Frontiers of Medicine

, Volume 13, Issue 2, pp 138–151 | Cite as

Mesenchymal stem cells and immune disorders: from basic science to clinical transition

  • Shihua Wang
  • Rongjia Zhu
  • Hongling Li
  • Jing Li
  • Qin Han
  • Robert Chunhua ZhaoEmail author


As a promising candidate seed cell type in regenerative medicine, mesenchymal stem cells (MSCs) have attracted considerable attention. The unique capacity of MSCs to exert a regulatory effect on immunity in an autologous/allergenic manner makes them an attractive therapeutic cell type for immune disorders. In this review, we discussed the current knowledge of and advances in MSCs, including its basic biological properties, i.e., multilineage differentiation, secretome, and immunomodulation. Specifically, on the basis of our previous work, we proposed three new concepts of MSCs, i.e., “subtotipotent stem cell” hypothesis, MSC system, and “Yin and Yang” balance of MSC regulation, which may bring new insights into our understanding of MSCs. Furthermore, we analyzed data from the Clinical Trials database ( on registered clinical trials using MSCs to treat a variety of immune diseases, such as graft-versus-host disease, systemic lupus erythematosus, and multiple sclerosis. In addition, we highlighted MSC clinical trials in China and discussed the challenges and future directions in the field of MSC clinical application.


mesenchymal stem cell clinical transition immune disorders 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



This work was supported by grants from the Key Program for Beijing Municipal Natural Science Foundation (No. 7141006), National Collaborative Innovation Program (for Biotherapy), Beijing Science and Technology Project (No. Z151100001615- 063), National Key Research and Development Program (Nos. 2016YFA0101000 and 2016YFA0101003), and PUMC Youth Fund and the Fundamental Research Funds for the Central Universities (No. 3332013141).


  1. 1.
    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): 230–247Google Scholar
  2. 2.
    Caplan AI. Mesenchymal stem cells. J Orthop Res 1991; 9(5): 641–650Google Scholar
  3. 3.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284(5411): 143–147Google Scholar
  4. 4.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315–317Google Scholar
  5. 5.
    Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 1999; 96(19): 10711–10716Google Scholar
  6. 6.
    Salem HK, Thiemermann C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 2010; 28(3): 585–596Google Scholar
  7. 7.
    Han X, Wan Q, Wu W, Zheng A, Li L, Liu X, Activin A an. BMP- 4 induce cardiomyocyte-like cells differentiation of human amniotic epithelial cells. J Biomedical Eng (Sheng Wu Yi Xue Gong Cheng Xue Za Zhi) 2011; 28(6): 1217–1222 (in Chinese)Google Scholar
  8. 8.
    Asumda FZ, Chase PB. Nuclear cardiac troponin and tropomyosin are expressed early in cardiac differentiation of rat mesenchymal stem cells. Differentiation 2012; 83(3): 106–115Google Scholar
  9. 9.
    Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, Henegariu O, Krause DS. Liver from bone marrow in humans. Hepatology 2000; 32(1): 11–16Google Scholar
  10. 10.
    Theise ND, Badve S, Saxena R, Henegariu O, Sell S, Crawford JM, Krause DS. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology 2000; 31(1): 235–240Google Scholar
  11. 11.
    Bornstein R, Macias MI,de la Torre P, Grande J, Flores AI. Human decidua-derived mesenchymal stromal cells differentiate into hepatic-like cells and form functional three-dimensional structures. Cytotherapy 2012; 14(10): 1182–1192Google Scholar
  12. 12.
    He H, Liu X, Peng L, Gao Z, Ye Y, Su Y, Zhao Q, Wang K, Gong Y, He F. Promotion of hepatic differentiation of bone marrow mesenchymal stem cells on decellularized cell-deposited extracellular matrix. Biomed Res Int 2013; 2013: 406871Google Scholar
  13. 13.
    Xu D, Nishimura T, Zheng M, Wu M, Su H, Sato N, Lee G, Michie S, Glenn J, Peltz G. Enabling autologous human liver regeneration with differentiated adipocyte stem cells. Cell Transplant 2014; 23(12): 1573–1584Google Scholar
  14. 14.
    Chen Z, Kuang Q, Lao XJ, Yang J, Huang W, Zhou D. Differentiation of UC-MSCs into hepatocyte-like cells in partially hepatectomized model rats. Exp Ther Med 2016; 12(3): 1775–1779Google Scholar
  15. 15.
