Molecular and Cellular Biochemistry

, Volume 446, Issue 1–2, pp 171–184 | Cite as

The biological changes of umbilical cord mesenchymal stem cells in inflammatory environment induced by different cytokines

  • Chao Yang
  • Yu Chen
  • Fan Li
  • Min You
  • Liwu Zhong
  • Wenxian Li
  • Bo Zhang
  • Qiang ChenEmail author


Mesenchymal stem cells (MSCs) are used as therapeutic tool for the treatment of immune diseases. The inflammatory environment also influences the characteristics of MSCs after transplantation. The aim of the study was to investigate the effects of pro-inflammatory cytokines on the characteristics of umbilical cord mesenchymal stem cells (UCMSCs). UCMSCs were exposed to pro-inflammatory cytokines in vitro for 3 and 7 days, and the biological properties were analyzed. The results showed that the proliferation ability was suppressed by interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). The adipogenic capacity was inhibited in all conditioned medium, while the chondrogenic and osteogenic capacity was enhanced by TNF-α and IL-1β in vitro. Prostaglandin E2 (PGE2) was increased by IL-1β on the third day, and angiopoietin-1 (Ang-1) was inhibited appreciably by TNF-α on the seventh day. Interleukin-6 (IL-6) was increased by TNF-α and IL-1β, and hepatocyte growth factor (HGF) was inhibited by all inflammatory cytokines. IFN-γ secretion level from human peripheral mononuclear cells (hPBMCs) was lowered by UCMSCs which had been stimulated by TNF-α or IL-1β for 3 days. Moreover, IFN-γ and TNF-α secretion level was only inhibited by UCMSCs which had been by stimulated IFN-γ for 3 days but not 7 days. Our data demonstrated that different inflammatory cytokines and the duration of treatment had different effects on the properties of UCMSCs, which might be instructive for clinical pretreatment in cellular therapeutics.


Umbilical cord mesenchymal stem cells Pro-inflammatory cytokines Proliferation Differentiation Paracrine Immunomodulatory capacity 


Compliance with ethical standards

Conflict of interest

No potential conflicts of interest were disclosed.


