Clinical Reviews in Allergy & Immunology

, Volume 52, Issue 2, pp 234–259 | Cite as

Adipose-Derived Mesenchymal Stem Cells in Autoimmune Disorders: State of the Art and Perspectives for Systemic Sclerosis

  • Alexandre T. J. Maria
  • Marie Maumus
  • Alain Le Quellec
  • Christian Jorgensen
  • Danièle Noël
  • Philippe Guilpain


Mesenchymal stromal/stem cells (MSC) are non-hematopoietic multipotent progenitor cells, first described in bone marrow in the middle of last century. Since then, MSC have been the objects of a myriad of publications, progressively increasing our knowledge on their potentialities and bringing high expectancies for their regenerative properties. During the same period, numerous tissues, such as adipose tissue, placenta, or umbilical cord, have been used as alternative sources of MSC in comparison with bone marrow. In particular, considering the accessibility and ease to harvest fat tissue, adipose-derived MSC have gained interest above bone marrow-derived MSC. More recently, the discovery of MSC immunomodulatory properties made MSC-based therapy progressively slip from the field of regenerative medicine to the one of autoimmunity. Indeed, in this group of disorders caused by aberrant activation of the immune system resulting in loss of self-tolerance and auto-reactivity, conventional immunosuppressant may be harmful. One advantage of MSC-based therapy would lie in their immune plasticity, resulting in space and time-limited immunosuppression. More specifically, among autoimmune disorders, systemic sclerosis appears as a peculiar multifaceted disease, in which autoimmune phenomena coexist with vascular abnormalities and multi-visceral fibrosis. Considering the pleiotropic effects of MSC, displaying immunomodulatory, angiogenic and antifibrotic capabilities, MSC-based therapy could counteract the three main pathogenic axes of systemic sclerosis and might thus represent a complete breakthrough in this intractable disease with unmet medical need. In this article, while reviewing most recent literature on MSC biology, we itemize their current applications in the field of autoimmunity and shed light onto the potential use of adipose-derived MSC as an innovative strategy to cure systemic sclerosis.


Autoimmune disorders Systemic sclerosis Mesenchymal stem cells (MSC) Adipose-derived mesenchymal stem cells (ASC) Cell therapy Fibrosis Autoimmunity 



Alpha-smooth actin muscle


Autoimmune disorders


Advanced oxidation protein products


Antineutrophil cytoplasm antibodies


Adipose-derived mesenchymal stem cells


Adipose tissue


Advanced-therapy medicinal product


Basic fibroblast growth factor


British Isles Lupus Assessment Group


Crohn’s disease


Colony-forming unit fibroblasts


Comparative genomic hybridization


Collagen-induced arthritis


Central nervous system


Chemokine C-X-C motif receptor 4


Dendritic cells (mDC: mature, iDC: immature)


