Mesenchymal Stem/ Stromal Cells metabolomic and bioactive factors profiles: A comparative analysis on the umbilical cord and dental pulp derived Stem/ Stromal Cells secretome

1. Bianco P, Robey PG, Simmons PJ. Mesenchymal Stem Cells: Revisiting History, Concepts, and Assays. Cell Stem Cell. 2008;2(4):313–9. http://dx.doi.org/10.1016/j.stem.2008.03.002.

2. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7. Epub 2006/08/23. doi: 10.1080/14653240600855905 16923606.

3. Barry FP, Murphy JM. Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol. 2004;36(4):568–84. doi: 10.1016/j.biocel.2003.11.001 15010324.

4. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science (New York, NY). 1999;284(5411):143–7. Epub 1999/04/02. doi: 10.1126/science.284.5411.143 10102814.

5. Mendicino M, Bailey AM, Wonnacott K, Puri RK, Bauer SR. MSC-based product characterization for clinical trials: an FDA perspective. Cell Stem Cell. 2014;14(2):141–5. doi: 10.1016/j.stem.2014.01.013 24506881.

6. Silachev DN, Goryunov KV, Shpilyuk MA, Beznoschenko OS, Morozova NY, Kraevaya EE, et al. Effect of MSCs and MSC-Derived Extracellular Vesicles on Human Blood Coagulation. Cells. 2019;8(3):258.

7. da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. Journal of Cell Science. 2006;119(11):2204–13.

8. Carvalho MM, Teixeira FG, Reis RL, Sousa N, Salgado AJ. Mesenchymal Stem Cells in the Umbilical Cord: Phenotypic Characterization, Secretome and Applications in Central Nervous System Regenerative Medicine. Curr Stem Cell Res T. 2011;6(3):221–8. WOS:000301639800005.

9. Patel AN, Vargas V, Revello P, Bull DA. Mesenchymal Stem Cell Population Isolated From the Subepithelial Layer of Umbilical Cord Tissue. Cell Transplant. 2013;22(3):513–9. doi: 10.3727/096368912x655064 WOS:000317257000013. 23057960

10. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230–47. Epub 1968/03/01. 5654088.

11. Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keilissb.Iv. Stromal Cells Responsible for Transferring Microenvironment of Hematopoietic Tissues—Cloning Invitro and Retransplantation Invivo. Transplantation. 1974;17(4):331–40. doi: 10.1097/00007890-197404000-00001 WOS:A1974S668500001. 4150881

12. Arutyunyan I, Fatkhudinov T, Sukhikh G. Umbilical cord tissue cryopreservation: a short review. Stem cell research & therapy. 2018;9(1):236.

13. Doorn J, Moll G, Le Blanc K, van Blitterswijk C, de Boer J. Therapeutic applications of mesenchymal stromal cells: paracrine effects and potential improvements. Tissue Engineering Part B: Reviews. 2012;18(2):101–15.

14. da Silva Meirelles L, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine & Growth Factor Reviews. 2009;20(5–6):419–27. http://dx.doi.org/10.1016/j.cytogfr.2009.10.002.

15. Natsu K, Ochi M, Mochizuki Y, Hachisuka H, Yanada S, Yasunaga Y. Allogeneic bone marrow-derived mesenchymal stromal cells promote the regeneration of injured skeletal muscle without differentiation into myofibers. Tissue engineering. 2004;10(7–8):1093–112. Epub 2004/09/15. doi: 10.1089/ten.2004.10.1093 15363167.

16. Merritt EK, Cannon MV, Hammers DW, Le LN, Gokhale R, Sarathy A, et al. Repair of traumatic skeletal muscle injury with bone-marrow-derived mesenchymal stem cells seeded on extracellular matrix. Tissue Eng Part A. 2010;16(9):2871–81. Epub 2010/04/24. doi: 10.1089/ten.TEA.2009.0826 20412030.

17. Haynesworth SE, Baber MA, Caplan AI. Cytokine expression by human marrow‐derived mesenchymal progenitor cells in vitro: Effects of dexamethasone and IL‐1α. Journal of cellular physiology. 1996;166(3):585–92.

18. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. Journal of Cellular Biochemistry. 2006;98(5):1076–84. doi: 10.1002/jcb.20886 16619257

19. Zimmerlin L, Park TS, Zambidis ET, Donnenberg VS, Donnenberg AD. Mesenchymal stem cell secretome and regenerative therapy after cancer. Biochimie. 2013;95(12):2235–45. doi: 10.1016/j.biochi.2013.05.010 WOS:000327805400006. 23747841

20. Chen L, Tredget EE, Wu PYG, Wu Y. Paracrine Factors of Mesenchymal Stem Cells Recruit Macrophages and Endothelial Lineage Cells and Enhance Wound Healing. PloS one. 2008;3(4):e1886. doi: 10.1371/journal.pone.0001886 18382669

21. Pereira T, Ivanova G, Caseiro AR, Barbosa P, Bartolo PJ, Santos JD, et al. MSCs Conditioned Media and Umbilical Cord Blood Plasma Metabolomics and Composition. PloS one. 2014;9(11):e113769. doi: 10.1371/journal.pone.0113769 25423186.

22. Lai RC, Arslan F, Tan SS, Tan B, Choo A, Lee MM, et al. Derivation and characterization of human fetal MSCs: An alternative cell source for large-scale production of cardioprotective microparticles. Journal of molecular and cellular cardiology. 2010;48(6):1215–24. doi: 10.1016/j.yjmcc.2009.12.021 WOS:000277944700025. 20064522

23. Timmers L, Lim SK, Hoefer IE, Arslan F, Lai RC, van Oorschot AAM, et al. Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem cell research. 2011;6(3):206–14. doi: 10.1016/j.scr.2011.01.001 WOS:000291295800002. 21419744

24. Vizoso F, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. International journal of molecular sciences. 2017;18(9):1852. doi: 10.3390/ijms18091852 28841158

25. Bronckaers A, Hilkens P, Martens W, Gervois P, Ratajczak J, Struys T, et al. Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis. Pharmacology & therapeutics. 2014;143(2):181–96.

26. Hocking AM. The role of chemokines in mesenchymal stem cell homing to wounds. Advances in wound care. 2015;4(11):623–30. doi: 10.1089/wound.2014.0579 26543676

27. Pereira T, Armada-da Silva P, Amorim I, Rêma A, Caseiro A, Gartner A, et al. Effects of Human Mesenchymal Stem Cells isolated from the Wharton’s jelly of the umbilical cord and conditioned media on skeletal muscle regeneration using a myectomy model. Cells, tissues, organs. 2014:(in revision).

28. Volarevic V, Markovic BS, Gazdic M, Volarevic A, Jovicic N, Arsenijevic N, et al. Ethical and safety issues of stem cell-based therapy. International journal of medical sciences. 2018;15(1):36.

29. Skalnikova HK. Proteomic techniques for characterisation of mesenchymal stem cell secretome. Biochimie. 2013;95(12):2196–211. doi: 10.1016/j.biochi.2013.07.015 WOS:000327805400002. 23880644

30. Panfoli I, Calzia D, Santucci L, Ravera S, Bruschi M, Candiano G. A blue dive: from 'blue fingers' to 'blue silver'. A comparative overview of staining methods for in-gel proteomics. Expert Rev Proteomic. 2012;9(6):627–34. doi: 10.1586/Epr.12.63 WOS:000312604700013. 23256673

31. Malmstrom J, Lee H, Aebersold R. Advances in proteomic workflows for systems biology. Curr Opin Biotech. 2007;18(4):378–84. doi: 10.1016/j.copbio.2007.07.005 WOS:000249980400015. 17698335

32. Brown KJ, Formolo CA, Seol H, Marathi RL, Duguez S, An E, et al. Advances in the proteomic investigation of the cell secretome. Expert Rev Proteomic. 2012;9(3):337–45. doi: 10.1586/Epr.12.21 WOS:000306542300015. 22809211

33. Beckonert O, Keun HC, Ebbels TM, Bundy J, Holmes E, Lindon JC, et al. Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nature protocols. 2007;2(11):2692–703. doi: 10.1038/nprot.2007.376 18007604

34. Zhang S, Nagana Gowda GA, Ye T, Raftery D. Advances in NMR-based biofluid analysis and metabolite profiling. Analyst. 2010;135(7):1490–8. doi: 10.1039/c000091d 20379603

35. Madhu B, Narita M, Jauhiainen A, Menon S, Stubbs M, Tavare S, et al. Metabolomic changes during cellular transformation monitored by metabolite-metabolite correlation analysis and correlated with gene expression. Metabolomics. 2015;11(6):1848–63. doi: 10.1007/s11306-015-0838-z WOS:000363040600032. 26491426