    Seo MJ, Suh SY, Bae YC, Jung JS. Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo. Biochem Biophys Res Commun 2005; 328(1): 258–264Google Scholar
  16. 16.
    Yu YB, Bian JM, Gu DH. Transplantation of insulin-producing cells to treat diabetic rats after 90% pancreatectomy. World J Gastroenterol 2015; 21(21): 6582–6590Google Scholar
  17. 17.
    Kim SY, Kim YR, Park WJ, Kim HS, Jun SC, Woo SY, Jo I, Ryu KH, Park JW. Characterisation of insulin-producing cells differentiated from tonsil derived mesenchymal stem cells. Differentiation 2015; 90(1–3): 27–39Google Scholar
  18. 18.
    Lee J, Han DJ, Kim SC. In vitro differentiation of human adipose tissue-derived stem cells into cells with pancreatic phenotype by regenerating pancreas extract. Biochem Biophys Res Commun 2008; 375(4): 547–551Google Scholar
  19. 19.
    Hefei W, Yu R, Haiqing W, Xiao W, Jingyuan W, Dongjun L. Morphological characteristics and identification of islet-like cells derived from rat adipose-derived stem cells cocultured with pancreas adult stem cells. Cell Biol Int 2015; 39(3): 253–263Google Scholar
  20. 20.
    Mehrfarjam Z, Esmaeili F, Shabani L, Ebrahimie E. Induction of pancreatic β cell gene expression in mesenchymal stem cells. Cell Biol Int 2016; 40(5): 486–500Google Scholar
  21. 21.
    Xin Y, Jiang X, Wang Y, Su X, Sun M, Zhang L, Tan Y, Wintergerst KA, Li Y, Li Y. Insulin-producing cells differentiated from human bone marrow mesenchymal stem cells in vitro ameliorate streptozotocin-induced diabetic hyperglycemia. PLoS One 2016; 11(1): e0145838Google Scholar
  22. 22.
    O’Dell JW. Spectral analysis of interviews conducted by Rogers and Ellis. Psychol Rep 1990; 67(3 Pt 1): 819–825Google Scholar
  23. 23.
    Wang C, Zhu H, Sun Z, Xiang Z, Ge Y, Ni C, Luo Z, Qian W, Han X. Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycininduced lung injury. Am J Physiol Cell Physiol 2014; 307(3): C234–C244Google Scholar
  24. 24.
    Hsueh YY, Chiang YL, Wu CC, Lin SC. Spheroid formation and neural induction in human adipose-derived stem cells on a chitosan-coated surface. Cells Tissues Organs 2012; 196(2): 117–128Google Scholar
  25. 25.
    Ahmadi N, Razavi S, Kazemi M, Oryan S. Stability of neural differentiation in human adipose derived stem cells by two induction protocols. Tissue Cell 2012; 44(2): 87–94Google Scholar
  26. 26.
    Feng N, Han Q, Li J, Wang S, Li H, Yao X, Zhao RC. Generation of highly purified neural stem cells from human adipose-derived mesenchymal stem cells by Sox1 activation. Stem Cells Dev 2014; 23(5): 515–529Google Scholar
  27. 27.
    Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R. The current landscape of the mesenchymal stromal cell secretome: a new paradigm for cell-free regeneration. Cytotherapy 2016; 18(1): 13–24Google Scholar
  28. 28.
    Gu Y, He M, Zhou X, Liu J, Hou N, Bin T, Zhang Y, Li T, Chen J. Endogenous IL-6 of mesenchymal stem cell improves behavioral outcome of hypoxic-ischemic brain damage neonatal rats by supressing apoptosis in astrocyte. Sci Rep 2016; 6: 18587Google Scholar
  29. 29.
    Zimmerlin L, Park TS, Zambidis ET, Donnenberg VS, Donnenberg AD. Mesenchymal stem cell secretome and regenerative therapy after cancer. Biochimie 2013; 95(12): 2235–2245Google Scholar
  30. 30.
    Ke F, Zhang L, Liu Z, Yan S, Xu Z, Bai J, Zhu H, Lou F, Cai W, Sun Y, Gao Y, Wang H, Wang H. Soluble tumor necrosis factor receptor 1 released by skin-derived mesenchymal stem cells is critical for inhibiting Th17 Cell differentiation. Stem Cells Transl Med 2016; 5(3): 301–313Google Scholar
  31. 31.