Experimental acute encephalomyelitis


Endothelial cells


Food and Drug Administration


Fluorescence in situ hybridization


Green fluorescent protein


Glucocorticoid-induced leucin zipper


Granulocyte macrophage stimulating growth factor


Good manufacturing practices


Graft vs host disease


Heme oxygenase 1




Hematopoietic stem cell transplantation




Inflammatory bowel diseases


Indoleamine 2,3 dioxygenase








Interleukin 1 receptor antagonist


Inducible NO synthase




Induced pluripotent stem cells


International Society for Stem Cell Therapy






Leukemia inhibitory factor




Major histocompatibility complex




Myelin oligodendrocyte glycoprotein


Multipotent progenitor cells


Modified Rodnan skin score


Multiple sclerosis


Mesenchymal stromal/stem cells


Murine MSC


Human MSC


Bone-marrow derived mesenchymal stem cells


Umbilical cord MSC


Natural killer




Pulmonary arterial hypertension


Peripheral blood mononuclear cell


Programmed death-1/ programmed death ligand-1


Prostaglandin E2




Proteolipid proteins


Rheumatoid arthritis


Receptor activator of nuclear factor kappa-B/RANK ligand


Reactive oxygen species


Severe combined immunodeficiency


Stem cell factor


Stromal cell derived factor-1


Systemic Lupus Erythematosus


SLE disease activity score


Sex region of Y chromosome


Systemic sclerosis


Stromal vascular fraction


Tissue inhibitor of metalloprotease


Tumor necrosis factor


Tumor necrosis factor inducible gene 6


Vascular cell adhesion molecule


  1. 1.
    Zhao Y, Mazzone T (2010) Human cord blood stem cells and the journey to a cure for type 1 diabetes. Autoimmun Rev 10(2):103–107. doi: 10.1016/j.autrev.2010.08.011 PubMedCrossRefGoogle Scholar
  2. 2.
    Ben-Ami E, Berrih-Aknin S, Miller A (2011) Mesenchymal stem cells as an immunomodulatory therapeutic strategy for autoimmune diseases. Autoimmun Rev 10(7):410–415. doi: 10.1016/j.autrev.2011.01.005 PubMedCrossRefGoogle Scholar
  3. 3.
    Cipriani P, Carubbi F, Liakouli V, Marrelli A, Perricone C, Perricone R, Alesse E, Giacomelli R (2013) Stem cells in autoimmune diseases: implications for pathogenesis and future trends in therapy. Autoimmun Rev 12(7):709–716. doi: 10.1016/j.autrev.2012.10.004 PubMedCrossRefGoogle Scholar
  4. 4.
    Cipriani P, Ruscitti P, Di Benedetto P, Carubbi F, Liakouli V, Berardicurti O, Ciccia F, Triolo G, Giacomelli R (2015) Mesenchymal stromal cells and rheumatic diseases: new tools from pathogenesis to regenerative therapies. Cytotherapy 17(7):832–849. doi: 10.1016/j.jcyt.2014.12.006 PubMedCrossRefGoogle Scholar
  5. 5.
    Chighizola C, Shoenfeld Y, Meroni PL (2011) Systemic sclerosis. Introduction. Autoimmun Rev 10(5):239–240. doi: 10.1016/j.autrev.2011.02.005 PubMedCrossRefGoogle Scholar
  6. 6.
    Desbois AC, Cacoub P (2016) Systemic sclerosis: an update in 2016. Autoimmun Rev. doi: 10.1016/j.autrev.2016.01.007 Google Scholar
  7. 7.
    Cras A, Farge D, Carmoi T, Lataillade JJ, Wang DD, Sun L (2015) Update on mesenchymal stem cell-based therapy in lupus and scleroderma. Arthritis Res Ther 17:301. doi: 10.1186/s13075-015-0819-7 PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Friedenstein AJ, Gorskaja JF, Kulagina NN (1976) Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 4(5):267–274PubMedGoogle Scholar
  9. 9.
    Lv FJ, Tuan RS, Cheung KM, Leung VY (2014) Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells 32(6):1408–1419. doi: 10.1002/stem.1681 PubMedCrossRefGoogle Scholar
  10. 10.
    Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI (1995) Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant 16(4):557–564PubMedGoogle Scholar
  11. 11.
    Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A, International Society for Cellular T (2005) Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 7(5):393–395. doi: 10.1080/14653240500319234 PubMedCrossRefGoogle Scholar
  12. 12.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4):315–317. doi: 10.1080/14653240600855905 PubMedCrossRefGoogle Scholar
  13. 13.
    Nauta AJ, Fibbe WE (2007) Immunomodulatory properties of mesenchymal stromal cells. Blood 110(10):3499–3506. doi: 10.1182/blood-2007-02-069716 PubMedCrossRefGoogle Scholar
  14. 14.
    Maumus M, Peyrafitte JA, D’Angelo R, Fournier-Wirth C, Bouloumie A, Casteilla L, Sengenes C, Bourin P (2011) Native human adipose stromal cells: localization, morphology and phenotype. Int J Obes 35(9):1141–1153. doi: 10.1038/ijo.2010.269 CrossRefGoogle Scholar
  15. 15.
    Tropel P, Noel D, Platet N, Legrand P, Benabid AL, Berger F (2004) Isolation and characterisation of mesenchymal stem cells from adult mouse bone marrow. Exp Cell Res 295(2):395–406. doi: 10.1016/j.yexcr.2003.12.030 PubMedCrossRefGoogle Scholar
  16. 16.
    Samsonraj RM, Rai B, Sathiyanathan P, Puan KJ, Rotzschke O, Hui JH, Raghunath M, Stanton LW, Nurcombe V, Cool SM (2015) Establishing criteria for human mesenchymal stem cell potency. Stem Cells 33(6):1878–1891. doi: 10.1002/stem.1982 PubMedCrossRefGoogle Scholar
  17. 17.
    Galipeau J, Krampera M, Barrett J, Dazzi F, Deans RJ, DeBruijn J, Dominici M, Fibbe WE, Gee AP, Gimble JM, Hematti P, Koh MB, LeBlanc K, Martin I, McNiece IK, Mendicino M, Oh S, Ortiz L, Phinney DG, Planat V, Shi Y, Stroncek DF, Viswanathan S, Weiss DJ, Sensebe L (2016) International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy 18(2):151–159. doi: 10.1016/j.jcyt.2015.11.008 PubMedCrossRefGoogle Scholar
  18. 18.
    Bravery CA, Carmen J, Fong T, Oprea W, Hoogendoorn KH, Woda J, Burger SR, Rowley JA, Bonyhadi ML, Van’t Hof W (2013) Potency assay development for cellular therapy products: an ISCT review of the requirements and experiences in the industry. Cytotherapy 15(1):9–19. doi: 10.1016/j.jcyt.2012.10.008 PubMedCrossRefGoogle Scholar
  19. 19.
    Menard C, Pacelli L, Bassi G, Dulong J, Bifari F, Bezier I, Zanoncello J, Ricciardi M, Latour M, Bourin P, Schrezenmeier H, Sensebe L, Tarte K, Krampera M (2013) Clinical-grade mesenchymal stromal cells produced under various good manufacturing practice processes differ in their immunomodulatory properties: standardization of immune quality controls. Stem Cells Dev 22(12):1789–1801. doi: 10.1089/scd.2012.0594 PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Mendicino M, Bailey AM, Wonnacott K, Puri RK, Bauer SR (2014) MSC-based product characterization for clinical trials: an FDA perspective. Cell Stem Cell 14(2):141–145. doi: 10.1016/j.stem.2014.01.013 PubMedCrossRefGoogle Scholar
  21. 21.
    Sensebe L, Gadelorge M, Fleury-Cappellesso S (2013) Production of mesenchymal stromal/stem cells according to good manufacturing practices: a review. Stem Cell Res Ther 4(3):66. doi: 10.1186/scrt217 PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, Deans R, Moseley A, Hoffman R (2002) Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30(1):42–48PubMedCrossRefGoogle Scholar
  23. 23.
    Deans RJ, Moseley AB (2000) Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 28(8):875–884PubMedCrossRefGoogle Scholar
  24. 24.
    Ghannam S, Bouffi C, Djouad F, Jorgensen C, Noel D (2010) Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther 1(1):2. doi: 10.1186/scrt2 PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Krampera M, Galipeau J, Shi Y, Tarte K, Sensebe L, Therapy MSCCotISfC (2013) Immunological characterization of multipotent mesenchymal stromal cells—the International Society for Cellular Therapy (ISCT) working proposal. Cytotherapy 15(9):1054–1061. doi: 10.1016/j.jcyt.2013.02.010 PubMedCrossRefGoogle Scholar
  26. 26.
    Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM (2010) A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PLoS One 5(4):e10088. doi: 10.1371/journal.pone.0010088 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Solari MG, Srinivasan S, Boumaza I, Unadkat J, Harb G, Garcia-Ocana A, Feili-Hariri M (2009) Marginal mass islet transplantation with autologous mesenchymal stem cells promotes long-term islet allograft survival and sustained normoglycemia. J Autoimmun 32(2):116–124. doi: 10.1016/j.jaut.2009.01.003 PubMedCrossRefGoogle Scholar
