Prenatal Mesenchymal Stem Cell Secretome and Its Clinical Implication

  • Lu Liang


Mesenchymal stem cells (MSCs) possess paracrine characteristic involving in the main therapeutic effects. The soluble factors secreted by MSCs are responsible for the paracrine activity, which have attracted more and more attention. These protein factors named secretome could be related to the biological processes such as wound healing, inflammatory response, angiogenesis, cell proliferation, chemotaxis, and neurogenesis. And they have bypassed the confounding issues of MSCs themselves. The MSC secretome in MSC-conditioned media (CM) could be manufactured and used as protein drugs. The cost of manufacturing, transport, and storage of secretome is lower than that of MSCs. Prenatal MSC secretome, especially placenta MSC secretome, has higher concentration and stronger capacities than that of other origins, which is a promising alternative to stem cell therapy for various diseases treatment.


  1. 1.
    Liang L, Li Z, Ma T, et al. Transplantation of human placenta-derived mesenchymal stem cells alleviates critical limb ischemia in diabetic nude rats. Cell Transplant. 2017;26(1):45–61.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Creane M, Howard L, O'Brien T, et al. Biodistribution and retention of locally administered human mesenchymal stromal cells: quantitative polymerase chain reaction-based detection of human DNA in murine organs. Cytotherapy. 2017;19(3):384–94.PubMedGoogle Scholar
  3. 3.
    Gnecchi M, Danieli P, Malpasso G, et al. Paracrine mechanisms of mesenchymal stem cells in tissue repair. Methods Mol Biol. 2016;1416:123–46.PubMedGoogle Scholar
  4. 4.
    Sarojini H, Estrada R, Lu H, et al. PEDF from mouse mesenchymal stem cell secretome attracts fibroblasts. J Cell Biochem. 2008;104(5):1793–802.PubMedGoogle Scholar
  5. 5.
    Estrada R, Li N, Sarojini H, et al. Secretome from mesenchymal stem cells induces angiogenesis via Cyr61. J Cell Physiol. 2009;219:563–71.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Ionescu L, Byrne RN, van Haaften T, et al. Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action. Am J Physiol Lung Cell Mol Physiol. 2012;303(11):L967–77.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Parekkadan B, van Poll D, Suganuma K, et al. Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS One. 2007;2(9):e941.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Xiang MX, He AN, Wang JA, et al. Protective paracrine effect of mesenchymal stem cells on cardiomyocytes. J Zhejiang Univ Sci B. 2009;10:619–24.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Xagorari A, Siotou E, Yiangou M, et al. Protective effect of mesenchymal stem cell-conditioned medium on hepatic cell apoptosis after acute liver injury. Int J Clin Exp Pathol. 2013;6(5):831–40.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Nakahara M, Okumura N, Kay EP, et al. Corneal endothelial expansion promoted by human bone marrow mesenchymal stem cell-derived conditioned medium. PLoS One. 2013;8(7):e69009.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Huang TF, Yew TL, Chiang ER, et al. Mesenchymal stem cells from a hypoxic culture improve and engraft Achilles tendon repair. Am J Sports Med. 2013;41:1117–25.PubMedGoogle Scholar
  12. 12.
    Hwang HJ, Chang W, Song BW, et al. Antiarrhythmic potential of mesenchymal stem cell is modulated by hypoxic environment. J Am Coll Cardiol. 2012;60:1698–706.PubMedGoogle Scholar
  13. 13.
    Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99:3838–43.PubMedGoogle Scholar
  14. 14.
    Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood. 2005;105:2214–9.PubMedGoogle Scholar
  15. 15.
    Meisel R, Zibert A, Laryea M, et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood. 2004;103:4619–21.PubMedGoogle Scholar
  16. 16.
    Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815–22.PubMedGoogle Scholar
  17. 17.
    Nauta AJ, Kruisselbrink AB, Lurvink E, et al. Mesenchymal stem cells inhibit generation and function of both CD34+−derived and monocyte-derived dendritic cells. J Immunol. 2006;177:2080–7.PubMedGoogle Scholar
  18. 18.
    Le Blanc K. Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy. 2003;5:485–9.PubMedGoogle Scholar
  19. 19.
    Khubutiya MS, Vagabov AV, Temnov AA, et al. Paracrine mechanisms of proliferative, anti-apoptotic and anti-inflammatory effects of mesenchymal stromal cells in models of acute organ injury. Cytotherapy. 2014;16:579–85.PubMedGoogle Scholar
  20. 20.
    Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11:723–37.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Svensson J, Jenmalm M, Matussek A, et al. Macrophages at the fetal-maternal interface express markers of alternative activation and are induced by M-CSF and IL-10. J Immunol. 2011;7:3671–82.Google Scholar
  22. 22.
    Jeannin P, Duluc D, Delneste Y. IL-6 and leukemia-inhibitory factor are involved in the generation of tumor-associated macrophage: regulation by IFN-gamma. Immunotherapy. 2011;3:23–6.PubMedGoogle Scholar
  23. 23.
    Buechler C, Ritter M, Orso E, et al. Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol. 2000;67:97–103.PubMedGoogle Scholar
  24. 24.
    Heusinkveld M, de Vos van Steenwijk PJ, Goedemans R, et al. M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4+ Th1 cells. J Immunol. 2011;187:1157–65.PubMedGoogle Scholar
  25. 25.
    Asami T, Ishii M, Fujii H, et al. Modulation of murine macrophage TLR7/8-mediated cytokine expression by mesenchymal stem cell-conditioned medium. Mediators Inflamm. 2013;2013:264260.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Kuraitis D, Giordano C, Ruel M, et al. Exploiting extracellular matrix-stem cell interactions: a review of natural materials for therapeutic muscle regeneration. Biomaterials. 2012;33:428–43.PubMedGoogle Scholar
