BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Global knockdown of microRNAs affects the expression of growth factors and cytokines in human adipose-derived mesenchymal stem cells

  • Park, Seul-Ki (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Jung Shin (Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Choi, Eun Kyung (Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine) ;
  • You, Dalsan (Department of Urology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Choung-Soo (Department of Urology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Suh, Nayoung (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2014.05.20
  • Accepted : 2014.06.09
  • Published : 2014.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

Cell therapies utilizing mesenchymal stem cells (MSCs) have a great potential in many research and clinical settings. The mechanisms underlying the therapeutic effects of MSCs have been studied previously and the paracrine effects elicited by their production of various growth factors and cytokines were recognized as being crucial. However, the molecular controls that govern these paracrine effects remain poorly understood. To elucidate the molecular regulators of this process, we performed a global knockdown of microRNAs (miRNAs) in human adipose-derived mesenchymal stem cells (hADSCs) by inhibiting DGCR8, a key protein in miRNA biogenesis. Global disruption of miRNA biogenesis in hADSCs caused dramatic changes in the expression of subsets of growth factors and cytokines. By performing an extensive bioinformatic analysis, we were able to associate numerous putative miRNAs with these genes. Taken together, our results strongly suggest that miRNAs are essential for the production of growth factors and cytokines in hADSCs.