  28. 28.
    Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y (2008) Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2(2):141–150. doi: 10.1016/j.stem.2007.11.014 PubMedCrossRefGoogle Scholar
  29. 29.
    Noel D, Djouad F, Bouffi C, Mrugala D, Jorgensen C (2007) Multipotent mesenchymal stromal cells and immune tolerance. Leuk Lymphoma 48(7):1283–1289. doi: 10.1080/10428190701361869 PubMedCrossRefGoogle Scholar
  30. 30.
    Jorgensen C, Djouad F, Apparailly F, Noel D (2003) Engineering mesenchymal stem cells for immunotherapy. Gene Ther 10(10):928–931. doi: 10.1038/ PubMedCrossRefGoogle Scholar
  31. 31.
    Ankrum JA, Ong JF, Karp JM (2014) Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol 32(3):252–260. doi: 10.1038/nbt.2816 PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Meisel R, Brockers S, Heseler K, Degistirici O, Bulle H, Woite C, Stuhlsatz S, Schwippert W, Jager M, Sorg R, Henschler R, Seissler J, Dilloo D, Daubener W (2011) Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. Leukemia 25(4):648–654. doi: 10.1038/leu.2010.310 PubMedCrossRefGoogle Scholar
  33. 33.
    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(12):4619–4621. doi: 10.1182/blood-2003-11-3909 PubMedCrossRefGoogle Scholar
  34. 34.
    Djouad F, Bouffi C, Ghannam S, Noel D, Jorgensen C (2009) Mesenchymal stem cells: innovative therapeutic tools for rheumatic diseases. Nat Rev Rheumatol 5(7):392–399. doi: 10.1038/nrrheum.2009.104 PubMedCrossRefGoogle Scholar
  35. 35.
    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(1):42–49. doi: 10.1038/nm.1905 PubMedCrossRefGoogle Scholar
  36. 36.
    Bouffi C, Bony C, Courties G, Jorgensen C, Noel D (2010) IL-6-dependent PGE2 secretion by mesenchymal stem cells inhibits local inflammation in experimental arthritis. PLoS One 5(12):e14247. doi: 10.1371/journal.pone.0014247 PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Luz-Crawford P, Djouad F, Toupet K, Bony C, Franquesa M, Hoogduijn MJ, Jorgensen C, Noel D (2015) Mesenchymal stem cell-derived IL1RA promotes macrophage polarization and inhibits B cell differentiation. Stem Cells. doi: 10.1002/stem.2254 Google Scholar
  38. 38.
    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 (2016) Soluble tumor necrosis factor receptor 1 Released by skin-derived mesenchymal stem cells is critical for inhibiting Th17 cell differentiation. Stem Cells Transl Med. doi: 10.5966/sctm.2015-0179 PubMedCentralGoogle Scholar
  39. 39.
    Luz-Crawford P, Tejedor G, Mausset-Bonnefont AL, Beaulieu E, Morand EF, Jorgensen C, Noel D, Djouad F (2015) Glucocorticoid-induced leucine zipper governs the therapeutic potential of mesenchymal stem cells by inducing a switch from pathogenic to regulatory Th17 cells in a mouse model of collagen-induced arthritis. Arthritis Rheum 67(6):1514–1524. doi: 10.1002/art.39069 CrossRefGoogle Scholar
  40. 40.
    Luz-Crawford P, Noel D, Fernandez X, Khoury M, Figueroa F, Carrion F, Jorgensen C, Djouad F (2012) Mesenchymal stem cells repress Th17 molecular program through the PD-1 pathway. PLoS One 7(9):e45272. doi: 10.1371/journal.pone.0045272 PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Luz-Crawford P, Kurte M, Bravo-Alegria J, Contreras R, Nova-Lamperti E, Tejedor G, Noel D, Jorgensen C, Figueroa F, Djouad F, Carrion F (2013) Mesenchymal stem cells generate a CD4 + CD25 + Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther 4(3):65. doi: 10.1186/scrt216 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M (2006) Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24(1):74–85. doi: 10.1634/stemcells.2004-0359 PubMedCrossRefGoogle Scholar
  43. 43.
    Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, Risso M, Gualandi F, Mancardi GL, Pistoia V, Uccelli A (2006) Human mesenchymal stem cells modulate B-cell functions. Blood 107(1):367–372. doi: 10.1182/blood-2005-07-2657 PubMedCrossRefGoogle Scholar
  44. 44.
    Rosado MM, Bernardo ME, Scarsella M, Conforti A, Giorda E, Biagini S, Cascioli S, Rossi F, Guzzo I, Vivarelli M, Dello Strologo L, Emma F, Locatelli F, Carsetti R (2015) Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells. Stem Cells Dev 24(1):93–103. doi: 10.1089/scd.2014.0155 PubMedCrossRefGoogle Scholar
  45. 45.
    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(8):2025–2032. doi: 10.1634/stemcells.2006-0548 PubMedCrossRefGoogle Scholar
  46. 46.
    Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD, Mao N (2005) Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105(10):4120–4126. doi: 10.1182/blood-2004-02-0586 PubMedCrossRefGoogle Scholar
  47. 47.
    Najar M, Raicevic G, Fayyad-Kazan H, Bron D, Toungouz M, Lagneaux L (2016) Mesenchymal stromal cells and immunomodulation: a gathering of regulatory immune cells. Cytotherapy 18(2):160–171. doi: 10.1016/j.jcyt.2015.10.011 PubMedCrossRefGoogle Scholar
  48. 48.
    Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, Noel D, Jorgensen C (2003) Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 102(10):3837–3844. doi: 10.1182/blood-2003-04-1193 PubMedCrossRefGoogle Scholar
  49. 49.
    Patel DM, Shah J, Srivastava AS (2013) Therapeutic potential of mesenchymal stem cells in regenerative medicine. Stem Cells Int 2013:496218. doi: 10.1155/2013/496218 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Hwang NS, Zhang C, Hwang YS, Varghese S (2009) Mesenchymal stem cell differentiation and roles in regenerative medicine. Wiley Interdiscip Rev Syst Biol Med 1(1):97–106. doi: 10.1002/wsbm.26 PubMedCrossRefGoogle Scholar
  51. 51.
    Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG (2003) Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A 100(14):8407–8411. doi: 10.1073/pnas.1432929100 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Zhao F, Zhang YF, Liu YG, Zhou JJ, Li ZK, Wu CG, Qi HW (2008) Therapeutic effects of bone marrow-derived mesenchymal stem cells engraftment on bleomycin-induced lung injury in rats. Transplant Proc 40(5):1700–1705. doi: 10.1016/j.transproceed.2008.01.080 PubMedCrossRefGoogle Scholar
  53. 53.
    Croft AP, Przyborski SA (2006) Formation of neurons by non-neural adult stem cells: potential mechanism implicates an artifact of growth in culture. Stem Cells 24(8):1841–1851. doi: 10.1634/stemcells.2005-0609 PubMedCrossRefGoogle Scholar
  54. 54.
    von Bahr L, Batsis I, Moll G, Hagg M, Szakos A, Sundberg B, Uzunel M, Ringden O, Le Blanc K (2012) Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells 30(7):1575–1578. doi: 10.1002/stem.1118 CrossRefGoogle Scholar
  55. 55.
    Huang K, Kang X, Wang X, Wu S, Xiao J, Li Z, Wu X, Zhang W (2015) Conversion of bone marrow mesenchymal stem cells into type II alveolar epithelial cells reduces pulmonary fibrosis by decreasing oxidative stress in rats. Mol Med Rep 11(3):1685–1692. doi: 10.3892/mmr.2014.2981 PubMedGoogle Scholar
  56. 56.
    Hashemi SM, Ghods S, Kolodgie FD, Parcham-Azad K, Keane M, Hamamdzic D, Young R, Rippy MK, Virmani R, Litt H, Wilensky RL (2008) A placebo controlled, dose-ranging, safety study of allogenic mesenchymal stem cells injected by endomyocardial delivery after an acute myocardial infarction. Eur Heart J 29(2):251–259. doi: 10.1093/eurheartj/ehm559 PubMedCrossRefGoogle Scholar
  57. 57.
    Leroy A, Nottelet B, Bony C, Pinese C, Charlot B, Garric X, Noel D, Coudane J (2015) PLA-poloxamer/poloxamine copolymers for ligament tissue engineering: sound macromolecular design for degradable scaffolds and MSC differentiation. Biomater Sci 3(4):617–626. doi: 10.1039/c4bm00433g PubMedCrossRefGoogle Scholar
  58. 58.
