Skip to main content

Advertisement

SpringerLink
Log in

MicroRNAomic Transcriptomic Analysis Reveal Deregulation of Clustered Cellular Functions in Human Mesenchymal Stem Cells During in Vitro Passaging

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

A Correction to this article was published on 17 July 2020

This article has been updated

Abstract

Clinical trials using human mesenchymal stem/stromal cells (hMSCs) for cell replacement therapy showed varied outcomes, where cells’ efficacy has been perceived as the limiting factor. In particular, the quality and number of the expanded cells in vitro. In this study, we aimed to determine molecular signatures of hMSCs derived from the pulp of extracted deciduous teeth (SHED) and Wharton’s jelly (WJSCs) that associated with cellular ageing during in vitro passaging. We observed distinct phenotypic changes resembling proliferation reduction, cell enlargement, an increase cell population in G2/M phase, and differentially expressed of tumor suppressor p53 in passage (P) 6 as compared to P3, which indicating in vitro cell senescence. The subsequent molecular analysis showed a set of diverse differentially expressed miRNAs and mRNAs involved in maintaining cell proliferation and stemness properties. Considering the signaling pathway related to G2/M DNA damage regulation is widely recognized as part of anti-proliferation mechanism controlled by p53, we explored possible miRNA-mRNA interaction in this regulatory pathway based on genomic coordinates retrieved from miRanda. Our work reveals the potential reason for SHED underwent proliferation arrest due to the direct impinge on the expression of CKS1 by miRNAs specifically miR-22 and miR-485-5p which lead to down regulation of CDK1 and Cyclin B. It is intended that our study will contribute to the understanding of these miRNA/mRNA driving the biological process and regulating different stages of cell cycle is beneficial in developing effective rejuvenation strategies in order to obtain quality stem cells for transplantation.

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
Fig. 5
Fig. 6

Similar content being viewed by others

Change history

  • 17 July 2020

    The original version of this article unfortunately contained a mistake.

References

  1. Estrada, J. C., Torres, Y., Benguria, A., Dopazo, A., Roche, E., Carrera-Quintanar, L., Perez, R. A., Enriquez, J. A., Torres, R., Ramirez, J. C., Samper, E., & Bernad, A. (2013). Human mesenchymal stem cell-replicative senescence and oxidative stress are closely linked to aneuploidy. Cell Death & Disease, 4, e691. https://doi.org/10.1038/cddis.2013.211.

    Article  CAS  Google Scholar 

  2. Sepulveda, J. C., Tome, M., Fernandez, M. E., Delgado, M., Campisi, J., Bernad, A., & Gonzalez, M. A. (2014). Cell senescence abrogates the therapeutic potential of human mesenchymal stem cells in the lethal endotoxemia model. Stem Cells (Dayton, Ohio), 32, 1865–1877. https://doi.org/10.1002/stem.1654.

    Article  CAS  Google Scholar 

  3. Wagner, W., Bork, S., Lepperdinger, G., Joussen, S., Ma, N., Strunk, D., & Koch, C. (2010). How to track cellular aging of mesenchymal stromal cells? Aging, 2, 224–230. https://doi.org/10.18632/aging.100136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wagner, W., Horn, P., Castoldi, M., Diehlmann, A., Bork, S., Saffrich, R., Benes, V., Blake, J., Pfister, S., Eckstein, V., & Ho, A. D. (2008). Replicative senescence of mesenchymal stem cells: A continuous and organized process. PLoS One, 3, e2213. https://doi.org/10.1371/journal.pone.0002213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bentivegna, A., Roversi, G., Riva, G., Paoletta, L., Redaelli, S., Miloso, M., Tredici, G., & Dalpra, L. (2016). The effect of culture on human bone marrow Mesenchymal stem cells: Focus on DNA methylation profiles. Stem Cells International, 2016, 5656701. https://doi.org/10.1155/2016/5656701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Legzdina, D., Romanauska, A., Nikulshin, S., Kozlovska, T., & Berzins, U. (2016). Characterization of senescence of culture-expanded human adipose-derived Mesenchymal stem cells. International Journal of Stem Cells, 9, 124–136. https://doi.org/10.15283/ijsc.2016.9.1.124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bartel, D. P. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 116, 281–297.