    Reikvam H, Brenner AK, Hagen KM, Liseth K, Skrede S, Hatfield KJ, Bruserud O. The cytokine-mediated crosstalk between primary human acute myeloid cells and mesenchymal stem cells alters the local cytokine network and the global gene expression profile of the mesenchymal cells. Stem Cell Res (Amst) 2015; 15(3): 530–541Google Scholar
  32. 32.
    Hsiao ST, Asgari A, Lokmic Z, Sinclair R, Dusting GJ, Lim SY, Dilley RJ. Comparative analysis of paracrine factor expression in human adult mesenchymal stem cells derived from bone marrow, adipose, and dermal tissue. Stem Cells Dev 2012; 21(12): 2189–2203Google Scholar
  33. 33.
    Lopatina T, Kalinina N, Karagyaur M, Stambolsky D, Rubina K, Revischin A, Pavlova G, Parfyonova Y, Tkachuk V. Adiposederived stem cells stimulate regeneration of peripheral nerves: BDNF secreted by these cells promotes nerve healing and axon growth de novo. PLoS One 2011; 6(3): e17899Google Scholar
  34. 34.
    Lee Y, El Andaloussi S, Wood MJ. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet 2012; 21(R1): R125–R134Google Scholar
  35. 35.
    Eldh M, Ekstrom K, Valadi H, Sjostrand M, Olsson B, Jernas M, Lotvall J. Exosomes communicate protective messages during oxidative stress; possible role of exosomal shuttle RNA. PLoS One 2010; 5(12): e15353Google Scholar
  36. 36.
    Doeppner TR, Herz J, Gorgens A, Schlechter J, Ludwig AK, Radtke S, de Miroschedji K, Horn PA, Giebel B, Hermann DM. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med 2015; 4(10): 1131–1143Google Scholar
  37. 37.
    Liang X, Zhang L, Wang S, Han Q, Zhao RC. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci 2016; 129(11): 2182–2189Google Scholar
  38. 38.
    Wang L, Gu Z, Zhao X, Yang N, Wang F, Deng A, Zhao S, Luo L, Wei H, Guan L, Gao Z, Li Y, Liu D, Gao C. Extracellular vesicles released from human umbilical cord-derived mesenchymal stromal cells prevent life-threatening acute graft-versus-host disease in a mouse model of allogeneic hematopoietic stem cell transplantation. Stem Cells Dev 2016; 25(24): 1874–1883Google Scholar
  39. 39.
    Wang S, Qu X, Zhao RC. Clinical applications of mesenchymal stem cells. J Hematol Oncol 2012; 5: 19Google Scholar
  40. 40.
    Zhang W, Ge W, Li C, You S, Liao L, Han Q, Deng W, Zhao RC. Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev 2004; 13(3): 263–271Google Scholar
  41. 41.
    Chen L, Zhang W, Yue H, Han Q, Chen B, Shi M, Li J, Li B, You S, Shi Y, Zhao RC. Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells. Stem Cells Dev 2007; 16(5): 719–731Google Scholar
  42. 42.
    Zhang B, Liu R, Shi D, Liu X, Chen Y, Dou X, Zhu X, Lu C, Liang W, Liao L, Zenke M, Zhao RC. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population. Blood 2009; 113(1): 46–57Google Scholar
  43. 43.
    Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W, Gao L, Shen L, Huang Y, Xie G, Zhao H, Jin Y, Tang B, Yu Y, Zhao J, Pei G. Direct conversion of normal and Alzheimer’s disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell 2015; 17(2): 204–212Google Scholar
  44. 44.
    Thier M, Worsdorfer P, Lakes YB, Gorris R, Herms S, Opitz T, Seiferling D, Quandel T, Hoffmann P, Nothen MM, Brustle O, Edenhofer F. Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell 2012; 10(4): 473–479Google Scholar
  45. 45.
    Huang P, Zhang L, Gao Y, He Z, Yao D, Wu Z, Cen J, Chen X, Liu C, Hu Y, Lai D, Hu Z, Chen L, Zhang Y, Cheng X, Ma X, Pan G, Wang X, Hui L. Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell 2014; 14((3)): 370–384Google Scholar
  46. 46.
    Wang Q, Ye L, Liu H, Liu X, Li S, Chen Z. Reprogramming of bone marrow-derived mesenchymal stem cells into functional insulin-producing cells by chemical regimen. Am J Stem Cells 2012; 1(2): 128–137Google Scholar
  47. 47.
