DOI QR코드

DOI QR Code

Hypoxia Upregulates Mitotic Cyclins Which Contribute to the Multipotency of Human Mesenchymal Stem Cells by Expanding Proliferation Lifespan

  • Lee, Janet (Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Hyun-Soo (Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Su-Min (Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Dong-Ik (Department of Vascular Surgery, Samsung Seoul Hospital, Sungkyunkwan University School of Medicine) ;
  • Lee, Chang-Woo (Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine)
  • Received : 2017.09.22
  • Accepted : 2017.12.26
  • Published : 2018.03.31

Abstract

Hypoxic culture is widely recognized as a method to efficiently expand human mesenchymal stem cells (MSCs) without loss of stem cell properties. However, the molecular basis of how hypoxia priming benefits MSC expansion remains unclear. In this report, our systemic quantitative proteomic and RT-PCR analyses revealed the involvement of hypoxic conditioning activated genes in the signaling process of the mitotic cell cycle. Introduction of screened two mitotic cyclins, CCNA2 and CCNB1, significantly extended the proliferation lifespan of MSCs in normoxic condition. Our results provide important molecular evidence that multipotency of human MSCs by hypoxic conditioning is determined by the mitotic cell cycle duration. Thus, the activation of mitotic cyclins could be a potential strategy to the application of stem cell therapy.

Acknowledgement

Supported by : National Research Foundation

References

  1. Cairns, R.A., Harris, I.S., and Mak, T. W. (2011). Regulation of cancer cell metabolism. Nat. Rev. Cancer 11, 85-95. https://doi.org/10.1038/nrc2981
  2. Das, R., Jahr, H., van Osch, G.J., and Farrell, E. (2012). The role of hypoxia in bone marrow-derived mesenchymal stem cells: considerations for regenerative medicine approaches. Tissue Eng. Part B Rev. 16, 159-168.
  3. Davy, P., and Allsopp, R. (2011). Hypoxia: are stem cells in it for the long run? Cell Cycle 10, 206-211. https://doi.org/10.4161/cc.10.2.14535
  4. Goda, N., Ryan, H.E., Khadivi, B., McNulty, W., Rickert, R.C., and Johnson, R.S. (2003). Hypoxia-inducible factor 1 is essential for cell cycle arrest during hypoxia. Mol. Cell. Biol. 23, 359-369. https://doi.org/10.1128/MCB.23.1.359-369.2003
  5. Greer, S.N., Metcalf, J.L., Wang, Y., and Ohh, M. (2012). The updated biology of hypoxia-inducible factor. EMBO J. 31, 2448-2460. https://doi.org/10.1038/emboj.2012.125
  6. Hu, X., Wu, R., Jiang, Z., Wang, L., Chen, P., Zhang, L., Yang, L., Wu, Y., Chen, H., Chen, H., et al. (2014). Leptin signaling is required for augmented therapeutic properties of mesenchymal stem cells conferred by hypoxia preconditioning. Stem Cells 32, 2702-2713. https://doi.org/10.1002/stem.1784
  7. Ito, K., and Suda, T. (2014). Metabolic requirements for the maintenance of self-renewing stem cells. Nat. Rev. Mol. Cell Biol. 15, 243-256. https://doi.org/10.1038/nrm3772
  8. Mathieu, J., Zhou, W., Xing, Y., Sperber, H., Ferreccio, A., Agoston, Z., Kuppusamy, K.T., Moon, R.T., and Ruohola-Baker, H. (2014). Hypoxia-inducible factors have distinct and stage-specific roles during reprogramming of human cells to pluripotency. Cell Stem Cell 14, 592-605. https://doi.org/10.1016/j.stem.2014.02.012
  9. Mohyeldin, A., Garzon-Muvdi, T., and Quinones-Hinojosa, A. (2010). Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 7, 150-161 https://doi.org/10.1016/j.stem.2010.07.007
  10. Nagano, M., Kimura, K., Yamashita, T., Ohneda, K., Nozawa, D., Hamada, H., Yoshikawa, H., Ochiai, N., and Ohneda, O. (2010). Hypoxia responsive mesenchymal stem cells derived from human umbilical cord blood are effective for bone repair. Stem Cells Dev. 19, 1195-1210. https://doi.org/10.1089/scd.2009.0447
  11. Pattappa, G., Heywood, H.K., de Bruijn, J.D., and Lee, D.A. (2011). The metabolism of human mesenchymal stem cells during proliferation and differentiation. J. Cell Physiol. 226, 2562-2570. https://doi.org/10.1002/jcp.22605
  12. Rafalski, V.A., Mancini, E., and Brunet, A. (2003). Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate. J. Cell Sci. 125, 5597-5608.
  13. Rosova, I., Dao, M., Capoccia, B., Link, D., and Nolta, J.A. (2008). Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 26, 2173-2182. https://doi.org/10.1634/stemcells.2007-1104
  14. Suda, T., Takubo, K. and Semenza, G.L. (2011). Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell 9, 298-310. https://doi.org/10.1016/j.stem.2011.09.010
  15. Tsai, C.C., Chen, Y.J., Yew, T.L., Chen, L.L., Wang, J.Y., Chiu, C.H., and Hung, S.C. (2011). Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2Ap21 by HIF-TWIST. Blood 117, 459-469. https://doi.org/10.1182/blood-2010-05-287508
  16. Varum, S., Rodrigues, A.S., Moura, M.B., Momcilovic, O., Easley, C.A. 4th., Ramalho-Santos, J., Van Houten, B., and Schatten, G. (2011). Energy metabolism in human pluripotent stem cells and their differentiated counterparts. PloS One 6, e20914. https://doi.org/10.1371/journal.pone.0020914
  17. Yanes, O., Clark, J., Wong, D.M., Patti, G.J., Sanchez-Ruiz, A., Benton, H.P., Trauger, S.A., Desponts, C., Ding, S., and Siuzdak, G. (2010). Metabolic oxidation regulates embryonic stem cell differentiation. Nat. Chem. Biol. 6, 411-417. https://doi.org/10.1038/nchembio.364
  18. Youn, J.I., Park, S.H., Jin, H.T., Lee, C.G., Seo, S.H., Song, M.Y., Lee, C.W., and Sung, Y.C. (2008). Enhanced delivery efficiency of recombinant adenovirus into tumor and mesenchymal stem cells by a novel PTD. Cancer Gene Ther. 15, 703-712. https://doi.org/10.1038/cgt.2008.45
  19. Zhang, J., Nuebel, E., Daley, G.Q., Koehler, C.M., and Teitell, M.A. (2012). Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal. Cell Stem Cell 11, 589-595. https://doi.org/10.1016/j.stem.2012.10.005