    Article  CAS  Google Scholar 

  8. Shomron, N., & Levy, C. (2009). MicroRNA-biogenesis and pre-mRNA splicing crosstalk. Journal of Biomedicine & Biotechnology, 2009, 594678. https://doi.org/10.1155/2009/594678.

    Article  CAS  Google Scholar 

  9. Lee, J., Li, Z., Brower-Sinning, R., & John, B. (2007). Regulatory circuit of human microRNA biogenesis. PLoS Computational Biology, 3, e67. https://doi.org/10.1371/journal.pcbi.0030067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Benhamed, M., Herbig, U., Ye, T., Dejean, A., & Bischof, O. (2012). Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells. Nature Cell Biology, 14, 266–275. https://doi.org/10.1038/ncb2443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dhahbi, J. M., Atamna, H., Boffelli, D., Magis, W., Spindler, S. R., & Martin, D. I. (2011). Deep sequencing reveals novel microRNAs and regulation of microRNA expression during cell senescence. PLoS One, 6, e20509. https://doi.org/10.1371/journal.pone.0020509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu, F. J., Wen, T., & Liu, L. (2012). MicroRNAs as a novel cellular senescence regulator. Ageing Research Reviews, 11, 41–50. https://doi.org/10.1016/j.arr.2011.06.001.

    Article  CAS  PubMed  Google Scholar 

  13. Govindasamy, V., Abdullah, A. N., Ronald, V. S., Musa, S., Ab Aziz, Z. A., Zain, R. B., Totey, S., Bhonde, R. R., & Abu Kasim, N. H. (2010). Inherent differential propensity of dental pulp stem cells derived from human deciduous and permanent teeth. Journal of Endodontics, 36, 1504–1515. https://doi.org/10.1016/j.joen.2010.05.006.

    Article  PubMed  Google Scholar 

  14. Koch, C. M., Reck, K., Shao, K., Lin, Q., Joussen, S., Ziegler, P., Walenda, G., Drescher, W., Opalka, B., May, T., Brummendorf, T., Zenke, M., Saric, T., & Wagner, W. (2013). Pluripotent stem cells escape from senescence-associated DNA methylation changes. Genome Research, 23, 248–259. https://doi.org/10.1101/gr.141945.112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Brown, P. T., Squire, M. W., & Li, W. J. (2014). Characterization and evaluation of mesenchymal stem cells derived from human embryonic stem cells and bone marrow. Cell and Tissue Research, 358, 149–164. https://doi.org/10.1007/s00441-014-1926-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wegmeyer, H., Broske, A. M., Leddin, M., Kuentzer, K., Nisslbeck, A. K., Hupfeld, J., Wiechmann, K., Kuhlen, J., von Schwerin, C., Stein, C., Knothe, S., Funk, J., Huss, R., & Neubauer, M. (2013). Mesenchymal stromal cell characteristics vary depending on their origin. Stem Cells and Development, 22, 2606–2618. https://doi.org/10.1089/scd.2013.0016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hong, H., Takahashi, K., Ichisaka, T., Aoi, T., Kanagawa, O., Nakagawa, M., Okita, K., & Yamanaka, S. (2009). Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature, 460, 1132–1135. https://doi.org/10.1038/nature08235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kawamura, T., Suzuki, J., Wang, Y. V., Menendez, S., Morera, L. B., Raya, A., Wahl, G. M., & Izpisua Belmonte, J. C. (2009). Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature, 460, 1140–1144. https://doi.org/10.1038/nature08311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Solozobova, V., & Blattner, C. (2011). p53 in stem cells. World Journal of Biological Chemistry, 2, 202–214. https://doi.org/10.4331/wjbc.v2.i9.202.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Gu, Y., Li, T., Ding, Y., Sun, L., Tu, T., Zhu, W., Hu, J., & Sun, X. (2016). Changes in mesenchymal stem cells following long-term culture in vitro. Molecular Medicine Reports, 13, 5207–5215. https://doi.org/10.3892/mmr.2016.5169.

    Article  CAS  PubMed  Google Scholar 

  21. Mandal, P. K., Blanpain, C., & Rossi, D. J. (2011). DNA damage response in adult stem cells: Pathways and consequences. Nature reviews. Molecular Cell Biology, 12, 198–202. https://doi.org/10.1038/nrm3060.