    Koch P. Direct conversion provides old neurons from aged donor’s skin. Cell Stem Cell 2015; 17(6): 637–638Google Scholar
  48. 48.
    Han DW, Tapia N, Hermann A, Hemmer K, Hoing S, Arauzo-Bravo MJ, Zaehres H, Wu G, Frank S, Moritz S, Greber B, Yang JH, Lee HT, Schwamborn JC, Storch A, Scholer HR. Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell 2012; 10(4): 465–472Google Scholar
  49. 49.
    Han JK, Chang SH, Cho HJ, Choi SB, Ahn HS, Lee J, Jeong H, Youn SW, Lee HJ, Kwon YW, Oh BH, Oettgen P, Park YB, Kim HS. Direct conversion of adult skin fibroblasts to endothelial cells by defined factors. Circulation 2014; 130(14): 1168–1178Google Scholar
  50. 50.
    Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stange G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CV, Van de Casteele M, German MS, Bouwens L, Heimberg H. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional β cell mass in diabetic mice. Nat Biotechnol 2014; 32(1): 76–83Google Scholar
  51. 51.
    Zhao CH. Concept of mesenchymal stem cells: bring more insights into functional research of MSC. J Exp Hematol (Zhongguo Shi Yan Xue Ye Xue Za Zhi) 2013; 21(2): 263–267 (in Chinese)Google Scholar
  52. 52.
    Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a proinflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One 2010; 5(4): e10088Google Scholar
  53. 53.
    Carrion F, Nova E, Ruiz C, Diaz F, Inostroza C, Rojo D, Monckeberg G, Figueroa FE. Autologous mesenchymal stem cell treatment increased T regulatory cells with no effect on disease activity in two systemic lupus erythematosus patients. Lupus 2010; 19(3): 317–322Google Scholar
  54. 54.
    Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, Verspaget HW, Kooy-Winkelaar EM, Koning F, Zwaginga JJ, Fidder HH, Verhaar AP, Fibbe WE, van den Brink GR, Hommes DW. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut 2010; 59(12): 1662–1669Google Scholar
  55. 55.
    Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, Hou Y, Zeng X, Gilkeson GS, Sun L. Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis 2010; 69(8): 1423–1429Google Scholar
  56. 56.
    Sun L, Wang D, Liang J, Zhang H, Feng X, Wang H, Hua B, Liu B, Ye S, Hu X, Xu W, Zeng X, Hou Y, Gilkeson GS, Silver RM, Lu L, Shi S. Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum 2010; 62(8): 2467–2475Google Scholar
  57. 57.
    Jiang R, Han Z, Zhuo G, Qu X, Li X, Wang X, Shao Y, Yang S, Han ZC. Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: a pilot study. Front Med 2011; 5(1): 94–100Google Scholar
  58. 58.
    Fang B, Song Y, Lin Q, Zhang Y, Cao Y, Zhao RC, Ma Y. Human adipose tissue-derived mesenchymal stromal cells as salvage therapy for treatment of severe refractory acute graft-vs. -host disease in two children. Pediatr Transplant 2007; 11(7): 814–817Google Scholar
  59. 59.
    Kebriaei P, Isola L, Bahceci E, Holland K, Rowley S, McGuirk J, Devetten M, Jansen J, Herzig R, Schuster M, Monroy R, Uberti J. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant 2009; 15(7): 804–811Google Scholar
  60. 60.
    Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363(9419): 1439–1441Google Scholar
  61. 61.
    Prasad VK, Lucas KG, Kleiner GI, Talano JA, Jacobsohn D, Broadwater G, Monroy R, Kurtzberg J. Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol Blood Marrow Transplant 2011; 17(4): 534–541Google Scholar
  62. 62.
    Wu KH, Chan CK, Tsai C, Chang YH, Sieber M, Chiu TH, Ho M, Peng CT, Wu HP, Huang JL. Effective treatment of severe steroidresistant acute graft-versus-host disease with umbilical cordderived mesenchymal stem cells. Transplantation 2011; 91(12): 1412–1416Google Scholar
  63. 63.
    Copland IB, Qayed M, Garcia MA, Galipeau J, Waller EK. Bone marrow mesenchymal stromal cells from patients with acute and chronic graft-versus-host disease deploy normal phenotype, differentiation plasticity, and immune-suppressive activity. Biol Blood Marrow Transplant 2015; 21(5): 934–940Google Scholar
  64. 64.