    Bouffi C, Thomas O, Bony C, Giteau A, Venier-Julienne MC, Jorgensen C, Montero-Menei C, Noel D (2010) The role of pharmacologically active microcarriers releasing TGF-beta3 in cartilage formation in vivo by mesenchymal stem cells. Biomaterials 31(25):6485–6493. doi: 10.1016/j.biomaterials.2010.05.013 PubMedCrossRefGoogle Scholar
  59. 59.
    Jorgensen C, Gordeladze J, Noel D (2004) Tissue engineering through autologous mesenchymal stem cells. Curr Opin Biotechnol 15(5):406–410. doi: 10.1016/j.copbio.2004.08.003 PubMedCrossRefGoogle Scholar
  60. 60.
    Vinatier C, Bouffi C, Merceron C, Gordeladze J, Brondello JM, Jorgensen C, Weiss P, Guicheux J, Noel D (2009) Cartilage tissue engineering: towards a biomaterial-assisted mesenchymal stem cell therapy. Curr Stem Cell Res Ther 4(4):318–329PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Mathieu M, Vigier S, Labour MN, Jorgensen C, Belamie E, Noel D (2014) Induction of mesenchymal stem cell differentiation and cartilage formation by cross-linker-free collagen microspheres. Eur Cell Mater 28:82–96, discussion 96–87PubMedCrossRefGoogle Scholar
  62. 62.
    Morille M, Van-Thanh T, Garric X, Cayon J, Coudane J, Noel D, Venier-Julienne MC, Montero-Menei CN (2013) New PLGA-P188-PLGA matrix enhances TGF-beta3 release from pharmacologically active microcarriers and promotes chondrogenesis of mesenchymal stem cells. J Control Release 170(1):99–110. doi: 10.1016/j.jconrel.2013.04.017 PubMedCrossRefGoogle Scholar
  63. 63.
    Portron S, Hivernaud V, Merceron C, Lesoeur J, Masson M, Gauthier O, Vinatier C, Beck L, Guicheux J (2015) Inverse regulation of early and late chondrogenic differentiation by oxygen tension provides cues for stem cell-based cartilage tissue engineering. Cell Physiol Biochem 35(3):841–857. doi: 10.1159/000369742 PubMedCrossRefGoogle Scholar
  64. 64.
    Eap S, Keller L, Schiavi J, Huck O, Jacomine L, Fioretti F, Gauthier C, Sebastian V, Schwinte P, Benkirane-Jessel N (2015) A living thick nanofibrous implant bifunctionalized with active growth factor and stem cells for bone regeneration. Int J Nanomedicine 10:1061–1075. doi: 10.2147/IJN.S72670 PubMedPubMedCentralGoogle Scholar
  65. 65.
    Kim IG, Ko J, Lee HR, Do SH, Park K (2016) Mesenchymal cells condensation-inducible mesh scaffolds for cartilage tissue engineering. Biomaterials 85:18–29. doi: 10.1016/j.biomaterials.2016.01.048 PubMedCrossRefGoogle Scholar
  66. 66.
    Pers YM, Ruiz M, Noel D, Jorgensen C (2015) Mesenchymal stem cells for the management of inflammation in osteoarthritis: state of the art and perspectives. Osteoarthr Cartil 23(11):2027–2035. doi: 10.1016/j.joca.2015.07.004 PubMedCrossRefGoogle Scholar
  67. 67.
    Maumus M, Jorgensen C, Noel D (2013) Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: role of secretome and exosomes. Biochimie 95(12):2229–2234. doi: 10.1016/j.biochi.2013.04.017 PubMedCrossRefGoogle Scholar
  68. 68.
    Toupet K, Maumus M, Luz-Crawford P, Lombardo E, Lopez-Belmonte J, van Lent P, Garin MI, van den Berg W, Dalemans W, Jorgensen C, Noel D (2015) Survival and biodistribution of xenogenic adipose mesenchymal stem cells is not affected by the degree of inflammation in arthritis. PLoS One 10(1):e0114962. doi: 10.1371/journal.pone.0114962 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Toupet K, Maumus M, Peyrafitte JA, Bourin P, van Lent PL, Ferreira R, Orsetti B, Pirot N, Casteilla L, Jorgensen C, Noel D (2013) Long-term detection of human adipose-derived mesenchymal stem cells after intraarticular injection in SCID mice. Arthritis Rheum 65(7):1786–1794. doi: 10.1002/art.37960 PubMedCrossRefGoogle Scholar
  70. 70.
    Maria A, Toupet K, Bony C, Pirot N, Vozenin M-C, Benoit P, Roger P, Batteux F, Le Quellec A, Jorgensen C, Guilpain P, Noël D (2016) Anti-fibrotic, anti-oxidant and immunomodulatory effects of mesenchymal stem cells in HOCl-induced systemic sclerosis. Arthritis Rheum 68:1013–1025Google Scholar
  71. 71.
    Meyerrose TE, De Ugarte DA, Hofling AA, Herrbrich PE, Cordonnier TD, Shultz LD, Eagon JC, Wirthlin L, Sands MS, Hedrick MA, Nolta JA (2007) In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models. Stem Cells 25(1):220–227. doi: 10.1634/stemcells.2006-0243 PubMedCrossRefGoogle Scholar
  72. 72.
    Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI (2001) The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 169(1):12–20PubMedCrossRefGoogle Scholar
  73. 73.
    Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, Laine GA, Cox CS Jr (2009) Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev 18(5):683–692. doi: 10.1089/scd.2008.0253 PubMedCrossRefGoogle Scholar
  74. 74.
    Moodley Y, Atienza D, Manuelpillai U, Samuel CS, Tchongue J, Ilancheran S, Boyd R, Trounson A (2009) Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am J Pathol 175(1):303–313. doi: 10.2353/ajpath.2009.080629 PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Wolf D, Reinhard A, Seckinger A, Katus HA, Kuecherer H, Hansen A (2009) Dose-dependent effects of intravenous allogeneic mesenchymal stem cells in the infarcted porcine heart. Stem Cells Dev 18(2):321–329. doi: 10.1089/scd.2008.0019 PubMedCrossRefGoogle Scholar
  76. 76.
    Joo SY, Cho KA, Jung YJ, Kim HS, Park SY, Choi YB, Hong KM, Woo SY, Seoh JY, Cho SJ, Ryu KH (2010) Mesenchymal stromal cells inhibit graft-versus-host disease of mice in a dose-dependent manner. Cytotherapy 12(3):361–370. doi: 10.3109/14653240903502712 PubMedCrossRefGoogle Scholar
  77. 77.
    Desando G, Cavallo C, Sartoni F, Martini L, Parrilli A, Veronesi F, Fini M, Giardino R, Facchini A, Grigolo B (2013) Intra-articular delivery of adipose derived stromal cells attenuates osteoarthritis progression in an experimental rabbit model. Arthritis Res Ther 15(1):R22. doi: 10.1186/ar4156 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Murphy MB, Moncivais K, Caplan AI (2013) Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med 45:e54. doi: 10.1038/emm.2013.94 PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Le Blanc K, Mougiakakos D (2012) Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 12(5):383–396. doi: 10.1038/nri3209 PubMedCrossRefGoogle Scholar
  80. 80.
    Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L (2006) Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 107(4):1484–1490. doi: 10.1182/blood-2005-07-2775 PubMedCrossRefGoogle Scholar
  81. 81.
    Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE (2006) Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood 108(6):2114–2120. doi: 10.1182/blood-2005-11-011650 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Crop MJ, Korevaar SS, de Kuiper R, IJzermans JN, van Besouw NM, Baan CC, Weimar W, Hoogduijn MJ (2011) Human mesenchymal stem cells are susceptible to lysis by CD8(+) T cells and NK cells. Cell Transplant 20(10):1547–1559. doi: 10.3727/096368910X564076 PubMedCrossRefGoogle Scholar
  83. 83.
    Lim R, Milton P, Murphy SV, Dickinson H, Chan ST, Jenkin G (2013) Human mesenchymal stem cells reduce lung injury in immunocompromised mice but not in immunocompetent mice. Respiration 85(4):332–341. doi: 10.1159/000343078 PubMedCrossRefGoogle Scholar
  84. 84.
    Breitbach M, Bostani T, Roell W, Xia Y, Dewald O, Nygren JM, Fries JW, Tiemann K, Bohlen H, Hescheler J, Welz A, Bloch W, Jacobsen SE, Fleischmann BK (2007) Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 110(4):1362–1369. doi: 10.1182/blood-2006-12-063412 PubMedCrossRefGoogle Scholar
  85. 85.
    Bouffi C, Djouad F, Mathieu M, Noel D, Jorgensen C (2009) Multipotent mesenchymal stromal cells and rheumatoid arthritis: risk or benefit? Rheumatology (Oxford) 48(10):1185–1189. doi: 10.1093/rheumatology/kep162 CrossRefGoogle Scholar
  86. 86.
    Mishra PJ, Mishra PJ, Glod JW, Banerjee D (2009) Mesenchymal stem cells: flip side of the coin. Cancer Res 69(4):1255–1258. doi: 10.1158/0008-5472.CAN-08-3562 PubMedCrossRefGoogle Scholar
  87. 87.
    Miura M, Miura Y, Padilla-Nash HM, Molinolo AA, Fu B, Patel V, Seo BM, Sonoyama W, Zheng JJ, Baker CC, Chen W, Ried T, Shi S (2006) Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation. Stem Cells 24(4):1095–1103. doi: 10.1634/stemcells.2005-0403 PubMedCrossRefGoogle Scholar