    Article  CAS  PubMed  Google Scholar 

  22. Simara, P., Tesarova, L., Rehakova, D., Matula, P., Stejskal, S., Hampl, A., & Koutna, I. (2017). DNA double-strand breaks in human induced pluripotent stem cell reprogramming and long-term in vitro culturing. Stem Cell Research & Therapy, 8, 73. https://doi.org/10.1186/s13287-017-0522-5.

    Article  CAS  Google Scholar 

  23. Whitfield, M. J., Lee, W. C., & Van Vliet, K. J. (2013). Onset of heterogeneity in culture-expanded bone marrow stromal cells. Stem Cell Research, 11, 1365–1377. https://doi.org/10.1016/j.scr.2013.09.004.

    Article  CAS  PubMed  Google Scholar 

  24. Muraglia, A., Cancedda, R., & Quarto, R. (2000). Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model. Journal of Cell Science, 113(Pt 7), 1161–1166.

    CAS  PubMed  Google Scholar 

  25. Aponte, P. M., & Caicedo, A. (2017). Stemness in Cancer: Stem cells, Cancer stem cells, and their microenvironment. Stem Cells International, 2017, 5619472. https://doi.org/10.1155/2017/5619472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Viatour, P. (2012). Bridges between cell cycle regulation and self-renewal maintenance. Genes & Cancer, 3, 670–677. https://doi.org/10.1177/1947601913481355.

    Article  CAS  Google Scholar 

  27. Ba, H., Wang, D., & Li, C. (2016). MicroRNA profiling of antler stem cells in potentiated and dormant states and their potential roles in antler regeneration. Molecular Genetics and Genomics : MGG, 291, 943–955. https://doi.org/10.1007/s00438-015-1158-8.

    Article  CAS  PubMed  Google Scholar 

  28. Filipowicz, W., Bhattacharyya, S. N., & Sonenberg, N. (2008). Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nature Reviews. Genetics, 9, 102–114. https://doi.org/10.1038/nrg2290.

    Article  CAS  PubMed  Google Scholar 

  29. Heinrich, E. M., & Dimmeler, S. (2012). MicroRNAs and stem cells: Control of pluripotency, reprogramming, and lineage commitment. Circulation Research, 110, 1014–1022. https://doi.org/10.1161/circresaha.111.243394.

    Article  CAS  PubMed  Google Scholar 

  30. Maroney, P. A., Yu, Y., Fisher, J., & Nilsen, T. W. (2006). Evidence that microRNAs are associated with translating messenger RNAs in human cells. Nature Structural & Molecular Biology, 13, 1102–1107. https://doi.org/10.1038/nsmb1174.

    Article  CAS  Google Scholar 

  31. Thomson, J. M., Newman, M., Parker, J. S., Morin-Kensicki, E. M., Wright, T., & Hammond, S. M. (2006). Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes & Development, 20, 2202–2207. https://doi.org/10.1101/gad.1444406.

    Article  CAS  Google Scholar 

  32. Zhao, B., Yang, D., Jiang, J., Li, J., Fan, C., Huang, M., Fan, Y., Jin, Y., & Jin, Y. (2014). Genome-wide mapping of miRNAs expressed in embryonic stem cells and pluripotent stem cells generated by different reprogramming strategies. BMC Genomics, 15, 488. https://doi.org/10.1186/1471-2164-15-488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Guo, L., Zhao, R. C., & Wu, Y. (2011). The role of microRNAs in self-renewal and differentiation of mesenchymal stem cells. Experimental Hematology, 39, 608–616. https://doi.org/10.1016/j.exphem.2011.01.011.

    Article  CAS  PubMed  Google Scholar 

  34. Meng, X., Sun, B., Xue, M., Xu, P., Hu, F., & Xiao, Z. (2016). Comparative analysis of microRNA expression in human mesenchymal stem cells from umbilical cord and cord blood. Genomics, 107, 124–131. https://doi.org/10.1016/j.ygeno.2016.02.006.

    Article  CAS  PubMed  Google Scholar 

  35. Ren, J., Jin, P., Wang, E., Marincola, F. M., & Stroncek, D. F. (2009). MicroRNA and gene expression patterns in the differentiation of human embryonic stem cells. Journal of Translational Medicine, 7, 20. https://doi.org/10.1186/1479-5876-7-20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sharma, A., & Wu, J. C. (2013). MicroRNA expression profiling of human-induced pluripotent and embryonic stem cells. Methods in Molecular Biology (Clifton, N.J.), 936, 247–256. https://doi.org/10.1007/978-1-62703-083-0_19.