    Sanchez-Guijo F, Caballero-Velazquez T, Lopez-Villar O, Redondo A, Parody R, Martinez C, Olavarria E, Andreu E, Prosper F, Diez-Campelo M, Regidor C, Villaron E, Lopez-Corral L, Caballero D, Canizo MC, Perez-Simon JA. Sequential thirdparty mesenchymal stromal cell therapy for refractory acute graftversus- host disease. Biol Blood Marrow Transplant 2014; 20(10): 1580–1585Google Scholar
  65. 65.
    Maziarz RT, Devos T, Bachier CR, Goldstein SC, Leis JF, Devine SM, Meyers G, Gajewski JL, Maertens J, Deans RJ, Van't Hof W, Lazarus HM. Single and multiple dose MultiStem (multipotent adult progenitor cell) therapy prophylaxis of acute graft-versushost disease in myeloablative allogeneic hematopoietic cell transplantation: a phase 1 trial. Biol Blood Marrow Transplant 2015; 21(4): 720–728Google Scholar
  66. 66.
    Zhao K, Lou R, Huang F, Peng Y, Jiang Z, Huang K, Wu X, Zhang Y, Fan Z, Zhou H, Liu C, Xiao Y, Sun J, Li Y, Xiang P, Liu Q. Immunomodulation effects of mesenchymal stromal cells on acute graft-versus-host disease after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2015; 21(1): 97–104Google Scholar
  67. 67.
    Shipounova IN, Petinati NA, Bigildeev AE, Zezina EA, Drize NI, Kuzmina LA, Parovichnikova EN, Savchenko VG. Analysis of results of acute graft-versus-host disease prophylaxis with donor multipotent mesenchymal stromal cells in patients with hemoblastoses after allogeneic bone marrow transplantation. Biochemistry. Biokhimiia 2014; 79(12): 1363–1370Google Scholar
  68. 68.
    Te Boome LC, Mansilla C, van der Wagen LE, Lindemans CA, Petersen EJ, Spierings E, Thus KA, Westinga K, Plantinga M, Bierings M, Broers AE, Cuijpers ML, van Imhoff GW, Janssen JJ, Huisman C, Zeerleder S, Huls G, Boelens JJ, Wulffraat NM, Slaper-Cortenbach IC, Kuball J. Biomarker profiling of steroidresistant acute GVHD in patients after infusion of mesenchymal stromal cells. Leukemia 2015; 29(9): 1839–1846Google Scholar
  69. 69.
    Weng JY, Du X, Geng SX, Pen YW, Wang Z, Lu ZS, Wu SJ, Luo CW, Guo R, Ling W, Deng CX, Liao PJ, Xiang AP. Mesenchymal stem cell as salvage treatment for refractory chronic GVHD. Bone Marrow Transplant 2010; 45(12): 1732–1740Google Scholar
  70. 70.
    Perez-Simon JA, Lopez-Villar O, Andreu EJ, Rifon J, Muntion S, Diez Campelo M, Sanchez-Guijo FM, Martinez C, Valcarcel D, Canizo CD. Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial. Haematologica 2011; 96(7): 1072–1076Google Scholar
  71. 71.
    Yi HG, Yahng SA, Kim I, Lee JH, Min CK, Kim JH, Kim CS, Song SU. Allogeneic clonal mesenchymal stem cell therapy for refractory graft-versus-host disease to standard treatment: a phase I study. Korean J Physiol Pharmacol 2016; 20(1): 63–67Google Scholar
  72. 72.
    Erbey F, Atay D, Akcay A, Ovali E, Ozturk G. Mesenchymal stem cell treatment for steroid refractory graft-versus-host disease in children: a pilot and first study from Turkey. Stem Cells Int 2016; 2016: 1641402Google Scholar
  73. 73.
    Sun L, Akiyama K, Zhang H, Yamaza T, Hou Y, Zhao S, Xu T, Le A, Shi S. Mesenchymal stem cell transplantation reverses multi- organ dysfunction in systemic lupus erythematosus mice and humans. Stem Cells 2009; 27(6): 1421–1432Google Scholar
  74. 74.
    Wang D, Huang S, Yuan X, Liang J, Xu R, Yao G, Feng X, Sun L. The regulation of the Treg/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus. Cell Mol Immunol 2017; 14(5): 423–431Google Scholar
  75. 75.