Keywords

References

  1. Bianco, P., Cao, X., Frenette, P. S., Mao, J. J., Robey, P. G., Simmons, P. J. and Wang, C. Y. (2013) The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat. Med. 19, 35-42. https://doi.org/10.1038/nm.3028
  2. da Silva Meirelles, L., Chagastelles, P. C. and Nardi, N. B. (2006) Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J. Cell Sci. 119, 2204-2213. https://doi.org/10.1242/jcs.02932
  3. Brighton, C. T. and Hunt, R. M. (1991) Early histological and ultrastructural changes in medullary fracture callus. J. Bone Joint Surg. Am. 73, 832-847.
  4. Brighton, C. T. and Hunt, R. M. (1997) Early histologic and ultrastructural changes in microvessels of periosteal callus. J. Orthop. Trauma 11, 244-253. https://doi.org/10.1097/00005131-199705000-00002
  5. Kopen, G. C., Prockop, D. J. and Phinney, D. G. (1999) Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc. Natl. Acad. Sci. U. S. A. 96, 10711-10716. https://doi.org/10.1073/pnas.96.19.10711
  6. Mackenzie, T. C. and Flake, A. W. (2001) Human mesenchymal stem cells persist, demonstrate site-specific multipotential differentiation, and are present in sites of wound healing and tissue regeneration after transplantation into fetal sheep. Blood Cells Mol. Dis. 27, 601-604. https://doi.org/10.1006/bcmd.2001.0424
  7. Prockop, D. J. (2009) Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Mol. Ther. 17, 939-946. https://doi.org/10.1038/mt.2009.62
  8. Caplan, A. I. (2009) Why are MSCs therapeutic? New data: new insight. J. Pathol. 217, 318-324. https://doi.org/10.1002/path.2469
  9. Salgado, A. J., Reis, R. L., Sousa, N. J. and Gimble, J. M. (2010) Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine. Curr. Stem Cell Res. Ther. 5, 103-110. https://doi.org/10.2174/157488810791268564
  10. Chen, L., Tredget, E. E., Wu, P. Y. and Wu, Y. (2008) Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One 3, e1886. https://doi.org/10.1371/journal.pone.0001886
  11. Kinnaird, T., Stabile, E., Burnett, M. S., Lee, C. W., Barr, S., Fuchs, S. and Epstein, S. E. (2004) Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ. Res. 94, 678-685. https://doi.org/10.1161/01.RES.0000118601.37875.AC
  12. Fabian, M. R. and Sonenberg, N. (2012) The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC. Nat. Struct. Mol. Biol. 19, 586-593. https://doi.org/10.1038/nsmb.2296
  13. Gregory, R. I., Yan, K. P., Amuthan, G., Chendrimada, T., Doratotaj, B., Cooch, N. and Shiekhattar, R. (2004) The Microprocessor complex mediates the genesis of micro RNAs. Nature 432, 235-240. https://doi.org/10.1038/nature03120
  14. Denli, A. M., Tops, B. B., Plasterk, R. H., Ketting, R. F. and Hannon, G. J. (2004) Processing of primary microRNAs by the Microprocessor complex. Nature 432, 231-235. https://doi.org/10.1038/nature03049
  15. Han, J., Lee, Y., Yeom, K. H., Kim, Y. K., Jin, H. and Kim, V. N. (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev. 18, 3016-3027. https://doi.org/10.1101/gad.1262504
  16. Bernstein, E., Caudy, A. A., Hammond, S. M. and Hannon, G. J. (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 363-366. https://doi.org/10.1038/35053110
  17. Hutvagner, G., McLachlan, J., Pasquinelli, A. E., Balint, E., Tuschl, T. and Zamore, P. D. (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293, 834-838. https://doi.org/10.1126/science.1062961
  18. Guo, L., Zhao, R. C. and Wu, Y. (2011) The role of microRNAs in self-renewal and differentiation of mesenchymal stem cells. Exp. Hematol. 39, 608-616. https://doi.org/10.1016/j.exphem.2011.01.011
  19. Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Deans, R., Keating, A., Prockop, D. and Horwitz, E. (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315-317. https://doi.org/10.1080/14653240600855905
  20. Han, J., Pedersen, J. S., Kwon, S. C., Belair, C. D., Kim, Y. K., Yeom, K. H., Yang, W. Y., Haussler, D., Blelloch, R. and Kim, V. N. (2009) Posttranscriptional crossregulation between Drosha and DGCR8. Cell 136, 75-84. https://doi.org/10.1016/j.cell.2008.10.053
  21. Wang, Y., Medvid, R., Melton, C., Jaenisch, R. and Blelloch, R. (2007) DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat. Genet. 39, 380-385. https://doi.org/10.1038/ng1969
  22. Lewis, B. P., Shih, I. H., Jones-Rhoades, M. W., Bartel, D. P. and Burge, C. B. (2003) Prediction of mammalian microRNA targets. Cell 115, 787-798. https://doi.org/10.1016/S0092-8674(03)01018-3
  23. Suh, N. and Blelloch, R. (2011) Small RNAs in early mammalian development: from gametes to gastrulation. Development 138, 1653-1661. https://doi.org/10.1242/dev.056234
  24. Baek, D., Villen, J., Shin, C., Camargo, F. D., Gygi, S. P. and Bartel, D. P. (2008) The impact of microRNAs on protein output. Nature 455, 64-71. https://doi.org/10.1038/nature07242
  25. Selbach, M., Schwanhausser, B., Thierfelder, N., Fang, Z., Khanin, R. and Rajewsky, N. (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58-63. https://doi.org/10.1038/nature07228
  26. Guo, H., Ingolia, N. T., Weissman, J. S. and Bartel, D. P. (2010) Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466, 835-840. https://doi.org/10.1038/nature09267
  27. Haider, H., Jiang, S., Idris, N. M. and Ashraf, M. (2008) IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair. Circ. Res. 103, 1300-1308. https://doi.org/10.1161/CIRCRESAHA.108.186742
  28. Zuk, P. A., Zhu, M., Mizuno, H., Huang, J., Futrell, J. W., Katz, A. J., Benhaim, P., Lorenz, H. P. and Hedrick, M. H. (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 7, 211-228. https://doi.org/10.1089/107632701300062859
  29. Zuk, P. A., Zhu, M., Ashjian, P., De Ugarte, D. A., Huang, J. I., Mizuno, H., Alfonso, Z. C., Fraser, J. K., Benhaim, P. and Hedrick, M. H. (2002) Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell. 13, 4279-4295. https://doi.org/10.1091/mbc.E02-02-0105

Cited by

  1. Wall teichoic acid is an essential component of Staphylococcus aureus for the induction of human dendritic cell maturation vol.81, 2017, https://doi.org/10.1016/j.molimm.2016.12.008
  2. Antioxidant effects of selenocysteine on replicative senescence in human adipose-derived mesenchymal stem cells vol.50, pp.11, 2017, https://doi.org/10.5483/BMBRep.2017.50.11.174