    Article  CAS  Google Scholar 

  37. Tang, F., Hajkova, P., Barton, S. C., Lao, K., & Surani, M. A. (2006). MicroRNA expression profiling of single whole embryonic stem cells. Nucleic Acids Research, 34, e9. https://doi.org/10.1093/nar/gnj009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dalton, S. (2013). Signaling networks in human pluripotent stem cells. Current Opinion in Cell Biology, 25, 241–246. https://doi.org/10.1016/j.ceb.2012.09.005.

    Article  CAS  PubMed  Google Scholar 

  39. Ito, K., & Suda, T. (2014). Metabolic requirements for the maintenance of self-renewing stem cells. Nature reviews. Molecular Cell Biology, 15, 243–256. https://doi.org/10.1038/nrm3772.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Qi, Y., Liu, J., Saadat, S., Tian, X., Han, Y., Fong, G. H., Pandolfi, P. P., Lee, L. Y., & Li, S. (2015). PTEN induces apoptosis and cavitation via HIF-2-dependent Bnip3 upregulation during epithelial lumen formation. Cell Death and Differentiation, 22, 875–884. https://doi.org/10.1038/cdd.2014.185.

    Article  CAS  PubMed  Google Scholar 

  41. Takase, O., Yoshikawa, M., Idei, M., Hirahashi, J., Fujita, T., Takato, T., Isagawa, T., Nagae, G., Suemori, H., Aburatani, H., & Hishikawa, K. (2013). The role of NF-kappaB signaling in the maintenance of pluripotency of human induced pluripotent stem cells. PLoS One, 8, e56399. https://doi.org/10.1371/journal.pone.0056399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ming, M., & He, Y. Y. (2012). PTEN in DNA damage repair. Cancer Letters, 319, 125–129. https://doi.org/10.1016/j.canlet.2012.01.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shen, W. H., Balajee, A. S., Wang, J., Wu, H., Eng, C., Pandolfi, P. P., & Yin, Y. (2007). Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell, 128, 157–170. https://doi.org/10.1016/j.cell.2006.11.042.

    Article  CAS  PubMed  Google Scholar 

  44. Chien, Y., Scuoppo, C., Wang, X., Fang, X., Balgley, B., Bolden, J. E., Premsrirut, P., Luo, W., Chicas, A., Lee, C. S., Kogan, S. C., & Lowe, S. W. (2011). Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity. Genes & Development, 25, 2125–2136. https://doi.org/10.1101/gad.17276711.

    Article  CAS  Google Scholar 

  45. Hermeking, H., & Benzinger, A. (2006). 14-3-3 proteins in cell cycle regulation. Seminars in Cancer Biology, 16, 183–192. https://doi.org/10.1016/j.semcancer.2006.03.002.

    Article  CAS  PubMed  Google Scholar 

  46. Morrison, D. K. (2009). The 14-3-3 proteins: Integrators of diverse signaling cues that impact cell fate and cancer development. Trends in Cell Biology, 19, 16–23. https://doi.org/10.1016/j.tcb.2008.10.003.

    Article  CAS  PubMed  Google Scholar 

  47. Harries, L. W., Fellows, A. D., Pilling, L. C., Hernandez, D., Singleton, A., Bandinelli, S., Guralnik, J., Powell, J., Ferrucci, L., & Melzer, D. (2012). Advancing age is associated with gene expression changes resembling mTOR inhibition: Evidence from two human populations. Mechanisms of Ageing and Development, 133, 556–562. https://doi.org/10.1016/j.mad.2012.07.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jung, C. H., Ro, S. H., Cao, J., Otto, N. M., & Kim, D. H. (2010). mTOR regulation of autophagy. FEBS Letters, 584, 1287–1295. https://doi.org/10.1016/j.febslet.2010.01.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Inoki, K., Zhu, T., & Guan, K. L. (2003). TSC2 mediates cellular energy response to control cell growth and survival. Cell, 115, 577–590.

    Article  CAS  Google Scholar 

  50. Shaltiel, I. A., Krenning, L., Bruinsma, W., & Medema, R. H. (2015). The same, only different - DNA damage checkpoints and their reversal throughout the cell cycle. Journal of Cell Science, 128, 607–620. https://doi.org/10.1242/jcs.163766.