  88. 88.
    Tolar J, Nauta AJ, Osborn MJ, Panoskaltsis Mortari A, McElmurry RT, Bell S, Xia L, Zhou N, Riddle M, Schroeder TM, Westendorf JJ, McIvor RS, Hogendoorn PC, Szuhai K, Oseth L, Hirsch B, Yant SR, Kay MA, Peister A, Prockop DJ, Fibbe WE, Blazar BR (2007) Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 25(2):371–379. doi: 10.1634/stemcells.2005-0620 PubMedCrossRefGoogle Scholar
  89. 89.
    Tarte K, Gaillard J, Lataillade JJ, Fouillard L, Becker M, Mossafa H, Tchirkov A, Rouard H, Henry C, Splingard M, Dulong J, Monnier D, Gourmelon P, Gorin NC, Sensebe L, Societe Francaise de Greffe de Moelle et Therapie C (2010) Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation. Blood 115(8):1549–1553. doi: 10.1182/blood-2009-05-219907 PubMedCrossRefGoogle Scholar
  90. 90.
    Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, Montagna D, Maccario R, Villa R, Daidone MG, Zuffardi O, Locatelli F (2007) Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res 67(19):9142–9149. doi: 10.1158/0008-5472.CAN-06-4690 PubMedCrossRefGoogle Scholar
  91. 91.
    Djouad F, Bony C, Apparailly F, Louis-Plence P, Jorgensen C, Noel D (2006) Earlier onset of syngeneic tumors in the presence of mesenchymal stem cells. Transplantation 82(8):1060–1066. doi: 10.1097/ PubMedCrossRefGoogle Scholar
  92. 92.
    Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ, Canadian Critical Care Trials G (2012) Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One 7(10):e47559. doi: 10.1371/journal.pone.0047559 PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    da Silva Meirelles L, Chagastelles PC, Nardi NB (2006) Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 119(Pt 11):2204–2213. doi: 10.1242/jcs.02932 PubMedCrossRefGoogle Scholar
  94. 94.
    Najar M, Raicevic G, Boufker HI, Fayyad Kazan H, De Bruyn C, Meuleman N, Bron D, Toungouz M, Lagneaux L (2010) Mesenchymal stromal cells use PGE2 to modulate activation and proliferation of lymphocyte subsets: Combined comparison of adipose tissue, Wharton’s Jelly and bone marrow sources. Cell Immunol 264(2):171–179. doi: 10.1016/j.cellimm.2010.06.006 PubMedCrossRefGoogle Scholar
  95. 95.
    Montesinos JJ, Flores-Figueroa E, Castillo-Medina S, Flores-Guzman P, Hernandez-Estevez E, Fajardo-Orduna G, Orozco S, Mayani H (2009) Human mesenchymal stromal cells from adult and neonatal sources: comparative analysis of their morphology, immunophenotype, differentiation patterns and neural protein expression. Cytotherapy 11(2):163–176. doi: 10.1080/14653240802582075 PubMedCrossRefGoogle Scholar
  96. 96.
    Luz-Crawford P, Torres MJ, Noel D, Fernandez A, Toupet K, Alcayaga-Miranda F, Tejedor G, Jorgensen C, Illanes SE, Figueroa FE, Djouad F, Khoury M (2015) The immunosuppressive signature of menstrual blood mesenchymal stem cells entails opposite effects on experimental arthritis and graft versus host diseases. Stem Cells. doi: 10.1002/stem.2244 Google Scholar
  97. 97.
    Kaltz N, Funari A, Hippauf S, Delorme B, Noel D, Riminucci M, Jacobs VR, Haupl T, Jorgensen C, Charbord P, Peschel C, Bianco P, Oostendorp RA (2008) In vivo osteoprogenitor potency of human stromal cells from different tissues does not correlate with expression of POU5F1 or its pseudogenes. Stem Cells 26(9):2419–2424. doi: 10.1634/stemcells.2008-0304 PubMedCrossRefGoogle Scholar
  98. 98.
    Sousa BR, Parreira RC, Fonseca EA, Amaya MJ, Tonelli FM, Lacerda SM, Lalwani P, Santos AK, Gomes KN, Ulrich H, Kihara AH, Resende RR (2014) Human adult stem cells from diverse origins: an overview from multiparametric immunophenotyping to clinical applications. Cytometry A 85(1):43–77. doi: 10.1002/cyto.a.22402 PubMedCrossRefGoogle Scholar
  99. 99.
    De Ugarte DA, Morizono K, Elbarbary A, Alfonso Z, Zuk PA, Zhu M, Dragoo JL, Ashjian P, Thomas B, Benhaim P, Chen I, Fraser J, Hedrick MH (2003) Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs 174(3):101–109PubMedCrossRefGoogle Scholar
  100. 100.
    Roche S, Delorme B, Oostendorp RA, Barbet R, Caton D, Noel D, Boumediene K, Papadaki HA, Cousin B, Crozet C, Milhavet O, Casteilla L, Hatzfeld J, Jorgensen C, Charbord P, Lehmann S (2009) Comparative proteomic analysis of human mesenchymal and embryonic stem cells: towards the definition of a mesenchymal stem cell proteomic signature. Proteomics 9(2):223–232. doi: 10.1002/pmic.200800035 PubMedCrossRefGoogle Scholar
  101. 101.
    Sivasubramaniyan K, Lehnen D, Ghazanfari R, Sobiesiak M, Harichandan A, Mortha E, Petkova N, Grimm S, Cerabona F, de Zwart P, Abele H, Aicher WK, Faul C, Kanz L, Buhring HJ (2012) Phenotypic and functional heterogeneity of human bone marrow- and amnion-derived MSC subsets. Ann N Y Acad Sci 1266:94–106. doi: 10.1111/j.1749-6632.2012.06551.x PubMedCrossRefGoogle Scholar
  102. 102.
    Djouad F, Bony C, Haupl T, Uze G, Lahlou N, Louis-Plence P, Apparailly F, Canovas F, Reme T, Sany J, Jorgensen C, Noel D (2005) Transcriptional profiles discriminate bone marrow-derived and synovium-derived mesenchymal stem cells. Arthritis Res Ther 7(6):R1304–R1315. doi: 10.1186/ar1827 PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Phinney DG, Sensebe L (2013) Mesenchymal stromal cells: misconceptions and evolving concepts. Cytotherapy 15(2):140–145. doi: 10.1016/j.jcyt.2012.11.005 PubMedCrossRefGoogle Scholar
  104. 104.
    Deuse T, Stubbendorff M, Tang-Quan K, Phillips N, Kay MA, Eiermann T, Phan TT, Volk HD, Reichenspurner H, Robbins RC, Schrepfer S (2011) Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell Transplant 20(5):655–667. doi: 10.3727/096368910X536473 PubMedCrossRefGoogle Scholar
  105. 105.
    Wegmeyer H, Broske AM, Leddin M, Kuentzer K, Nisslbeck AK, 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 Dev 22(19):2606–2618. doi: 10.1089/scd.2013.0016 PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Noel D, Caton D, Roche S, Bony C, Lehmann S, Casteilla L, Jorgensen C, Cousin B (2008) Cell specific differences between human adipose-derived and mesenchymal-stromal cells despite similar differentiation potentials. Exp Cell Res 314(7):1575–1584. doi: 10.1016/j.yexcr.2007.12.022 PubMedCrossRefGoogle Scholar
  107. 107.
    Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, Taureau C, Cousin B, Abbal M, Laharrague P, Penicaud L, Casteilla L, Blancher A (2005) Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 129(1):118–129. doi: 10.1111/j.1365-2141.2005.05409.x PubMedCrossRefGoogle Scholar
  108. 108.
    Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J (2012) Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev 21(14):2724–2752. doi: 10.1089/scd.2011.0722 PubMedCrossRefGoogle Scholar
  109. 109.
    Gupta MK, Ajay AK (2015) Fat on sale: role of adipose-derived stem cells as anti-fibrosis agent in regenerative medicine. Stem Cell Res Ther 6:233. doi: 10.1186/s13287-015-0246-3 PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Pikula M, Marek-Trzonkowska N, Wardowska A, Renkielska A, Trzonkowski P (2013) Adipose tissue-derived stem cells in clinical applications. Expert Opin Biol Ther 13(10):1357–1370. doi: 10.1517/14712598.2013.823153 PubMedCrossRefGoogle Scholar
  111. 111.
    Lin K, Matsubara Y, Masuda Y, Togashi K, Ohno T, Tamura T, Toyoshima Y, Sugimachi K, Toyoda M, Marc H, Douglas A (2008) Characterization of adipose tissue-derived cells isolated with the Celution system. Cytotherapy 10(4):417–426. doi: 10.1080/14653240801982979 PubMedCrossRefGoogle Scholar
  112. 112.
    Gimble JM, Guilak F, Bunnell BA (2010) Clinical and preclinical translation of cell-based therapies using adipose tissue-derived cells. Stem Cell Res Ther 1(2):19. doi: 10.1186/scrt19 PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Bailey AM, Kapur S, Katz AJ (2010) Characterization of adipose-derived stem cells: an update. Curr Stem Cell Res Ther 5(2):95–102PubMedCrossRefGoogle Scholar