    Wang D, Akiyama K, Zhang H, Yamaza T, Li X, Feng X, Wang H, Hua B, Liu B, Xu H, Chen W, Shi S, Sun L. Double allogenic mesenchymal stem cells transplantations could not enhance therapeutic effect compared with single transplantation in systemic lupus erythematosus. Clin Dev Immunol 2012; 2012: 273291Google Scholar
  76. 76.
    Wang D, Niu L, Feng X, Yuan X, Zhao S, Zhang H, Liang J, Zhao C, Wang H, Hua B, Sun L. Long-term safety of umbilical cord mesenchymal stem cells transplantation for systemic lupus erythematosus: a 6-year follow-up study. Clin Exp Med 2017;17(3): 333–340Google Scholar
  77. 77.
    de la Portilla F, Alba F, Garcia-Olmo D, Herrerias JM, Gonzalez FX, Galindo A. Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease: results from a multicenter phase I/IIa clinical trial. Int J Colorectal Dis 2013; 28(3): 313–323Google Scholar
  78. 78.
    Forbes GM, Sturm MJ, Leong RW, Sparrow MP, Segarajasingam D, Cummins AG, Phillips M, Herrmann RP. A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn’s disease refractory to biologic therapy. Clin Gastroenterol Hepatol 2014; 12((1): 64–71Google Scholar
  79. 79.
    Garcia-Arranz M, Dolores Herreros M, Gonzalez-Gomez C, de la Quintana P, Guadalajara H, Georgiev-Hristov T, Trebol J, Garcia-Olmo D. Treatment of Crohn’s-related rectovaginal fistula with allogeneic expanded-adipose derived stem cells: a phase I–IIa clinical trial. Stem Cells Transl Med 2016; 5(11): 1441–1446Google Scholar
  80. 80.
    Molendijk I, Bonsing BA, Roelofs H, Peeters KC, Wasser MN, Dijkstra G, van der Woude CJ, Duijvestein M, Veenendaal RA, Zwaginga JJ, Verspaget HW, Fibbe WE, van de Meulen-de Jong AE, Hommes DW. Allogeneic bone marrow-derived mesenchymal stromal cells promote healing of refractory perianal fistulas in patients with Crohn’s disease. Gastroenterology 2015; 149(4): 918–927e916Google Scholar
  81. 81.
    Sanz-Baro R, Garcia-Arranz M, Guadalajara H, de la Quintana P, Herreros MD, Garcia-Olmo D. First-in-human case study: pregnancy in women with Crohn’s perianal fistula treated with adipose-derived stem cells: a safety study. Stem Cells Transl Med 2015; 4(6): 598–602Google Scholar
  82. 82.
    Ciccocioppo R, Gallia A, Sgarella A, Kruzliak P, Gobbi PG, Corazza GR. Long-term follow-up of Crohn disease fistulas after local injections of bone marrow-derived mesenchymal stem cells. Mayo Clin Proc 2015; 90(6): 747–755Google Scholar
  83. 83.
    Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, Minelli A, Alvisi C, Vanoli A, Calliada F, Dionigi P, Perotti C, Locatelli F, Corazza GR. Autologous bone marrowderived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut 2011; 60(6): 788–798Google Scholar
  84. 84.
    Peng Y, Ke M, Xu L, Liu L, Chen X, Xia W, Li X, Chen Z, Ma J, Liao D, Li G, Fang J, Pan G, Xiang AP. Donor-derived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study. Transplantation 2013; 95(1): 161–168Google Scholar
  85. 85.
    Pan GH, Chen Z, Xu L, Zhu JH, Xiang P, Ma JJ, Peng YW, Li GH, Chen XY, Fang JL, Guo YH, Zhang L, Liu LS. Low-dose tacrolimus combined with donor-derived mesenchymal stem cells after renal transplantation: a prospective, non-randomized study. Oncotarget 2016; 7(11): 12089–12101Google Scholar
  86. 86.
    Lee H, Park JB, Lee S, Baek S, Kim H, Kim SJ. Intra-osseous injection of donor mesenchymal stem cell (MSC) into the bone marrow in living donor kidney transplantation; a pilot study. J Transl Med 2013; 11: 96Google Scholar
  87. 87.