    Article  CAS  PubMed  Google Scholar 

  51. Schwermer, M., Lee, S., Koster, J., van Maerken, T., Stephan, H., Eggert, A., Morik, K., Schulte, J. H., & Schramm, A. (2015). Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors. Oncotarget, 6, 15425–15435. https://doi.org/10.18632/oncotarget.3908.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Branzei, D., & Foiani, M. (2008). Regulation of DNA repair throughout the cell cycle. Nature reviews. Molecular Cell Biology, 9, 297–308. https://doi.org/10.1038/nrm2351.

    Article  CAS  PubMed  Google Scholar 

  53. Rhind, N., & Russell, P. (2012). Signaling pathways that regulate cell division. Cold Spring Harbor Perspectives in Biology, 4. https://doi.org/10.1101/cshperspect.a005942.

  54. Westbrook, L., Manuvakhova, M., Kern, F. G., Estes, N. R., 2nd, Ramanathan, H. N., & Thottassery, J. V. (2007). Cks1 regulates cdk1 expression: A novel role during mitotic entry in breast cancer cells. Cancer Research, 67, 11393–11401. https://doi.org/10.1158/0008-5472.can-06-4173.

    Article  CAS  PubMed  Google Scholar 

  55. Satyanarayana, A., Berthet, C., Lopez-Molina, J., Coppola, V., Tessarollo, L., & Kaldis, P. (2008). Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2. Development (Cambridge, England), 135, 3389–3400. https://doi.org/10.1242/dev.024919.

    Article  CAS  Google Scholar 

  56. Tsai, Y. S., Chang, H. C., Chuang, L. Y., & Hung, W. C. (2005). RNA silencing of Cks1 induced G2/M arrest and apoptosis in human lung cancer cells. IUBMB Life, 57, 583–589. https://doi.org/10.1080/15216540500215531.

    Article  CAS  PubMed  Google Scholar 

  57. Chen, H., Lu, Q., Fei, X., Shen, L., Jiang, D., & Dai, D. (2016). miR-22 inhibits the proliferation, motility, and invasion of human glioblastoma cells by directly targeting SIRT1. Tumour biology : The Journal of The International Society for Oncodevelopmental Biology and Medicine, 37, 6761–6768. https://doi.org/10.1007/s13277-015-4575-8.

    Article  CAS  Google Scholar 

  58. Lou, C., Xiao, M., Cheng, S., Lu, X., Jia, S., Ren, Y., & Li, Z. (2016). MiR-485-3p and miR-485-5p suppress breast cancer cell metastasis by inhibiting PGC-1alpha expression. Cell Death & Disease, 7, e2159. https://doi.org/10.1038/cddis.2016.27.

    Article  CAS  Google Scholar 

  59. Wakeling, L. A., Ions, L. J., & Ford, D. (2009). Could Sirt1-mediated epigenetic effects contribute to the longevity response to dietary restriction and be mimicked by other dietary interventions? Age (Dordrecht, Netherlands), 31, 327–341. https://doi.org/10.1007/s11357-009-9104-5.

    Article  CAS  Google Scholar 

  60. Luo, J., Nikolaev, A. Y., Imai, S., Chen, D., Su, F., Shiloh, A., Guarente, L., & Gu, W. (2001). Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell, 107, 137–148.

    Article  CAS  Google Scholar 

  61. Ong, A. L. C., & Ramasamy, T. S. (2018). Role of Sirtuin1-p53 regulatory axis in aging, cancer and cellular reprogramming. Ageing Research Reviews, 43, 64–80. https://doi.org/10.1016/j.arr.2018.02.004.

    Article  CAS  PubMed  Google Scholar 

  62. Yeung, F., Hoberg, J. E., Ramsey, C. S., Keller, M. D., Jones, D. R., Frye, R. A., & Mayo, M. W. (2004). Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. The EMBO Journal, 23, 2369–2380. https://doi.org/10.1038/sj.emboj.7600244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Nemoto, S., Fergusson, M. M., & Finkel, T. (2005). SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. The Journal of Biological Chemistry, 280, 16456–16460. https://doi.org/10.1074/jbc.M501485200.