  1. 1.
    Murphy MB, Moncivais K, Caplan AI (2013) Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med 45:e54. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Niu P, Smagul A, Wang L, Sadvakas A, Sha Y, Perez LM, Nussupbekova A, Amirbekov A, Akanov AA, Galvez BG, Jordan IK, Lunyak VV (2015) Transcriptional profiling of interleukin-2-primed human adipose derived mesenchymal stem cells revealed dramatic changes in stem cells response imposed by replicative senescence. Oncotarget 6:17938–17957. PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Teshima T, Reddy P, Zeiser R (2016) Acute graft-versus-host disease: novel biological insights. Biol Blood Marrow Transplant 22:11–16. CrossRefGoogle Scholar
  4. 4.
    Resende RG, Abreu MH, de Souza LN, Silva ME, Gomez RS, Correia-Silva JF (2013) Association between IL1B (+3954) polymorphisms and IL-1beta levels in blood and saliva, together with acute graft-versus-host disease. J Interferon Cytokine Res 33:392–397. CrossRefPubMedGoogle Scholar
  5. 5.
    Weiss ML, Medicetty S, Bledsoe AR, Rachakatla RS, Choi M, Merchav S, Luo Y, Rao MS, Velagaleti G, Troyer D (2006) Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson’s disease. Stem Cells 24:781–792. CrossRefPubMedGoogle Scholar
  6. 6.
    Watson N, Divers R, Kedar R, Mehindru A, Mehindru A, Borlongan MC, Borlongan CV (2015) Discarded Wharton jelly of the human umbilical cord: a viable source for mesenchymal stromal cells. Cytotherapy 17:18–24. CrossRefPubMedGoogle Scholar
  7. 7.
    Kikuchi-Taura A, Taguchi A, Kanda T, Inoue T, Kasahara Y, Hirose H, Sato I, Matsuyama T, Nakagomi T, Yamahara K, Stern D, Ogawa H, Soma T (2012) Human umbilical cord provides a significant source of unexpanded mesenchymal stromal cells. Cytotherapy 14:441–450. CrossRefPubMedGoogle Scholar
  8. 8.
    Nagamura-Inoue T, Mukai T (2015) Umbilical cord is a rich source of mesenchymal stromal cells for cell therapy. Curr Stem Cell Res Ther 11:634–642CrossRefGoogle Scholar
  9. 9.
    Shi Z, Zhao L, Qiu G, He R, Detamore MS (2015) The effect of extended passaging on the phenotype and osteogenic potential of human umbilical cord mesenchymal stem cells. Mol Cell Biochem 401:155–164. CrossRefPubMedGoogle Scholar
  10. 10.
    Dehkordi MB, Madjd Z, Chaleshtori MH, Meshkani R, Nikfarjam L, Kajbafzadeh AM (2016) A simple, rapid, and efficient method for isolating mesenchymal stem cells from the entire umbilical cord. Cell Transplant 25:1287–1297. CrossRefPubMedGoogle Scholar
  11. 11.
    Li C, Li G, Liu M, Zhou T, Zhou H (2016) Paracrine effect of inflammatory cytokine-activated bone marrow mesenchymal stem cells and its role in osteoblast function. J Biosci Bioeng 121:213–219. CrossRefPubMedGoogle Scholar
  12. 12.
    Naaldijk Y, Johnson AA, Ishak S, Meisel HJ, Hohaus C, Stolzing A (2015) Migrational changes of mesenchymal stem cells in response to cytokines, growth factors, hypoxia, and aging. Exp Cell Res 338:97–104. CrossRefPubMedGoogle Scholar
  13. 13.
    Liang CC, Park AY, Guan JL (2007) In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2:329–333. CrossRefPubMedGoogle Scholar
  14. 14.
    Yi T, Song SU (2012) Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications. Arch Pharm Res 35:213–221. CrossRefPubMedGoogle Scholar
  15. 15.
    Feng X, Feng G, Xing J, Shen B, Tan W, Huang D, Lu X, Tao T, Zhang J, Li L, Gu Z (2014) Repeated lipopolysaccharide stimulation promotes cellular senescence in human dental pulp stem cells (DPSCs). Cell Tissue Res 356:369–380. CrossRefPubMedGoogle Scholar
  16. 16.
    Beyne-Rauzy O, Recher C, Dastugue N, Demur C, Pottier G, Laurent G, Sabatier L, Mansat-De Mas V (2004) Tumor necrosis factor alpha induces senescence and chromosomal instability in human leukemic cells. Oncogene 23:7507–7516. CrossRefPubMedGoogle Scholar
  17. 17.
    Kizil C, Kyritsis N, Brand M (2015) Effects of inflammation on stem cells: together they strive? EMBO Rep 16:416–426. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Liu C, Xiong H, Chen K, Huang Y, Huang Y, Yin X (2016) Long-term exposure to pro-inflammatory cytokines inhibits the osteogenic/dentinogenic differentiation of stem cells from the apical papilla. Int Endod J 49:950–959. CrossRefPubMedGoogle Scholar
  19. 19.
    Jadalannagari S, Aljitawi OS (2015) Ectodermal differentiation of Wharton’s jelly mesenchymal stem cells for tissue engineering and regenerative medicine applications. Tissue Eng B Rev 21:314–322. CrossRefGoogle Scholar