    Mudrabettu C, Kumar V, Rakha A, Yadav AK, Ramachandran R, Kanwar DB, Nada R, Minz M, Sakhuja V, Marwaha N, Jha V. Safety and efficacy of autologous mesenchymal stromal cells transplantation in patients undergoing living donor kidney transplantation: a pilot study. Nephrology (Carlton) 2015; 20(1): 25–33Google Scholar
  88. 88.
    Martino G, Franklin RJ, Baro Van Evercooren A, Kerr DA. Stem cell transplantation in multiple sclerosis: current status and future prospects. Nat Rev Neurol 2010; 6(5): 247–255Google Scholar
  89. 89.
    Freedman MS, Bar-Or A, Atkins HL, Karussis D, Frassoni F, Lazarus H, Scolding N, Slavin S, Le Blanc K, Uccelli A. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler 2010; 16(4): 503–510Google Scholar
  90. 90.
    Bonab MM, Sahraian MA, Aghsaie A, Karvigh SA, Hosseinian SM, Nikbin B, Lotfi J, Khorramnia S, Motamed MR, Togha M, Harirchian MH, Moghadam NB, Alikhani K, Yadegari S, Jafarian S, Gheini MR. Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study. Curr Stem Cell Res Ther 2012; 7(6): 407–414Google Scholar
  91. 91.
    Yamout B, Hourani R, Salti H, Barada W, El-Hajj T, Al-Kutoubi A, Herlopian A, Baz EK, Mahfouz R, Khalil-Hamdan R, Kreidieh NM, El-Sabban M, Bazarbachi A. Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J Neuroimmunol 2010; 227(1–2): 185–189Google Scholar
  92. 92.
    Mohajeri M, Farazmand A, Mohyeddin Bonab M, Nikbin B, Minagar A. FOXP3 gene expression in multiple sclerosis patients pre- and post mesenchymal stem cell therapy. Iran J Allergy Asthma Immunol 2011; 10(3): 155–161Google Scholar
  93. 93.
    Liang J, Li X, Zhang H, Wang D, Feng X, Wang H, Hua B, Liu B, Sun L. Allogeneic mesenchymal stem cells transplantation in patients with refractory RA. Clin Rheumatol 2012; 31(1): 157–161Google Scholar
  94. 94.
    Wang L, Cong X, Liu G, Zhou J, Bai B, Li Y, Bai W, Li M, Ji H, Zhu D, Wu M, Liu Y. Human umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis: safety and efficacy. Stem Cells Dev 2013; 22(24): 3192–3202Google Scholar
  95. 95.
    Wang L, Zhang Y, Li H, Hong J, Chen X, Li M, Bai W, Wang J, Liu Y, Wu M. Clinical observation of employment of umbilical cord derived mesenchymal stem cell for juvenile idiopathic arthritis therapy. Stem Cells Int 2016; 2016: 9165267Google Scholar
  96. 96.
    Keyszer G, Christopeit M, Fick S, Schendel M, Taute BM, Behre G, Muller LP, Schmoll HJ. Treatment of severe progressive systemic sclerosis with transplantation of mesenchymal stromal cells from allogeneic related donors: report of five cases. Arthritis Rheum 2011; 63(8): 2540–2542Google Scholar
  97. 97.
    Granel B, Daumas A, Jouve E, Harle JR, Nguyen PS, Chabannon C, Colavolpe N, Reynier JC, Truillet R, Mallet S, Baiada A, Casanova D, Giraudo L, Arnaud L, Veran J, Sabatier F, Magalon G. Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial. Ann Rheum Dis 2015; 74(12): 2175–2182Google Scholar
  98. 98.
    Scuderi N, Ceccarelli S, Onesti MG, Fioramonti P, Guidi C, Romano F, Frati L, Angeloni A, Marchese C. Human adiposederived stromal cells for cell-based therapies in the treatment of systemic sclerosis. Cell Transplant 2013; 22(5): 779–795Google Scholar
  99. 99.
    Xu J, Wang D, Liu D, Fan Z, Zhang H, Liu O, Ding G, Gao R, Zhang C, Ding Y, Bromberg JS, Chen W, Sun L, Wang S. Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjogren syndrome. Blood 2012; 120(15): 3142–3151Google Scholar
  100. 100.
    Sada PR, Isenberg D, Ciurtin C. Biologic treatment in Sjogren’s syndrome. Rheumatology (Oxford) 2015; 54(2): 219–230Google Scholar
  101. 101.