    Article  PubMed  Google Scholar 

  64. Faustman, D. L., & Davis, M. (2013). TNF receptor 2 and disease: Autoimmunity and regenerative medicine. Frontiers in Immunology, 4, 478. https://doi.org/10.3389/fimmu.2013.00478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Naude, P. J., den Boer, J. A., Luiten, P. G., & Eisel, U. L. (2011). Tumor necrosis factor receptor cross-talk. The FEBS Journal, 278, 888–898. https://doi.org/10.1111/j.1742-4658.2011.08017.x.

    Article  CAS  PubMed  Google Scholar 

  66. Rauert, H., Stuhmer, T., Bargou, R., Wajant, H., & Siegmund, D. (2011). TNFR1 and TNFR2 regulate the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms. Cell Death & Disease, 2, e194. https://doi.org/10.1038/cddis.2011.78.

    Article  CAS  Google Scholar 

  67. Tuncer, S., & Banerjee, S. (2015). Eicosanoid pathway in colorectal cancer: Recent updates. World Journal of Gastroenterology, 21, 11748–11766. https://doi.org/10.3748/wjg.v21.i41.11748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Mishra, K. P., Jain, S., Ganju, L., & Singh, S. B. (2014). Hypoxic stress induced TREM-1 and inflammatory chemokines in human peripheral blood mononuclear cells. Indian Journal of Clinical Biochemistry : IJCB, 29, 133–138. https://doi.org/10.1007/s12291-013-0345-9.

    Article  CAS  PubMed  Google Scholar 

  69. Hichor, M., Sundaram, V. K., Eid, S. A., Abdel-Rassoul, R., Petit, P. X., Borderie, D., Bastin, J., Eid, A. A., & Manuel, M. (2018). Liver X Receptor exerts a protective effect against the oxidative stress in the peripheral nerve. Liver X Receptor exerts a protective effect against the oxidative stress in the peripheral nerve., 8, 2524. https://doi.org/10.1038/s41598-018-20980-3.

    Article  CAS  Google Scholar 

  70. Lukin, D. J., Carvajal, L. A., Liu, W. J., Resnick-Silverman, L., & Manfredi, J. J. (2015). p53 promotes cell survival due to the reversibility of its cell-cycle checkpoints. Molecular cancer research : MCR, 13, 16–28. https://doi.org/10.1158/1541-7786.mcr-14-0177.

    Article  CAS  PubMed  Google Scholar 

  71. Lee, J. H., Park, S. J., Jeong, S. Y., Kim, M. J., Jun, S., Lee, H. S., Chang, I. Y., Lim, S. C., Yoon, S. P., Yong, J., & You, H. J. (2015). MicroRNA-22 suppresses DNA repair and promotes genomic instability through targeting of MDC1. Cancer Research, 75, 1298–1310. https://doi.org/10.1158/0008-5472.can-14-2783.

    Article  CAS  PubMed  Google Scholar 

  72. Huang, Z. P., Chen, J., Seok, H. Y., Zhang, Z., Kataoka, M., Hu, X., & Wang, D. Z. (2013). MicroRNA-22 regulates cardiac hypertrophy and remodeling in response to stress. Circulation Research, 112, 1234–1243. https://doi.org/10.1161/circresaha.112.300682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wang, Z., Qin, G., & Zhao, T. C. (2014). HDAC4: Mechanism of regulation and biological functions. Epigenomics, 6, 139–150. https://doi.org/10.2217/epi.13.73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Xu, D., Takeshita, F., Hino, Y., Fukunaga, S., Kudo, Y., Tamaki, A., Matsunaga, J., Takahashi, R. U., Takata, T., Shimamoto, A., Ochiya, T., & Tahara, H. (2011). miR-22 represses cancer progression by inducing cellular senescence. The Journal of Cell Biology, 193, 409–424. https://doi.org/10.1083/jcb.201010100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jazbutyte, V., Fiedler, J., Kneitz, S., Galuppo, P., Just, A., Holzmann, A., Bauersachs, J., & Thum, T. (2013). MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age (Dordrecht, Netherlands), 35, 747–762. https://doi.org/10.1007/s11357-012-9407-9.

    Article  CAS  Google Scholar 

  76. Bar, N., & Dikstein, R. (2010). miR-22 forms a regulatory loop in PTEN/AKT pathway and modulates signaling kinetics. PloS One, 5, e10859. https://doi.org/10.1371/journal.pone.0010859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Guo, M. M., Hu, L. H., Wang, Y. Q., Chen, P., Huang, J. G., Lu, N., He, J. H., & Liao, C. G. (2013). miR-22 is down-regulated in gastric cancer, and its overexpression inhibits cell migration and invasion via targeting transcription factor Sp1. Medical Oncology (Northwood, London, England), 30, 542. https://doi.org/10.1007/s12032-013-0542-7.

