Skip to main content
SpringerLink
Log in

Nicotinamide Inhibits Self-renewal and Induces Granulocyte Differentiation of Multipotent Progenitor Cells

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Nicotinamide (NAM) a form of vitamin B3, is an essential precursor of NAD. This dinucleotide (pyridine nucleotide) participates in the regulation of fundamental processes including transcription, cell cycle progression and DNA repair. Here we assessed the effect of NAM on myeloid differentiation of the IL-3 dependent, multipotent hematopoietic progenitor cell line FDCP-Mix. We found that NAM reduces the pSTAT5 signaling response, cell cycling and self-renewal potential. It initiates an atypical program of myeloid differentiation that results in the emergence of granulocytic cells in the absence of added myeloid differentiation factors. NAM did not affect the expression the of cell surface granulocyte marker GR1 but led to a strong downregulation of MHC-II molecules. Taken together our data show that NAM induces a differentiation program in hematopoietic progenitors prompting them to undergo differentiation along the granulocyte path without reaching the status of fully developed granulocytes.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 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. https://doi.org/10.1146/annurev.nutr.28.061807.155443.

  2. Berger, F., Ramírez-Hernández, M. H., & Ziegler, M. (2004). The new life of a centenarian: signalling functions of NAD(P). Trends in Biochemical Sciences, 29(3), 111–118. https://doi.org/10.1016/j.tibs.2004.01.007.

  3. Magni, G., Amici, A., Emanuelli, M., Raffaelli, N., & Ruggieri, S. (1999). Enzymology of NAD + synthesis. Advances in Enzymology and Related Areas of Molecular Biology, 73, 135 – 82, xi. https://doi.org/10.1002/9780470123195.ch5.

  4. Avalos, J. L., Bever, K. M., & Wolberger, C. (2005). Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Molecular Cell, 17(6), 855–868. https://doi.org/10.1016/j.molcel.2005.02.022.

  5. Lee, H. C. (1999). A unified mechanism of enzymatic synthesis of two calcium messengers: cyclic ADP-ribose and NAADP. Biological Chemistry, 380(7–8), 785–793. https://doi.org/10.1515/BC.1999.098.

  6. Lee, H. C. (2000). Enzymatic functions and structures of CD38 and homologs. Chemical Immunology, 75, 39–59. https://doi.org/10.1159/000058774.

  7. Hassa, P. O., & Hottiger, M. O. (2008). The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases. Frontiers in Bioscience: a Journal and Virtual Library, 13, 3046–3082. https://doi.org/10.2741/2909.

  8. Michan, S., & Sinclair, D. (2007). Sirtuins in mammals: insights into their biological function. The Biochemical Journal, 404(1), 1–13. https://doi.org/10.1042/BJ20070140.

  9. Vague, P., Picq, R., Bernal, M., Lassmann-Vague, V., & Vialettes, B. (1989). Effect of nicotinamide treatment on the residual insulin secretion in type 1 (insulin-dependent) diabetic patients. Diabetologia, 32(5), 316–321. https://doi.org/10.1007/bf00265549.

    Article  PubMed  CAS  Google Scholar 

  10. Grange, P. A., Raingeaud, J., Calvez, V., & Dupin, N. (2009). Nicotinamide inhibits Propionibacterium acnes-induced IL-8 production in keratinocytes through the NF-kappaB and MAPK pathways. Journal of Dermatological Science, 56(2), 106–112. https://doi.org/10.1016/j.jdermsci.2009.08.001.

  11. Audrito, V., Vaisitti, T., Rossi, D., Gottardi, D., D’Arena, G., Laurenti, L., et al. (2011). Nicotinamide blocks proliferation and induces apoptosis of chronic lymphocytic leukemia cells through activation of the p53/miR-34a/SIRT1 tumor suppressor network. Cancer Research, 71(13), 4473–4483. https://doi.org/10.1158/0008-5472.CAN-10-4452.

  12. Spooncer, E., Heyworth, C. M., Dunn, A., & Dexter, T. M. (1986). Self-renewal and differentiation of interleukin-3-dependent multipotent stem cells are modulated by stromal cells and serum factors. Differentiation; Research in Biological Diversity, 31(2), 111–118. https://doi.org/10.1111/j.1432-0436.1986.tb00391.x.