36. Beger RD. A review of applications of metabolomics in cancer. Metabolites. 2013;3(3):552–74. doi: 10.3390/metabo3030552 24958139

37. MacIntyre DA, Melguizo Sanchís D, Jiménez B, Moreno R, Stojkovic M, Pineda-Lucena A. Characterisation of Human Embryonic Stem Cells Conditioning Media by 1H-Nuclear Magnetic Resonance Spectroscopy. PloS one. 2011;6(2):e16732. doi: 10.1371/journal.pone.0016732 21347425

38. Baraniak PR, McDevitt TC. Stem cell paracrine actions and tissue regeneration. Regenerative medicine. 2010;5(1):121–43. doi: 10.2217/rme.09.74 20017699

39. Skalnikova H, Motlik J, Gadher SJ, Kovarova H. Mapping of the secretome of primary isolates of mammalian cells, stem cells and derived cell lines. Proteomics. 2011;11(4):691–708. doi: 10.1002/pmic.201000402 WOS:000287941800013. 21241017

40. Caseiro AR, Pereira T, Bártolo PJ, Santos JD, Luís AL, Maurício AC. Chapter—Trends in Mesenchymal Stem Cells Applications for Skeletal Muscle Repair and Regeneration, in PROGRESS IN STEM CELL TRANSPLANTATION: T Demirer 2015.

41. Caseiro AR, Pereira T, Ivanova G, Lu, #xed, s AL, et al. Neuromuscular Regeneration: Perspective on the Application of Mesenchymal Stem Cells and Their Secretion Products. Stem Cells International. 2016;2016:16. doi: 10.1155/2016/9756973 26880998

42. Pereira T, Armada-da Silva P, Amorim I, Rêma A, Caseiro A, Gärtner A, et al. Effects of Human Mesenchymal Stem Cells Isolated from Wharton’s Jelly of the Umbilical Cord and Conditioned Media on Skeletal Muscle Regeneration Using a Myectomy Model. Stem Cells International. 2014;2014.

43. Caseiro A, Ivanova G, Pedrosa S, Branquinho M, Georgieva P, Barbosa P, et al. Human umbilical cord blood plasma as an alternative to animal sera for mesenchymal stromal cells in vitro expansion–A multicomponent metabolomic analysis. PloS one. 2018;13(10):e0203936. doi: 10.1371/journal.pone.0203936 30304014

44. Jeener J, Meier BH, Bachmann P, Ernst RR. Investigation of Exchange Processes by 2-Dimensional Nmr-Spectroscopy. J Chem Phys. 1979;71(11):4546–53. doi: 10.1063/1.438208 WOS:A1979HW09500041.

45. Meiboom S, Gill D. Modified Spin-Echo Method for Measuring Nuclear Relaxation Times. Review of Scientific Instruments. 1958;29(8):688–91. doi: 10.1063/1.1716296 WOS:A1958WH51500003.

46. Liang X, Du L, Su F, Parekh HS, Su W. The application of quantitative NMR for the facile, rapid and reliable determination of clindamycin phosphate in a conventional tablet formulation. Magnetic Resonance in Chemistry. 2014.

47. Pereira T, Ivanova G, Caseiro AR, Barbosa P, Bártolo PJ, Santos JD, et al. MSCs conditioned media and umbilical cord blood plasma metabolomics and composition. PloS one. 2014;9(11):e113769. doi: 10.1371/journal.pone.0113769 25423186

48. Liang XR, Du LP, Su F, Parekh HS, Su WK. The application of quantitative NMR for the facile, rapid and reliable determination of clindamycin phosphate in a conventional tablet formulation. Magnetic Resonance in Chemistry. 2014;52(4):178–82. doi: 10.1002/mrc.4048 WOS:000332972700005. 24464591

49. Struys T, Moreels M, Martens W, Donders R, Wolfs E, Lambrichts I. Ultrastructural and immunocytochemical analysis of multilineage differentiated human dental pulp- and umbilical cord-derived mesenchymal stem cells. Cells Tissues Organs. 2011;193(6):366–78. doi: 10.1159/000321400 21124001.