  114. 114.
    Ong WK, Tan CS, Chan KL, Goesantoso GG, Chan XH, Chan E, Yin J, Yeo CR, Khoo CM, So JB, Shabbir A, Toh SA, Han W, Sugii S (2014) Identification of specific cell-surface markers of adipose-derived stem cells from subcutaneous and visceral fat depots. Stem Cell Rep 2(2):171–179. doi: 10.1016/j.stemcr.2014.01.002 CrossRefGoogle Scholar
  115. 115.
    Bony C, Cren M, Domergue S, Toupet K, Jorgensen C, Noel D (2015) Adipose mesenchymal stem cells isolated after manual or water-jet-assisted liposuction display similar properties. Front Immunol 6:655. doi: 10.3389/fimmu.2015.00655 PubMedGoogle Scholar
  116. 116.
    Bochev I, Elmadjian G, Kyurkchiev D, Tzvetanov L, Altankova I, Tivchev P, Kyurkchiev S (2008) Mesenchymal stem cells from human bone marrow or adipose tissue differently modulate mitogen-stimulated B-cell immunoglobulin production in vitro. Cell Biol Int 32(4):384–393. doi: 10.1016/j.cellbi.2007.12.007 PubMedCrossRefGoogle Scholar
  117. 117.
    Ivanova-Todorova E, Bochev I, Mourdjeva M, Dimitrov R, Bukarev D, Kyurkchiev S, Tivchev P, Altunkova I, Kyurkchiev DS (2009) Adipose tissue-derived mesenchymal stem cells are more potent suppressors of dendritic cells differentiation compared to bone marrow-derived mesenchymal stem cells. Immunol Lett 126(1–2):37–42. doi: 10.1016/j.imlet.2009.07.010 PubMedCrossRefGoogle Scholar
  118. 118.
    Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH, Considine RV, March KL (2004) Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 109(10):1292–1298. doi: 10.1161/01.CIR.0000121425.42966.F1 PubMedCrossRefGoogle Scholar
  119. 119.
    Kim WS, Park BS, Kim HK, Park JS, Kim KJ, Choi JS, Chung SJ, Kim DD, Sung JH (2008) Evidence supporting antioxidant action of adipose-derived stem cells: protection of human dermal fibroblasts from oxidative stress. J Dermatol Sci 49(2):133–142. doi: 10.1016/j.jdermsci.2007.08.004 PubMedCrossRefGoogle Scholar
  120. 120.
    Kim WS, Park BS, Sung JH (2009) The wound-healing and antioxidant effects of adipose-derived stem cells. Expert Opin Biol Ther 9(7):879–887. doi: 10.1517/14712590903039684 PubMedCrossRefGoogle Scholar
  121. 121.
    Chang C (2014) Unmet needs in the treatment of autoimmunity: from aspirin to stem cells. Autoimmun Rev 13(4–5):331–346. doi: 10.1016/j.autrev.2014.01.052 PubMedCrossRefGoogle Scholar
  122. 122.
    Nie Y, Lau C, Lie A, Chan G, Mok M (2010) Defective phenotype of mesenchymal stem cells in patients with systemic lupus erythematosus. Lupus 19(7):850–859. doi: 10.1177/0961203309361482 PubMedCrossRefGoogle Scholar
  123. 123.
    Kastrinaki MC, Sidiropoulos P, Roche S, Ringe J, Lehmann S, Kritikos H, Vlahava VM, Delorme B, Eliopoulos GD, Jorgensen C, Charbord P, Haupl T, Boumpas DT, Papadaki HA (2008) Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis. Ann Rheum Dis 67(6):741–749. doi: 10.1136/ard.2007.076174 PubMedCrossRefGoogle Scholar
  124. 124.
    Cipriani P, Di Benedetto P, Ruscitti P, Campese AF, Liakouli V, Carubbi F, Pantano I, Berardicurt O, Screpanti I, Giacomelli R (2014) Impaired endothelium-mesenchymal stem cells cross-talk in systemic sclerosis: a link between vascular and fibrotic features. Arthritis Res Ther 16(5):442. doi: 10.1186/s13075-014-0442-z PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Cipriani P, Marrelli A, Benedetto PD, Liakouli V, Carubbi F, Ruscitti P, Alvaro S, Pantano I, Campese AF, Grazioli P, Screpanti I, Giacomelli R (2013) Scleroderma mesenchymal stem cells display a different phenotype from healthy controls; implications for regenerative medicine. Angiogenesis 16(3):595–607. doi: 10.1007/s10456-013-9338-9 PubMedCrossRefGoogle Scholar
  126. 126.
    Orciani M, Svegliati S, Gorbi S, Spadoni T, Lazzarini R, Regoli F, Di Primio R, Gabrielli A (2013) Alterations of ROS pathways in scleroderma begin at stem cell level. J Biol Regul Homeost Agents 27(1):211–224PubMedGoogle Scholar
  127. 127.
    Bartholomew A, Patil S, Mackay A, Nelson M, Buyaner D, Hardy W, Mosca J, Sturgeon C, Siatskas M, Mahmud N, Ferrer K, Deans R, Moseley A, Hoffman R, Devine SM (2001) Baboon mesenchymal stem cells can be genetically modified to secrete human erythropoietin in vivo. Hum Gene Ther 12(12):1527–1541. doi: 10.1089/10430340152480258 PubMedCrossRefGoogle Scholar
  128. 128.
    Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, Mancardi G, Uccelli A (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106(5):1755–1761. doi: 10.1182/blood-2005-04-1496 PubMedCrossRefGoogle Scholar
  129. 129.
    Augello A, Tasso R, Negrini SM, Cancedda R, Pennesi G (2007) Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum 56(4):1175–1186. doi: 10.1002/art.22511 PubMedCrossRefGoogle Scholar
  130. 130.
    Bouffi C, Bony C, Jorgensen C, Noel D (2011) Skin fibroblasts are potent suppressors of inflammation in experimental arthritis. Ann Rheum Dis 70(9):1671–1676. doi: 10.1136/ard.2010.143297 PubMedCrossRefGoogle Scholar
  131. 131.
    Zhou K, Zhang H, Jin O, Feng X, Yao G, Hou Y, Sun L (2008) Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis in MRL/lpr mice. Cell Mol Immunol 5(6):417–424. doi: 10.1038/cmi.2008.52 PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Ringden O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lonnies H, Marschall HU, Dlugosz A, Szakos A, Hassan Z, Omazic B, Aschan J, Barkholt L, Le Blanc K (2006) Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81(10):1390–1397. doi: 10.1097/ PubMedCrossRefGoogle Scholar
  133. 133.
    Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, Olson SD, Prockop DJ (2006) Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A 103(46):17438–17443. doi: 10.1073/pnas.0608249103 PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Polchert D, Sobinsky J, Douglas G, Kidd M, Moadsiri A, Reina E, Genrich K, Mehrotra S, Setty S, Smith B, Bartholomew A (2008) IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol 38(6):1745–1755. doi: 10.1002/eji.200738129 PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Borchers AT, Leibushor N, Naguwa SM, Cheema GS, Shoenfeld Y, Gershwin ME (2012) Lupus nephritis: a critical review. Autoimmun Rev 12(2):174–194. doi: 10.1016/j.autrev.2012.08.018 PubMedCrossRefGoogle Scholar
  136. 136.
    Cervera R, Doria A, Amoura Z, Khamashta M, Schneider M, Guillemin F, Maurel F, Garofano A, Roset M, Perna A, Murray M, Schmitt C, Boucot I (2014) Patterns of systemic lupus erythematosus expression in Europe. Autoimmun Rev 13(6):621–629. doi: 10.1016/j.autrev.2013.11.007 PubMedCrossRefGoogle Scholar
  137. 137.
    Riboldi P, Gerosa M, Luzzana C, Catelli L (2002) Cardiac involvement in systemic autoimmune diseases. Clin Rev Allergy Immunol 23(3):247–261. doi: 10.1385/CRIAI:23:3:247 PubMedCrossRefGoogle Scholar
  138. 138.
    Sitia S, Atzeni F, Sarzi-Puttini P, Di Bello V, Tomasoni L, Delfino L, Antonini-Canterin F, Di Salvo G, De Gennaro Colonna V, La Carrubba S, Carerj S, Turiel M (2009) Cardiovascular involvement in systemic autoimmune diseases. Autoimmun Rev 8(4):281–286. doi: 10.1016/j.autrev.2008.08.004 PubMedCrossRefGoogle Scholar
  139. 139.
    Wu GC, Liu HR, Leng RX, Li XP, Li XM, Pan HF, Ye DQ (2016) Subclinical atherosclerosis in patients with systemic lupus erythematosus: a systemic review and meta-analysis. Autoimmun Rev 15(1):22–37. doi: 10.1016/j.autrev.2015.10.002 PubMedCrossRefGoogle Scholar
  140. 140.
    Qian J, Wang Y, Huang C, Yang X, Zhao J, Wang Q, Tian Z, Li M, Zeng X (2016) Survival and prognostic factors of systemic lupus erythematosus-associated pulmonary arterial hypertension: a PRISMA-compliant systematic review and meta-analysis. Autoimmun Rev 15(3):250–257. doi: 10.1016/j.autrev.2015.11.012 PubMedCrossRefGoogle Scholar
  141. 141.
