu, N. K., Han, Q., Dai, H., Shields, L. B., Shields, C. B., Sengelaub, D. R., Jones, K. J., Smith, G. M. & Xu, X. M. (2018). Remodeling of lumbar motor circuitry remote to a thoracic spinal cord injury promotes locomotor recovery. Elife, 7, e39016. https://doi.org/10.7554/eLife.39016

  66. Heinzel, J. C., et al. (2020). Evaluation of functional recovery in rats after median nerve resection and autograft repair using computerized gait analysis. Frontiers in Neuroscience, 14, 593545.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Key Research and Development Project of Stem Cell and Transformation Research (2019YFA0112100); National Natural Science Foundation of China (82102560, 82220108005) Tian** key research and development plan, key projects for science and technology support (19YFZCSY00660); The Scientific Research Program of Tian** Education Commission (2022KJ239). Clinical Research Center of Shandong University (No.2020SDUCRCA008). We thank Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work.

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  1. Jian** Zhang, Jun Shang and Han Ding contributed equally to this work.

Authors and Affiliations

  1. Institute of Medical Sciences, The Second Hospital & Orthopedic Research Center of Shandong University, Cheeloo College of Medicine, Shandong University, **an, Shandong, China

    Jun Shang, YongFu Lou, Shiqing Feng, ** Zhang, Han Ding & Shiqing Feng

  2. Department of Orthopedics, Qilu Hospital of Shandong University, **an, Shandong, China

    Wenxiang Li, Zonghao Li, Zhongze Yuan, Han Zheng, Zhijian Wei, Hengxing Zhou & Shiqing Feng

  3. Institute of Orthopaedic & Musculoskeletal Science, Division of Surgery and Interventional Science, University College London, Royal National Orthopaedic Hospital, London, HA7 4LP, UK

    Jian** Zhang

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Contributions

J.Z., J.S. and N.R. designed the project. J.Z., J.S., Z.Y., Z.L., W.L., H.Z., Y.L. and H.D. performed the experiments. Z.P, N.R, H.Z. and S.F. discussed the results. J.Z, N.R., wrote the manuscript. S.F, N.R and Z.W. revised the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Shiqing Feng, **aohong Kong or Ning Ran.

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The animal study was reviewed and approved by the Ethics Committee of the Institute of Tian** Medical University General Hospital (approval number: IRB2022-DW-46) and performed according to the national guidelines for laboratory animal use and care. All methods were performed in accordance with the relevant guidelines and regulations.

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Zhang, J., Shang, J., Ding, H. et al. Nicotinamide Riboside Promotes the Proliferation of Endogenous Neural Stem Cells to Repair Spinal Cord Injury. Stem Cell Rev and Rep (2024). https://doi.org/10.1007/s12015-024-10747-x

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