    Article  CAS  Google Scholar 

  78. Kong, L. M., Liao, C. G., Zhang, Y., Xu, J., Li, Y., Huang, W., Zhang, Y., Bian, H., & Chen, Z. N. (2014). A regulatory loop involving miR-22, Sp1, and c-Myc modulates CD147 expression in breast cancer invasion and metastasis. Cancer Research, 74, 3764–3778. https://doi.org/10.1158/0008-5472.can-13-3555.

    Article  CAS  PubMed  Google Scholar 

  79. Song, S. J., Ito, K., Ala, U., Kats, L., Webster, K., Sun, S. M., Jongen-Lavrencic, M., Manova-Todorova, K., Teruya-Feldstein, J., Avigan, D. E., Delwel, R., & Pandolfi, P. P. (2013). The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. Cell Stem Cell, 13, 87–101. https://doi.org/10.1016/j.stem.2013.06.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chen, Z., Li, Q., Wang, S., & Zhang, J. (2015). miR4855p inhibits bladder cancer metastasis by targeting HMGA2. International Journal of Molecular Medicine, 36, 1136–1142. https://doi.org/10.3892/ijmm.2015.2302.

    Article  CAS  PubMed  Google Scholar 

  81. Wu, A., Wu, K., Li, J., Mo, Y., Lin, Y., Wang, Y., Shen, X., Li, S., Li, L., & Yang, Z. (2015). Let-7a inhibits migration, invasion and epithelial-mesenchymal transition by targeting HMGA2 in nasopharyngeal carcinoma. Journal of Translational Medicine, 13, 105. https://doi.org/10.1186/s12967-015-0462-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sampson, V. B., Rong, N. H., Han, J., Yang, Q., Aris, V., Soteropoulos, P., Petrelli, N. J., Dunn, S. P., & Krueger, L. J. (2007). MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Research, 67, 9762–9770. https://doi.org/10.1158/0008-5472.can-07-2462.

    Article  CAS  PubMed  Google Scholar 

  83. Chang, H. M., Martinez, N. J., Thornton, J. E., Hagan, J. P., Nguyen, K. D., & Gregory, R. I. (2012). Trim71 cooperates with microRNAs to repress Cdkn1a expression and promote embryonic stem cell proliferation. Nature Communications, 3, 923. https://doi.org/10.1038/ncomms1909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Iwasaki, T., Tanaka, K., Kawano, M., Itonaga, I., & Tsumura, H. (2015). Tumor-suppressive microRNA-let-7a inhibits cell proliferation via targeting of E2F2 in osteosarcoma cells. International Journal of Oncology, 46, 1543–1550. https://doi.org/10.3892/ijo.2015.2867.

    Article  CAS  PubMed  Google Scholar 

  85. Faherty, N., Curran, S. P., O'Donovan, H., Martin, F., Godson, C., Brazil, D. P., & Crean, J. K. (2012). CCN2/CTGF increases expression of miR-302 microRNAs, which target the TGFbeta type II receptor with implications for nephropathic cell phenotypes. Journal of Cell Science, 125, 5621–5629. https://doi.org/10.1242/jcs.105528.

    Article  CAS  PubMed  Google Scholar 

  86. Keklikoglou, I., Koerner, C., Schmidt, C., Zhang, J. D., Heckmann, D., Shavinskaya, A., Allgayer, H., Guckel, B., Fehm, T., Schneeweiss, A., Sahin, O., Wiemann, S., & Tschulena, U. (2012). MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-kappaB and TGF-beta signaling pathways. Oncogene, 31, 4150–4163. https://doi.org/10.1038/onc.2011.571.

    Article  CAS  PubMed  Google Scholar 

  87. Subramanyam, D., Lamouille, S., Judson, R. L., Liu, J. Y., Bucay, N., Derynck, R., & Blelloch, R. (2011). Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nature Biotechnology, 29, 443–448. https://doi.org/10.1038/nbt.1862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Barroso-delJesus, A., Lucena-Aguilar, G., Sanchez, L., Ligero, G., Gutierrez-Aranda, I., & Menendez, P. (2011). The nodal inhibitor lefty is negatively modulated by the microRNA miR-302 in human embryonic stem cells. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 25, 1497–1508. https://doi.org/10.1096/fj.10-172221.