    Sarbu N, Alobeidi F, Toledano P, Espinosa G, Giles I, Rahman A, Yousry T, Capurro S, Jager R, Cervera R, Bargallo N (2015) Brain abnormalities in newly diagnosed neuropsychiatric lupus: systematic MRI approach and correlation with clinical and laboratory data in a large multicenter cohort. Autoimmun Rev 14(2):153–159. doi: 10.1016/j.autrev.2014.11.001 PubMedCrossRefGoogle Scholar
  142. 142.
    Roccatello D, Sciascia S, Baldovino S, Rossi D, Alpa M, Naretto C, Di Simone D, Simoncini M, Menegatti E (2015) A 4-year observation in lupus nephritis patients treated with an intensified B-lymphocyte depletion without immunosuppressive maintenance treatment—clinical response compared to literature and immunological re-assessment. Autoimmun Rev 14(12):1123–1130. doi: 10.1016/j.autrev.2015.07.017 PubMedCrossRefGoogle Scholar
  143. 143.
    Jeltsch-David H, Muller S (2014) Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: the MRL-lpr mouse strain as a model. Autoimmun Rev 13(9):963–973. doi: 10.1016/j.autrev.2014.08.015 PubMedCrossRefGoogle Scholar
  144. 144.
    Gatto M, Zen M, Ghirardello A, Bettio S, Bassi N, Iaccarino L, Punzi L, Doria A (2013) Emerging and critical issues in the pathogenesis of lupus. Autoimmun Rev 12(4):523–536. doi: 10.1016/j.autrev.2012.09.003 PubMedCrossRefGoogle Scholar
  145. 145.
    Sawla P, Hossain A, Hahn BH, Singh RP (2012) Regulatory T cells in systemic lupus erythematosus (SLE); role of peptide tolerance. Autoimmun Rev 11(9):611–614. doi: 10.1016/j.autrev.2011.09.008 PubMedCrossRefGoogle Scholar
  146. 146.
    Ruiz-Arruza I, Barbosa C, Ugarte A, Ruiz-Irastorza G (2015) Comparison of high versus low-medium prednisone doses for the treatment of systemic lupus erythematosus patients with high activity at diagnosis. Autoimmun Rev 14(10):875–879. doi: 10.1016/j.autrev.2015.05.011 PubMedCrossRefGoogle Scholar
  147. 147.
    Hannah J, Casian A, D’Cruz D (2016) Tacrolimus use in lupus nephritis: a systematic review and meta-analysis. Autoimmun Rev 15(1):93–101. doi: 10.1016/j.autrev.2015.09.006 PubMedCrossRefGoogle Scholar
  148. 148.
    Frieri M, Stampfl H (2016) Systemic lupus erythematosus and atherosclerosis: review of the literature. Autoimmun Rev 15(1):16–21. doi: 10.1016/j.autrev.2015.08.007 PubMedCrossRefGoogle Scholar
  149. 149.
    Cohen Y, Nagler A (2004) Treatment of refractory autoimmune diseases with ablative immunotherapy. Autoimmun Rev 3(2):21–29. doi: 10.1016/S1568-9972(03)00083-1 PubMedCrossRefGoogle Scholar
  150. 150.
    Sciascia S, Ceberio L, Garcia-Fernandez C, Roccatello D, Karim Y, Cuadrado MJ (2012) Systemic lupus erythematosus and infections: clinical importance of conventional and upcoming biomarkers. Autoimmun Rev 12(2):157–163. doi: 10.1016/j.autrev.2012.03.009 PubMedCrossRefGoogle Scholar
  151. 151.
    Davies RJ, Sangle SR, Jordan NP, Aslam L, Lewis MJ, Wedgwood R, D’Cruz DP (2013) Rituximab in the treatment of resistant lupus nephritis: therapy failure in rapidly progressive crescentic lupus nephritis. Lupus 22(6):574–582. doi: 10.1177/0961203313483376 PubMedCrossRefGoogle Scholar
  152. 152.
    Kamal A, Khamashta M (2014) The efficacy of novel B cell biologics as the future of SLE treatment: a review. Autoimmun Rev 13(11):1094–1101. doi: 10.1016/j.autrev.2014.08.020 PubMedCrossRefGoogle Scholar
  153. 153.
    Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, Sanchez-Guerrero J, Schwarting A, Merrill JT, Chatham WW, Stohl W, Ginzler EM, Hough DR, Zhong ZJ, Freimuth W, van Vollenhoven RF, Group B-S (2011) A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 63(12):3918–3930. doi: 10.1002/art.30613 PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Liao J, Chang C, Wu H, Lu Q (2015) Cell-based therapies for systemic lupus erythematosus. Autoimmun Rev 14(1):43–48. doi: 10.1016/j.autrev.2014.10.001 PubMedCrossRefGoogle Scholar
  155. 155.
    Papadaki HA, Boumpas DT, Gibson FM, Jayne DR, Axford JS, Gordon-Smith EC, Marsh JC, Eliopoulos GD (2001) Increased apoptosis of bone marrow CD34(+) cells and impaired function of bone marrow stromal cells in patients with systemic lupus erythematosus. Br J Haematol 115(1):167–174PubMedCrossRefGoogle Scholar
  156. 156.
    Sun L, Akiyama K, Zhang H, Yamaza T, Hou Y, Zhao S, Xu T, Le A, Shi S (2009) Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells 27(6):1421–1432. doi: 10.1002/stem.68 PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Sun LY, Zhang HY, Feng XB, Hou YY, Lu LW, Fan LM (2007) Abnormality of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Lupus 16(2):121–128PubMedCrossRefGoogle Scholar
  158. 158.
    Tang Y, Ma X, Zhang H, Gu Z, Hou Y, Gilkeson GS, Lu L, Zeng X, Sun L (2012) Gene expression profile reveals abnormalities of multiple signaling pathways in mesenchymal stem cell derived from patients with systemic lupus erythematosus. Clin Dev Immunol 2012:826182. doi: 10.1155/2012/826182 PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Gu Z, Cao X, Jiang J, Li L, Da Z, Liu H, Cheng C (2012) Upregulation of p16INK4A promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients. Cell Signal 24(12):2307–2314. doi: 10.1016/j.cellsig.2012.07.012 PubMedCrossRefGoogle Scholar
  160. 160.
    Gu Z, Tan W, Feng G, Meng Y, Shen B, Liu H, Cheng C (2014) Wnt/beta-catenin signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients through the p53/p21 pathway. Mol Cell Biochem 387(1–2):27–37. doi: 10.1007/s11010-013-1866-5 PubMedCrossRefGoogle Scholar
  161. 161.
    Li X, Liu L, Meng D, Wang D, Zhang J, Shi D, Liu H, Xu H, Lu L, Sun L (2012) Enhanced apoptosis and senescence of bone-marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Stem Cells Dev 21(13):2387–2394. doi: 10.1089/scd.2011.0447 PubMedCrossRefGoogle Scholar
  162. 162.
    Gu F, Molano I, Ruiz P, Sun L, Gilkeson GS (2012) Differential effect of allogeneic versus syngeneic mesenchymal stem cell transplantation in MRL/lpr and (NZB/NZW)F1 mice. Clin Immunol 145(2):142–152. doi: 10.1016/j.clim.2012.08.012 PubMedCrossRefGoogle Scholar
  163. 163.
    Collins E, Gu F, Qi M, Molano I, Ruiz P, Sun L, Gilkeson GS (2014) Differential efficacy of human mesenchymal stem cells based on source of origin. J Immunol 193(9):4381–4390. doi: 10.4049/jimmunol.1401636 PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Ma X, Che N, Gu Z, Huang J, Wang D, Liang J, Hou Y, Gilkeson G, Lu L, Sun L (2013) Allogenic mesenchymal stem cell transplantation ameliorates nephritis in lupus mice via inhibition of B-cell activation. Cell Transplant 22(12):2279–2290. doi: 10.3727/096368912X658692 PubMedCrossRefGoogle Scholar
  165. 165.
    Youd M, Blickarz C, Woodworth L, Touzjian T, Edling A, Tedstone J, Ruzek M, Tubo R, Kaplan J, Lodie T (2010) Allogeneic mesenchymal stem cells do not protect NZBxNZW F1 mice from developing lupus disease. Clin Exp Immunol 161(1):176–186. doi: 10.1111/j.1365-2249.2010.04158.x PubMedPubMedCentralGoogle Scholar
  166. 166.
    Schena F, Gambini C, Gregorio A, Mosconi M, Reverberi D, Gattorno M, Casazza S, Uccelli A, Moretta L, Martini A, Traggiai E (2010) Interferon-gamma-dependent inhibition of B cell activation by bone marrow-derived mesenchymal stem cells in a murine model of systemic lupus erythematosus. Arthritis Rheum 62(9):2776–2786. doi: 10.1002/art.27560 PubMedCrossRefGoogle Scholar
  167. 167.
    Park MJ, Kwok SK, Lee SH, Kim EK, Park SH, Cho ML (2015) Adipose tissue-derived mesenchymal stem cells induce expansion of interleukin-10-producing regulatory B cells and ameliorate autoimmunity in a murine model of systemic lupus erythematosus. Cell Transplant 24(11):2367–2377. doi: 10.3727/096368914X685645 PubMedCrossRefGoogle Scholar
  168. 168.
    Choi EW, Shin IS, Song JW, Yun TW, Yang J, Choi KS, Seong JK (2015) Transplantation of adipose tissue-derived mesenchymal stem cells prevents the development of lupus dermatitis. Stem Cells Dev 24(17):2041–2051. doi: 10.1089/scd.2015.0021 PubMedCrossRefGoogle Scholar
  169. 169.