50. Stefkova K, Prochazkova J, Pachernik J. Alkaline Phosphatase in Stem Cells. Stem cells international. 2015. Artn 628368 doi: 10.1155/2015/628368 WOS:000350163700001. 25767512

51. Pierantozzi E, Gava B, Manini I, Roviello F, Marotta G, Chiavarelli M, et al. Pluripotency Regulators in Human Mesenchymal Stem Cells: Expression of NANOG But Not of OCT-4 and SOX-2. Stem Cells and Development. 2011;20(5):915–23. doi: 10.1089/scd.2010.0353 WOS:000290255300015. 20879854

52. Blazquez-Martinez A, Chiesa M, Arnalich F, Fernandez-Delgado J, Nistal M, De Miguel MP. c-Kit identifies a subpopulation of mesenchymal stem cells in adipose tissue with higher telomerase expression and differentiation potential. Differentiation. 2014;87(3–4):147–60. doi: 10.1016/j.diff.2014.02.007 WOS:000339995900006. 24713343

53. Tsai C-C, Su P-F, Huang Y-F, Yew T-L, Hung S-C. Oct4 and Nanog Directly Regulate Dnmt1 to Maintain Self-Renewal and Undifferentiated State in Mesenchymal Stem Cells. Molecular Cell. 2012;47(2):169–82. doi: 10.1016/j.molcel.2012.06.020 22795133

54. Nuschke A, Rodrigues M, Wells AW, Sylakowski K, Wells A. Mesenchymal stem cells/multipotent stromal cells (MSCs) are glycolytic and thus glucose is a limiting factor of in vitro models of MSC starvation. Stem Cell Res Ther. 2016;7(1):179. doi: 10.1186/s13287-016-0436-7 27906055; PubMed Central PMCID: PMC5134064.

55. MacIntyre DA, Melguizo Sanchis D, Jimenez B, Moreno R, Stojkovic M, Pineda-Lucena A. Characterisation of human embryonic stem cells conditioning media by 1H-nuclear magnetic resonance spectroscopy. PloS one. 2011;6(2):e16732. doi: 10.1371/journal.pone.0016732 21347425; PubMed Central PMCID: PMC3036660.

56. Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem cells. 2007;25(10):2648–59. doi: 10.1634/stemcells.2007-0226 17615264

57. Gruber R, Kandler B, Holzmann P, Vögele-Kadletz M, Losert U, Fischer MB, et al. Bone marrow stromal cells can provide a local environment that favors migration and formation of tubular structures of endothelial cells. Tissue engineering. 2005;11(5–6):896–903. doi: 10.1089/ten.2005.11.896 15998229

58. Potapova IA, Gaudette GR, Brink PR, Robinson RB, Rosen MR, Cohen IS, et al. Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro. Stem cells. 2007;25(7):1761–8. doi: 10.1634/stemcells.2007-0022 17395769

59. Kinnaird T, Stabile E, Burnett M, Lee C, Barr S, Fuchs S, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circulation research. 2004;94(5):678–85.

60. Chang CP, Chio CC, Cheong CU, Chao CM, Cheng BC, Lin MT. Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury. Clin Sci. 2013;124(3–4):165–76. doi: 10.1042/Cs20120226 WOS:000314083000004. 22876972

61. Burlacu A, Grigorescu G, Rosca A-M, Preda MB, Simionescu M. Factors secreted by mesenchymal stem cells and endothelial progenitor cells have complementary effects on angiogenesis in vitro. Stem cells and development. 2012;22(4):643–53. doi: 10.1089/scd.2012.0273 22947186

62. Janebodin K, Zeng Y, Buranaphatthana W, Ieronimakis N, Reyes M. VEGFR2-dependent angiogenic capacity of pericyte-like dental pulp stem cells. Journal of dental research. 2013;92(6):524–31.

63. Ribot J, Caliaperoumal G, Paquet J, Boisson‐vidal C, Petite H, Anagnostou F. Type 2 diabetes alters mesenchymal stem cell secretome composition and angiogenic properties. J Cell Mol Med. 2017;21(2):349–63.

64. Kamprom W, Kheolamai P, U-Pratya Y, Supokawej A, Wattanapanitch M, Laowtammathron C, et al. Effects of mesenchymal stem cell-derived cytokines on the functional properties of endothelial progenitor cells. European Journal of Cell Biology. 2016;95(3):153–63. https://doi.org/10.1016/j.ejcb.2016.02.001.

65. Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109(10):1292–8.

66. Waters R, Alam P, Pacelli S, Chakravarti AR, Ahmed RPH, Paul A. Stem cell-inspired secretome-rich injectable hydrogel to repair injured cardiac tissue. Acta Biomaterialia. 2018;69:95–106. https://doi.org/10.1016/j.actbio.2017.12.025.