  20. 20.
    Wei H, Shen G, Deng X, Lou D, Sun B, Wu H, Long L, Ding T, Zhao J (2013) The role of IL-6 in bone marrow (BM)-derived mesenchymal stem cells (MSCs) proliferation and chondrogenesis. Cell Tissue Bank 14:699–706. CrossRefPubMedGoogle Scholar
  21. 21.
    Ahmed M, Gaffen SL (2013) IL-17 inhibits adipogenesis in part via C/EBPalpha, PPARgamma and Kruppel-like factors. Cytokine 61:898–905. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Shin JH, Shin DW, Noh M (2009) Interleukin-17A inhibits adipocyte differentiation in human mesenchymal stem cells and regulates pro-inflammatory responses in adipocytes. Biochem Pharmacol 77:1835–1844. CrossRefPubMedGoogle Scholar
  23. 23.
    Yan Z, Zhuansun Y, Chen R, Li J, Ran P (2014) Immunomodulation of mesenchymal stromal cells on regulatory T cells and its possible mechanism. Exp Cell Res 324:65–74. CrossRefPubMedGoogle Scholar
  24. 24.
    Castro-Manrreza ME, Montesinos JJ (2015) Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications. J Immunol Res 2015:394917. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Soleymaninejadian E, Pramanik K, Samadian E (2012) Immunomodulatory properties of mesenchymal stem cells: cytokines and factors. Am J Reprod Immunol 67:1–8. CrossRefPubMedGoogle Scholar
  26. 26.
    Bogdan C, Nathan C (1993) Modulation of macrophage function by transforming growth factor beta, interleukin-4, and interleukin-10. Ann N Y Acad Sci 685:713–739CrossRefPubMedGoogle Scholar
  27. 27.
    Minakuchi R, Wacholtz MC, Davis LS, Lipsky PE (1990) Delineation of the mechanism of inhibition of human T cell activation by PGE2. J Immunol 145:2616–2625PubMedGoogle Scholar
  28. 28.
    Scales WE, Chensue SW, Otterness I, Kunkel SL (1989) Regulation of monokine gene expression: prostaglandin E2 suppresses tumor necrosis factor but not interleukin-1 alpha or beta-mRNA and cell-associated bioactivity. J Leukoc Biol 45:416–421CrossRefPubMedGoogle Scholar
  29. 29.
    Benkhoucha M, Santiago-Raber ML, Schneiter G, Chofflon M, Funakoshi H, Nakamura T, Lalive PH (2010) Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 + Foxp3 + regulatory T cells. Proc Natl Acad Sci U S A 107:6424–6429. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Djouad F, Charbonnier LM, Bouffi C, Louis-Plence P, Bony C, Apparailly F, Cantos C, Jorgensen C, Noel D (2007) Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells 25:2025–2032. CrossRefPubMedGoogle Scholar
  31. 31.
    Selmani Z, Naji A, Gaiffe E, Obert L, Tiberghien P, Rouas-Freiss N, Carosella ED, Deschaseaux F (2009) HLA-G is a crucial immunosuppressive molecule secreted by adult human mesenchymal stem cells. Transplantation 87:S62–S66. CrossRefPubMedGoogle Scholar
  32. 32.
    Bruno S, Grange C, Tapparo M, Pasquino C, Romagnoli R, Dametto E, Amoroso A, Tetta C, Camussi G (2016) Human liver stem cells suppress T-cell proliferation, NK activity, and dendritic cell differentiation. Stem Cells Int 2016:8468549. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Wang X, Liu C, Li S, Xu Y, Chen P, Liu Y, Ding Q, Wahafu W, Hong B, Yang M (2015) Hypoxia precondition promotes adipose-derived mesenchymal stem cells based repair of diabetic erectile dysfunction via augmenting angiogenesis and neuroprotection. PLoS One 10:e0118951. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ren G, Zhao X, Zhang L, Zhang J, L’Huillier A, Ling W, Roberts AI, Le AD, Shi S, Shao C, Shi Y (2010) Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J Immunol 184:2321–2328. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Yang ZX, Han ZB, Ji YR, Wang YW, Liang L, Chi Y, Yang SG, Li LN, Luo WF, Li JP, Chen DD, Du WJ, Cao XC, Zhuo GS, Wang T, Han ZC (2013) CD106 identifies a subpopulation of mesenchymal stem cells with unique immunomodulatory properties. PLoS One 8:e59354. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D (2004) Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 103:4619–4621. CrossRefPubMedGoogle Scholar
  37. 37.
    Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822. CrossRefPubMedGoogle Scholar
  38. 38.
    Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey E (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15:42–49. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Stem Cells and Regenerative Medicine Research CenterSichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc.ChengduChina

Personalised recommendations