  13. Heyworth, C. M., Alauldin, M., Cross, M. A., Fairbairn, L. J., Dexter, T. M., & Whetton, A. D. (1995). Erythroid development of the FDCP-Mix A4 multipotent cell line is governed by the relative concentrations of erythropoietin and interleukin 3. British Journal of Haematology, 91(1), 15–22. https://doi.org/10.1111/j.1365-2141.1995.tb05238.x.

  14. Karasuyama, H., & Melchers, F. (1988). Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. European Journal of Immunology, 18(1), 97–104. https://doi.org/10.1002/eji.1830180115.

  15. Wu, X., Kong, X., Chen, D., Li, H., Zhao, Y., Xia, M., et al. (2011). SIRT1 links CIITA deacetylation to MHC II activation. Nucleic Acids Research, 39(22), 9549–9558. https://doi.org/10.1093/nar/gkr651.

  16. Horwitz, M. E., Wease, S., Blackwell, B., Valcarcel, D., Frassoni, F., Boelens, J. J., et al. (2018). Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo With Nicotinamide. Journal of Clinical Oncology, 37(5), 367–374. https://doi.org/10.1200/JCO.18.00053.

  17. Anand, S., Thomas, S., Hyslop, T., Adcock, J., Corbet, K., Gasparetto, C., et al. (2017). Transplantation of Ex Vivo Expanded Umbilical Cord Blood (NiCord) Decreases Early Infection and Hospitalization. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation, 23(7), 1151–1157. https://doi.org/10.1016/j.bbmt.2017.04.001.

  18. Peled, T., Shoham, H., Aschengrau, D., Yackoubov, D., Frei, G., Rosenheimer, G., N., et al (2012). Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment. Experimental Hematology, 40(4), 342 – 55.e1. https://doi.org/10.1016/j.exphem.2011.12.005.

  19. Ratajczak, M. Z., Ratajczak, J., & Kucia, M. (2019). Very Small Embryonic-Like Stem Cells (VSELs). Circulation Research, 124(2), 208–210. https://doi.org/10.1161/CIRCRESAHA.118.314287.

  20. Son, M. J., Son, M.-Y., Seol, B., Kim, M.-J., Yoo, C. H., Han, M.-K., et al. (2013). Nicotinamide overcomes pluripotency deficits and reprogramming barriers. Stem Cells (Dayton, Ohio), 31(6), 1121–1135. https://doi.org/10.1002/stem.1368.

  21. Moon, J., Kim, H. R., & Shin, M. G. (2018). Rejuvenating Aged Hematopoietic Stem Cells Through Improvement of Mitochondrial Function. Annals of Laboratory Medicine, 38(5), 395–401. https://doi.org/10.3343/alm.2018.38.5.395.

  22. Vannini, N., Campos, V., Girotra, M., Trachsel, V., Rojas-Sutterlin, S., Tratwal, J., et al. (2019). The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance. Cell Stem Cell, 24(3), 405–418.e7. https://doi.org/10.1016/j.stem.2019.02.012.

  23. Song, J., Li, J., Yang, F., Ning, G., Zhen, L., Wu, L., et al. (2019). Nicotinamide mononucleotide promotes osteogenesis and reduces adipogenesis by regulating mesenchymal stromal cells via the SIRT1 pathway in aged bone marrow. Cell Death & Disease, 10(5), 336. https://doi.org/10.1038/s41419-019-1569-2.

  24. Cantó, C., Houtkooper, R. H., Pirinen, E., Youn, D. Y., Oosterveer, M. H., Cen, Y., et al. (2012). The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metabolism, 15(6), 838–847. https://doi.org/10.1016/j.cmet.2012.04.022.

  25. Skokowa, J., Lan, D., Thakur, B. K., Wang, F., Gupta, K., Cario, G., et al. (2009). NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD(+)-sirtuin-1-dependent pathway. Nature Medicine, 15(2), 151–158. https://doi.org/10.1038/nm.1913.

  26. Chaurasia, P., Gajzer, D. C., Schaniel, C., D’Souza, S., & Hoffman, R. (2014). Epigenetic reprogramming induces the expansion of cord blood stem cells. The Journal of Clinical Investigation, 124(6), 2378–2395. https://doi.org/10.1172/JCI70313.