67. Rubina K, Kalinina N, Efimenko A, Lopatina T, Melikhova V, Tsokolaeva Z, et al. Adipose stromal cells stimulate angiogenesis via promoting progenitor cell differentiation, secretion of angiogenic factors, and enhancing vessel maturation. Tissue Engineering Part A. 2009;15(8):2039–50. doi: 10.1089/ten.tea.2008.0359 19368510

68. Kilroy GE, Foster SJ, Wu X, Ruiz J, Sherwood S, Heifetz A, et al. Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors. Journal of cellular physiology. 2007;212(3):702–9. doi: 10.1002/jcp.21068 17477371.

69. Bronckaers A, Hilkens P, Fanton Y, Struys T, Gervois P, Politis C, et al. Angiogenic properties of human dental pulp stem cells. PloS one. 2013;8(8):e71104. doi: 10.1371/journal.pone.0071104 23951091

70. Tran-Hung L, Laurent P, Camps J, About I. Quantification of angiogenic growth factors released by human dental cells after injury. Archives of oral biology. 2008;53(1):9–13.

71. Hilkens P, Fanton Y, Martens W, Gervois P, Struys T, Politis C, et al. Pro-angiogenic impact of dental stem cells in vitro and in vivo. Stem Cell Research. 2014;12(3):778–90. doi: 10.1016/j.scr.2014.03.008 24747218

72. Yalvaç ME, Yarat A, Mercan D, Rizvanov AA, Palotás A, Şahin F. Characterization of the secretome of human tooth germ stem cells (hTGSCs) reveals neuro-protection by fine-tuning micro-environment. Brain, Behavior, and Immunity. 2013;32:122–30. https://doi.org/10.1016/j.bbi.2013.03.007.

73. Choi M, Lee H-S, Naidansaren P, Kim H-K, Eunju O, Cha J-H, et al. Proangiogenic features of Wharton's jelly-derived mesenchymal stromal/stem cells and their ability to form functional vessels. Int J Biochem Cell Biol. 2013;45(3):560–70. doi: 10.1016/j.biocel.2012.12.001 23246593

74. Montemurro T, Viganò M, Ragni E, Barilani M, Parazzi V, Boldrin V, et al. Angiogenic and anti-inflammatory properties of mesenchymal stem cells from cord blood: soluble factors and extracellular vesicles for cell regeneration. European Journal of Cell Biology. 2016;95(6):228–38. https://doi.org/10.1016/j.ejcb.2016.04.003.

75. Kim S-W, Zhang H-Z, Kim C-E, Kim J-M, Kim MH. Amniotic mesenchymal stem cells with robust chemotactic properties are effective in the treatment of a myocardial infarction model. International journal of cardiology. 2013;168(2):1062–9. doi: 10.1016/j.ijcard.2012.11.003 23218573

76. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76. doi: 10.1038/nm0603-669 12778165.

77. Di GH, Liu Y, Lu Y, Liu J, Wu CT, Duan HF. IL-6 Secreted from Senescent Mesenchymal Stem Cells Promotes Proliferation and Migration of Breast Cancer Cells. PloS one. 2014;9(11). ARTN e113572 doi: 10.1371/journal.pone.0113572 WOS:000346766900049. 25419563

78. Mecollari V, Nieuwenhuis B, Verhaagen J. A perspective on the role of class III semaphorin signaling in central nervous system trauma. Frontiers in Cellular Neuroscience. 2014;8(328). doi: 10.3389/fncel.2014.00328 25386118

79. Shin YJ, Choi JS, Choi JY, Hou Y, Cha JH, Chun MH, et al. Induction of vascular endothelial growth factor receptor-3 mRNA in glial cells following focal cerebral ischemia in rats. J Neuroimmunol. 2010;229(1–2):81–90. doi: 10.1016/j.jneuroim.2010.07.008 20692049.

80. Cao R, Bråkenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E, et al. Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nature Medicine. 2003;9:604. doi: 10.1038/nm848 https://www.nature.com/articles/nm848#supplementary-information. 12669032

81. Kinnaird T, Stabile E, Burnett M, Shou M, Lee C, Barr S, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 2004;109(12):1543–9.

82. Nakamura T, Mizuno S. The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(6):588–610. doi: 10.2183/pjab.86.588 20551596; PubMed Central PMCID: PMC3081175.