    Article  CAS  Google Scholar 

  89. Rosa, A., Papaioannou, M. D., Krzyspiak, J. E., & Brivanlou, A. H. (2014). miR-373 is regulated by TGFbeta signaling and promotes mesendoderm differentiation in human embryonic stem cells. Developmental Biology, 391, 81–88. https://doi.org/10.1016/j.ydbio.2014.03.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhou, A. D., Diao, L. T., Xu, H., Xiao, Z. D., Li, J. H., Zhou, H., & Qu, L. H. (2012). Beta-catenin/LEF1 transactivates the microRNA-371-373 cluster that modulates the Wnt/beta-catenin-signaling pathway. Oncogene, 31, 2968–2978. https://doi.org/10.1038/onc.2011.461.

    Article  CAS  PubMed  Google Scholar 

  91. Chen, Y. J., Luo, J., Yang, G. Y., Yang, K., Wen, S. Q., & Zou, S. Q. (2012). Mutual regulation between microRNA-373 and methyl-CpG-binding domain protein 2 in hilar cholangiocarcinoma. World Journal of Gastroenterology, 18, 3849–3861. https://doi.org/10.3748/wjg.v18.i29.3849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lee, M. R., Prasain, N., Chae, H. D., Kim, Y. J., Mantel, C., Yoder, M. C., & Broxmeyer, H. E. (2013). Epigenetic regulation of NANOG by miR-302 cluster-MBD2 completes induced pluripotent stem cell reprogramming. Stem cells (Dayton, Ohio), 31, 666–681. https://doi.org/10.1002/stem.1302.

    Article  CAS  Google Scholar 

  93. Lee, K. H., Goan, Y. G., Hsiao, M., Lee, C. H., Jian, S. H., Lin, J. T., Chen, Y. L., & Lu, P. J. (2009). MicroRNA-373 (miR-373) post-transcriptionally regulates large tumor suppressor, homolog 2 (LATS2) and stimulates proliferation in human esophageal cancer. Experimental Cell Research, 315, 2529–2538. https://doi.org/10.1016/j.yexcr.2009.06.001.

    Article  CAS  PubMed  Google Scholar 

  94. Tian, Y., Liu, Y., Wang, T., Zhou, N., Kong, J., Chen, L., Snitow, M., Morley, M., Li, D., Petrenko, N., Zhou, S., Lu, M., Gao, E., Koch, W. J., Stewart, K. M., & Morrisey, E. E. (2015). A microRNA-hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice. Science Translational Medicine, 7, 279ra238. https://doi.org/10.1126/scitranslmed.3010841.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by High Impact Research MOHE Grant UM.C/625/1/HIR/MOHE/DENT/01 from Ministry of Higher Education Malaysia, Fundamental Research Grant Scheme (FRGS FP044-2014B) from Ministry of Education, Malaysia and University of Malaya Research Grant (RP019C-13HTM) from University of Malaya. We would like to thank Prof. Dr. Sabri Musa for providing SHED samples.

Author information

Authors and Affiliations

  1. Department of Restorative Dentistry, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Shuh-Wen Aung & Noor Hayaty Abu Kasim

  2. Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Shamsul Azlin Ahmad Shamsuddin

  3. Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Thamil Selvee Ramasamy

Authors
  1. Shuh-Wen Aung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Noor Hayaty Abu Kasim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shamsul Azlin Ahmad Shamsuddin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thamil Selvee Ramasamy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thamil Selvee Ramasamy.

Ethics declarations

Conflict of Interest

The authors have declared no conflict of interest.

Additional information

Publisher’s Note

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

Electronic Supplementary Material

ESM 1

(DOCX 14 kb)

ESM 2

(DOCX 17 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aung, SW., Abu Kasim, N.H., Shamsuddin, S.A.A. et al. MicroRNAomic Transcriptomic Analysis Reveal Deregulation of Clustered Cellular Functions in Human Mesenchymal Stem Cells During in Vitro Passaging. Stem Cell Rev and Rep 16, 222–238 (2020). https://doi.org/10.1007/s12015-019-09924-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-019-09924-0

Keywords

Search

Navigation