    Wang P, Li Y, Huang L, Yang J, Yang R, Deng W, Liang B, Dai L, Meng Q, Gao L, Chen X, Shen J, Tang Y, Zhang X, Hou J, Ye J, Chen K, Cai Z, Wu Y, Shen H. Effects and safety of allogenic mesenchymal stem cell intravenous infusion in active ankylosing spondylitis patients who failed NSAIDs: a 20-week clinical trial. Cell Transplant 2014; 23(10): 1293–1303Google Scholar
  102. 102.
    Wang D, Zhang H, Cao M, Tang Y, Liang J, Feng X, Wang H, Hua B, Liu B, Sun L. Efficacy of allogeneic mesenchymal stem cell transplantation in patients with drug-resistant polymyositis and dermatomyositis. Ann Rheum Dis 2011; 70(7): 1285–1288Google Scholar
  103. 103.
    Ra JC, Kang SK, Shin IS, Park HG, Joo SA, Kim JG, Kang BC, Lee YS, Nakama K, Piao M, Sohl B, Kurtz A. Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells. J Transl Med 2011; 9: 181Google Scholar
  104. 104.
    Cle DV, Santana-Lemos B, Tellechea MF, Prata KL, Orellana MD, Covas DT, Calado RT. Intravenous infusion of allogeneic mesenchymal stromal cells in refractory or relapsed aplastic anemia. Cytotherapy 2015; 17(12): 1696–1705Google Scholar
  105. 105.
    Hashmi S, Ahmed M, Murad MH, Litzow MR, Adams RH, Ball LM, Prasad VK, Kebriaei P, Ringden O. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis. Lancet Haematol 2016; 3(1): e45–e52Google Scholar
  106. 106.
    Guo M, Sun Z, Sun QY, Han Q, Yu CL, Wang DH, Qiao JH, Chen B, Sun WJ, Hu KX, Liu GX, Liu B, Zhao RC, Ai H. A modified haploidentical nonmyeloablative transplantation without T cell depletion for high-risk acute leukemia: successful engraftment and mild GVHD. Biol Blood Marrow Transplant 2009; 15(8): 930–937Google Scholar
  107. 107.
    Liu K, Chen Y, Zeng Y, Xu L, Liu D, Chen H, Zhang X, Han W, Wang Y, Zhao T, Wang J, Han Q, Zhao C, Huang X. Coinfusion of mesenchymal stromal cells facilitates platelet recovery without increasing leukemia recurrence in haploidentical hematopoietic stem cell transplantation: a randomized, controlled clinical study. Stem Cells Dev 2011; 20(10): 1679–1685Google Scholar
  108. 108.
    Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, Zhang JJ, Chunhua RZ, Liao LM, Lin S, Sun JP. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 2004; 94(1): 92–95Google Scholar
  109. 109.
    Wang S, Qu X, Zhao RC. Clinical applications of mesenchymal stem cells. J Hematol Oncol 2012; 5(1): 19Google Scholar
  110. 110.
    Karp JM, Leng Teo GS. Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 2009; 4(3): 206–216Google Scholar
  111. 111.
    Payne NL, Dantanarayana A, Sun G, Moussa L, Caine S, McDonald C, Herszfeld D, Bernard CC, Siatskas C. Early intervention with gene-modified mesenchymal stem cells overexpressing interleukin-4 enhances anti-inflammatory responses and functional recovery in experimental autoimmune demyelination. Cell Adhes Migr 2012; 6(3): 179–189Google Scholar
  112. 112.
    Polchert D, Sobinsky J, Douglas G, Kidd M, Moadsiri A, Reina E, Genrich K, Mehrotra S, Setty S, Smith B, Bartholomew A. IFN-γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol 2008; 38(6): 1745–1755Google Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Shihua Wang
    • 1
    • 2
    • 3
    • 4
  • Rongjia Zhu
    • 1
    • 2
    • 3
    • 4
  • Hongling Li
    • 1
    • 2
    • 3
    • 4
  • Jing Li
    • 1
    • 2
    • 3
    • 4
  • Qin Han
    • 1
    • 2
    • 3
    • 4
  • Robert Chunhua Zhao
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Institute of Basic Medical SciencesChinese Academy of Medical SciencesBeijingChina
  2. 2.School of Basic MedicinePeking Union Medical CollegeBeijingChina
  3. 3.Peking Union Medical College HospitalBeijingChina
  4. 4.Center of Excellence in Tissue EngineeringChinese Academy of Medical SciencesBeijingChina

Personalised recommendations