83. Genovese JA, Spadaccio C, Rivello HG, Toyoda Y, Patel AN. Electrostimulated bone marrow human mesenchymal stem cells produce follistatin. Cytotherapy. 2009;11(4):448–56. Epub 2009/06/17. doi: 10.1080/14653240902960445 19530028.

84. Sumanasinghe RD, Pfeiler TW, Monteiro‐Riviere NA, Loboa EG. Expression of proinflammatory cytokines by human mesenchymal stem cells in response to cyclic tensile strain. Journal of cellular physiology. 2009;219(1):77–83.

85. Tang Y, Chen Y, Wang X, Song G, Li Y, Shi L. Combinatorial Intervention with Mesenchymal Stem Cells and Granulocyte Colony-Stimulating Factor in a Rat Model of Ulcerative Colitis. Digestive diseases and sciences. 2015;60(7):1948–57. doi: 10.1007/s10620-015-3655-3 25894931

86. Smith H, Whittall C, Weksler B, Middleton J. Chemokines stimulate bidirectional migration of human mesenchymal stem cells across bone marrow endothelial cells. Stem cells and development. 2011;21(3):476–86. doi: 10.1089/scd.2011.0025 21513440

87. Kroeze KL, Jurgens WJ, Doulabi BZ, Van Milligen FJ, Scheper RJ, Gibbs S. Chemokine-mediated migration of skin-derived stem cells: predominant role for CCL5/RANTES. Journal of Investigative Dermatology. 2009;129(6):1569–81. doi: 10.1038/jid.2008.405 19122644

88. Xia X, Chiu PWY, Lam PK, Chin WC, Ng EKW, Lau JYW. Secretome from hypoxia-conditioned adipose-derived mesenchymal stem cells promotes the healing of gastric mucosal injury in a rodent model. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2018;1864(1):178–88.

89. Yoon BS, Moon J-H, Jun EK, Kim J, Maeng I, Kim JS, et al. Secretory profiles and wound healing effects of human amniotic fluid–derived mesenchymal stem cells. Stem cells and development. 2009;19(6):887–902. doi: 10.1089/scd.2009.0138 19686050

90. Park S-R, Kim J-W, Jun H-S, Roh JY, Lee H-Y, Hong I-S. Stem cell secretome and its effect on cellular mechanisms relevant to wound healing. Molecular Therapy. 2018;26(2):606–17. doi: 10.1016/j.ymthe.2017.09.023 29066165

91. Akram KM, Samad S, Spiteri MA, Forsyth NR. Mesenchymal stem cells promote alveolar epithelial cell wound repair in vitro through distinct migratory and paracrine mechanisms. Respiratory Research. 2013;14(1):9. doi: 10.1186/1465-9921-14-9 23350749

92. Johnson TV, DeKorver NW, Levasseur VA, Osborne A, Tassoni A, Lorber B, et al. Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor through analysis of the mesenchymal stem cell secretome. Brain. 2013;137(2):503–19.

93. Azhdari ZT, Mahmoodi M, Hajizadeh MR, Ezzatizadeh V, Baharvand H, Vosough M, et al. Conditioned Media Derived from Human Adipose Tissue Mesenchymal Stromal Cells Improves Primary Hepatocyte Maintenance. Cell journal. 2018;20(3):377–87.

94. Teixeira FG, Panchalingam KM, Assunção-Silva R, Serra SC, Mendes-Pinheiro B, Patrício P, et al. Modulation of the Mesenchymal Stem Cell Secretome Using Computer-Controlled Bioreactors: Impact on Neuronal Cell Proliferation, Survival and Differentiation. Scientific Reports. 2016;6:27791. doi: 10.1038/srep27791 27301770

95. Assunção-Silva RC, Mendes-Pinheiro B, Patrício P, Behie LA, Teixeira FG, Pinto L, et al. Exploiting the impact of the secretome of MSCs isolated from different tissue sources on neuronal differentiation and axonal growth. Biochimie. 2018;155:83–91. https://doi.org/10.1016/j.biochi.2018.07.026.

96. Li C, Li G, Liu M, Zhou T, Zhou H. Paracrine effect of inflammatory cytokine-activated bone marrow mesenchymal stem cells and its role in osteoblast function. Journal of Bioscience and Bioengineering. 2016;121(2):213–9. https://doi.org/10.1016/j.jbiosc.2015.05.017.