  27. 27.
    Pawitan JA. Prospect of stem cell conditioned medium in regenerative medicine. Biomed Res Int. 2014;2014:965849.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Sassoli C, Frati A, Tani A, et al. Mesenchymal stromal cell secreted sphingosine 1-phosphate (S1P) exerts a stimulatory effect on skeletal myoblast proliferation. PLoS One. 2014;9(9):e108662.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Park YS, Hwang S, Jin YM. CCN1 secreted by tonsil derived mesenchymal stem cells promotes endothelial cell angiogenesis via integrinαvβ3 and AMPK. J Cell Physiol. 2015;230:140–9.PubMedGoogle Scholar
  30. 30.
    Shen C, Lie P, Miao T, et al. Conditioned medium from umbilical cord mesenchymal stem cells induces migration and angiogenesis. Mol Med Rep. 2015;12(1):20–30.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Komaki M, Numata Y, Morioka C, et al. Exosomes of human placenta-derived mesenchymal stem cells stimulate angiogenesis. Stem Cell Res Ther. 2017;8(1):219.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Zhao Q, Hu J, Xiang J, et al. Intranasal administration of human umbilical cord mesenchymal stem cells-conditioned medium enhances vascular remodeling after stroke. Brain Res. 2015;1624:489–96.PubMedGoogle Scholar
  33. 33.
    Kitaori T, Ito H, Schwarz EM, et al. Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum. 2009;60(3):813–23.PubMedGoogle Scholar
  34. 34.
    An JH, Park H, Song JA, et al. Transplantation of human umbilical cord blood-derived mesenchymal stem cells or their conditioned medium prevents bone loss in ovariectomized nude mice. Tissue Eng Part A. 2013;19(5–6):685–96.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Ando Y, Matsubara K, Ishikawa J, et al. Stem cell-conditioned medium accelerates distraction osteogenesis through multiple regenerative mechanisms. Bone. 2014;61:82–90.PubMedGoogle Scholar
  36. 36.
    Record M. Intercellular communication by exosomes in placenta: a possible role in cell fusion? Placenta. 2014;35(5):297–302.PubMedGoogle Scholar
  37. 37.
    Furuta T, Miyaki S, Ishitobi H, et al. Mesenchymal stem cell-derived exosomes promote fracture healing in a mouse model. Stem Cells Transl Med. 2016;5(12):1620–30.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9:581–93.PubMedGoogle Scholar
  39. 39.
    Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics. 2010;73:1907–20.PubMedGoogle Scholar
  40. 40.
    Bruno S, Grange C, Deregibus MC, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20:1053–67.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Herrera MB, Fonsato V, Gatti S, et al. Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats. J Cell Mol Med. 2010;14(6b):1605–18.PubMedGoogle Scholar
  42. 42.
    Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res (Amst). 2010;4:214–22.Google Scholar
  43. 43.
    Zhang S, Chu WC, Lai RC, et al. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthr Cartil. 2016;24(12):2135–40.PubMedGoogle Scholar
  44. 44.
    Yu B, Kim HW, Gong M, et al. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol. 2015;182:349–60.PubMedGoogle Scholar
  45. 45.
    Timmers L, Lim SK, Hoefer IE, et al. Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Res. 2011;6(3):206–14.PubMedGoogle Scholar
  46. 46.
    Gnecchi M, Zhang Z, Ni A, et al. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103:1204–19.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Jun EK, Zhang Q, Yoon BS, et al. Hypoxic conditioned medium from human amniotic fluid-derived mesenchymal stem cells accelerates skin wound healing through TGF-β/SMAD2 and PI3K/Akt pathways. Int J Mol Sci. 2014;15(1):605–28.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Walter MN, Wright KT, Fuller HR, et al. Mesenchymal stem cell-conditioned medium accelerates skin wound healing: an in vitro study of fibroblast and keratinocyte scratch assays. Exp Cell Res. 2010;316(7):1271–81.PubMedGoogle Scholar
  49. 49.
    Toupadakis CA, Wong A, Genetos DC, et al. Long-term administration of AMD3100, an antagonist of SDF-1/CXCR4 signaling, alters fracture repair. J Orthop Res. 2012;30:1853–9.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Ishikawa M, Ito H, Kitaori T, et al. MCP/CCR2 signaling is essential for recruitment of mesenchymal progenitor cells during the early phase of fracture healing. PLoS One. 2014;9:e104954.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Li X, Bai J, Ji X, et al. Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation and differentiation. Int J Mol Med. 2014;34(3):695–704.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Hwang JH, Lee MJ, Seok OS. Cytokine expression in placenta-derived mesenchymal stem cells in patients with pre-eclampsia and normal pregnancies. Cytokine. 2010;49(1):95–101.PubMedGoogle Scholar
  53. 53.
    Chen L, Xu Y, Zhao J, et al. Conditioned medium from hypoxic bone marrow-derived mesenchymal stem cells enhances wound healing in mice. PLoS One. 2014;9(4):e96161.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Tasso R, Gaetani M, Molino E, et al. The role of bFGF on the ability of MSC to activate endogenous regenerative mechanisms in an ectopic bone formation model. Biomaterials. 2012;33(7):2086–96.PubMedGoogle Scholar
  55. 55.
    Clabaut A, Grare C, Léger T, et al. Variations of secretome profiles according to conditioned medium preparation: the example of human mesenchymal stem cell-derived adipocytes. Electrophoresis. 2015;36(20):2587–93.PubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Lu Liang
    • 1
  1. 1.Tianjin Bion Bio-tech Co., Ltd.TianjinChina

Personalised recommendations