  27. Petin, K., Weiss, R., Müller, G., Garten, A., Grahnert, A., Sack, U., et al. (2019). NAD metabolites interfere with proliferation and functional properties of THP-1 cells. Innate Immunity, 25(5), 280–293. https://doi.org/10.1177/1753425919844587.

  28. Qiao, L., & Shao, J. (2006). SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex. The Journal of Biological Chemistry, 281(52), 39915–39924. https://doi.org/10.1074/jbc.M607215200.

  29. Lenny, N., Westendorf, J. J., & Hiebert, S. W. (1997). Transcriptional regulation during myelopoiesis. Molecular Biology Reports, 24(3), 157–168. https://doi.org/10.1023/a:1006859700409.

  30. Smith, L. T., Hohaus, S., Gonzalez, D. A., Dziennis, S. E., & Tenen, D. G. (1996). PU.1 (Spi-1) and C/EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells. Blood, 88(4), 1234–1247.

  31. Papaccio, G., Ammendola, E., & Pisanti, F. A. (1999). Nicotinamide decreases MHC class II but not MHC class I expression and increases intercellular adhesion molecule-1 structures in non-obese diabetic mouse pancreas. The Journal of Endocrinology, 160(3), 389–400. https://doi.org/10.1677/joe.0.1600389.

  32. Kim, K.-A., Kim, S., Chang, I., Kim, G. S., Min, Y.-K., Lee, M.-K., et al. (2002). IFN gamma/TNF alpha synergism in MHC class II induction: effect of nicotinamide on MHC class II expression but not on islet-cell apoptosis. Diabetologia, 45(3), 385–393. https://doi.org/10.1007/s00125-001-0755-8.

  33. Pellat-Deceunynck, C., Wietzerbin, J., & Drapier, J. C. (1994). Nicotinamide inhibits nitric oxide synthase mRNA induction in activated macrophages. Biochemical Journal, 297(Pt 1), 53–58. https://doi.org/10.1042/bj2970053.

Download references

Funding

WN was supported by the Ministry of Higher Education and Scientific Research, Republic of Sudan.

Author information

Author notes

  1. Michael Cross and Sunna Hauschildt contribute equally to this work.

Authors and Affiliations

  1. Medical Faculty, Institute of Clinical Immunology, Leipzig University, Johannisallee 30, 04103, Leipzig, Germany

    Waseem Nasr, Ulrike Köhl, Ulrich Sack, Ronald Weiss & Sunna Hauschildt

  2. Hematology and Cellular Therapy, University Hospital Leipzig, Medical Clinic and Policlinic 1, Johannisallee 32a, 04103, Leipzig, Germany

    Waseem Nasr & Michael Cross

  3. Department of Hematology and Immunohematology, Faculty of Medical Laboratory Sciences, Khartoum University, P.O. BOX 321, Khartoum, Sudan

    Waseem Nasr

  4. Fraunhofer Institute for Cell Therapy and Immunology, Perlickstraße 1, 04103, Leipzig, Germany

    Claire Fabian, Katrin Arnold & Ulrike Köhl

  5. Institute of Cellular Therapeutics, Hannover Medical School, Feodor-Lynen-Str. 21, 30625, Hannover, Germany

    Ulrike Köhl

  6. Institute of Biology, Leipzig University, Talstraße 33, 04103, Leipzig, Germany

    Sunna Hauschildt

Authors
  1. Waseem Nasr
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claire Fabian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katrin Arnold
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ulrike Köhl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ulrich Sack
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ronald Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Cross
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sunna Hauschildt
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Waseem Nasr, Claire Fabian, and Katrin Arnold. The first draft of the manuscript was written by Michael Cross, and Sunna Hauschildt and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sunna Hauschildt.

Ethics declarations

Conflict of Interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript apart from those disclosed.

Ethics Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nasr, W., Fabian, C., Arnold, K. et al. Nicotinamide Inhibits Self-renewal and Induces Granulocyte Differentiation of Multipotent Progenitor Cells. Stem Cell Rev and Rep 16, 1335–1342 (2020). https://doi.org/10.1007/s12015-020-10019-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-020-10019-4

Keywords

Search

Navigation