    Choi EW, Lee HW, Shin S, Park JH, Yun TW, Youn HY, Kim SJ (2015) Comparative efficacies of long-term serial transplantation of syngeneic, allogeneic, xenogeneic, or CTLA4Ig overproducing xenogeneic adipose tissue-derived mesenchymal stem cells on murine systemic lupus erythematosus. Cell Transplant. doi: 10.3727/096368915X689442 PubMedCentralGoogle Scholar
  170. 170.
    Choi EW, Shin IS, Park SY, Park JH, Kim JS, Yoon EJ, Kang SK, Ra JC, Hong SH (2012) Reversal of serologic, immunologic, and histologic dysfunction in mice with systemic lupus erythematosus by long-term serial adipose tissue-derived mesenchymal stem cell transplantation. Arthritis Rheum 64(1):243–253. doi: 10.1002/art.33313 PubMedCrossRefGoogle Scholar
  171. 171.
    Gu Z, Akiyama K, Ma X, Zhang H, Feng X, Yao G, Hou Y, Lu L, Gilkeson GS, Silver RM, Zeng X, Shi S, Sun L (2010) Transplantation of umbilical cord mesenchymal stem cells alleviates lupus nephritis in MRL/lpr mice. Lupus 19(13):1502–1514. doi: 10.1177/0961203310373782 PubMedCrossRefGoogle Scholar
  172. 172.
    Chang JW, Hung SP, Wu HH, Wu WM, Yang AH, Tsai HL, Yang LY, Lee OK (2011) Therapeutic effects of umbilical cord blood-derived mesenchymal stem cell transplantation in experimental lupus nephritis. Cell Transplant 20(2):245–257. doi: 10.3727/096368910X520056 PubMedCrossRefGoogle Scholar
  173. 173.
    Carrion F, Nova E, Ruiz C, Diaz F, Inostroza C, Rojo D, Monckeberg G, Figueroa FE (2010) Autologous mesenchymal stem cell treatment increased T regulatory cells with no effect on disease activity in two systemic lupus erythematosus patients. Lupus 19(3):317–322. doi: 10.1177/0961203309348983 PubMedCrossRefGoogle Scholar
  174. 174.
    Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, Hou Y, Zeng X, Gilkeson GS, Sun L (2010) Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis 69(8):1423–1429. doi: 10.1136/ard.2009.123463 PubMedCrossRefGoogle Scholar
  175. 175.
    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 (2010) Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum 62(8):2467–2475. doi: 10.1002/art.27548 PubMedCrossRefGoogle Scholar
  176. 176.
    Li X, Wang D, Liang J, Zhang H, Sun L (2013) Mesenchymal SCT ameliorates refractory cytopenia in patients with systemic lupus erythematosus. Bone Marrow Transplant 48(4):544–550. doi: 10.1038/bmt.2012.184 PubMedCrossRefGoogle Scholar
  177. 177.
    Liang J, Gu F, Wang H, Hua B, Hou Y, Shi S, Lu L, Sun L (2010) Mesenchymal stem cell transplantation for diffuse alveolar hemorrhage in SLE. Nat Rev Rheumatol 6(8):486–489. doi: 10.1038/nrrheum.2010.80 PubMedCrossRefGoogle Scholar
  178. 178.
    Shi D, Wang D, Li X, Zhang H, Che N, Lu Z, Sun L (2012) Allogeneic transplantation of umbilical cord-derived mesenchymal stem cells for diffuse alveolar hemorrhage in systemic lupus erythematosus. Clin Rheumatol 31(5):841–846. doi: 10.1007/s10067-012-1943-2 PubMedCrossRefGoogle Scholar
  179. 179.
    Wang D, Zhang H, Liang J, Li X, Feng X, Wang H, Hua B, Liu B, Lu L, Gilkeson GS, Silver RM, Chen W, Shi S, Sun L (2013) Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience. Cell Transplant 22(12):2267–2277. doi: 10.3727/096368911X582769 PubMedCrossRefGoogle Scholar
  180. 180.
    Gu F, Wang D, Zhang H, Feng X, Gilkeson GS, Shi S, Sun L (2014) Allogeneic mesenchymal stem cell transplantation for lupus nephritis patients refractory to conventional therapy. Clin Rheumatol 33(11):1611–1619. doi: 10.1007/s10067-014-2754-4 PubMedCrossRefGoogle Scholar
  181. 181.
    Wang D, Li J, Zhang Y, Zhang M, Chen J, Li X, Hu X, Jiang S, Shi S, Sun L (2014) Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study. Arthritis Res Ther 16(2):R79. doi: 10.1186/ar4520 PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Modena V, Bianchi G, Roccatello D (2013) Cost-effectiveness of biologic treatment for rheumatoid arthritis in clinical practice: an achievable target? Autoimmun Rev 12(8):835–838. doi: 10.1016/j.autrev.2012.11.009 PubMedCrossRefGoogle Scholar
  183. 183.
    Epis OM, Giacomelli L, Deidda S, Bruschi E (2013) Tight control applied to the biological therapy of rheumatoid arthritis. Autoimmun Rev 12(8):839–841. doi: 10.1016/j.autrev.2012.11.010 PubMedCrossRefGoogle Scholar
  184. 184.
    Dimitroulas T, Nikas SN, Trontzas P, Kitas GD (2013) Biologic therapies and systemic bone loss in rheumatoid arthritis. Autoimmun Rev 12(10):958–966. doi: 10.1016/j.autrev.2013.03.015 PubMedCrossRefGoogle Scholar
  185. 185.
    Cutolo M, Nadler SG (2013) Advances in CTLA-4-Ig-mediated modulation of inflammatory cell and immune response activation in rheumatoid arthritis. Autoimmun Rev 12(7):758–767. doi: 10.1016/j.autrev.2013.01.001 PubMedCrossRefGoogle Scholar
  186. 186.
    Chen B, Hu J, Liao L, Sun Z, Han Q, Song Z, Zhao RC (2010) Flk-1+ mesenchymal stem cells aggravate collagen-induced arthritis by up-regulating interleukin-6. Clin Exp Immunol 159(3):292–302. doi: 10.1111/j.1365-2249.2009.04069.x PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Djouad F, Fritz V, Apparailly F, Louis-Plence P, Bony C, Sany J, Jorgensen C, Noel D (2005) Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis. Arthritis Rheum 52(5):1595–1603. doi: 10.1002/art.21012 PubMedCrossRefGoogle Scholar
  188. 188.
    Liu Y, Mu R, Wang S, Long L, Liu X, Li R, Sun J, Guo J, Zhang X, Guo J, Yu P, Li C, Liu X, Huang Z, Wang D, Li H, Gu Z, Liu B, Li Z (2010) Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis. Arthritis Res Ther 12(6):R210. doi: 10.1186/ar3187 PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Gonzalez MA, Gonzalez-Rey E, Rico L, Buscher D, Delgado M (2009) Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis Rheum 60(4):1006–1019. doi: 10.1002/art.24405 PubMedCrossRefGoogle Scholar
  190. 190.
    Wang L, Wang L, Cong X, Liu G, Zhou J, Bai B, Li Y, Bai W, Li M, Ji H, Zhu D, Wu M, Liu Y (2013) Human umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis: safety and efficacy. Stem Cells Dev 22(24):3192–3202. doi: 10.1089/scd.2013.0023 PubMedCrossRefGoogle Scholar
  191. 191.
    Wang L, Zhang Y, Li H, Hong J, Chen X, Li M, Bai W, Wang J, Liu Y, Wu M (2016) Clinical observation of employment of umbilical cord derived mesenchymal stem cell for juvenile idiopathic arthritis therapy. Stem Cells Int 2016:9165267. doi: 10.1155/2016/9165267 PubMedGoogle Scholar
  192. 192.
    Khalili S, Faustman DL, Liu Y, Sumita Y, Blank D, Peterson A, Kodama S, Tran SD (2014) Treatment for salivary gland hypofunction at both initial and advanced stages of Sjogren-like disease: a comparative study of bone marrow therapy versus spleen cell therapy with a 1-year monitoring period. Cytotherapy 16(3):412–423. doi: 10.1016/j.jcyt.2013.10.006 PubMedCrossRefGoogle Scholar
  193. 193.
    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 (2012) Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjogren syndrome. Blood 120(15):3142–3151. doi: 10.1182/blood-2011-11-391144 PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Voswinkel J, Francois S, Simon JM, Benderitter M, Gorin NC, Mohty M, Fouillard L, Chapel A (2013) Use of mesenchymal stem cells (MSC) in chronic inflammatory fistulizing and fibrotic diseases: a comprehensive review. Clin Rev Allergy Immunol 45(2):180–192. doi: 10.1007/s12016-012-8347-6 PubMedCrossRefGoogle Scholar
  195. 195.
    Cho YB, Lee WY, Park KJ, Kim M, Yoo HW, Yu CS (2013) Autologous adipose tissue-derived stem cells for the treatment of Crohn’s fistula: a phase I clinical study. Cell Transplant 22(2):279–285. doi: 10.3727/096368912X656045 PubMedCrossRefGoogle Scholar
  196. 196.
    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 (2010) Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut 59(12):1662–1669. doi: 10.1136/gut.2010.215152 PubMedCrossRefGoogle Scholar
  197. 197.
    de la Portilla F, Alba F, Garcia-Olmo D, Herrerias JM, Gonzalez FX, Galindo A (2013) 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 Color Dis 28(3):313–323. doi: 10.1007/s00384-012-1581-9 CrossRefGoogle Scholar
  198. 198.
    Gregorini M, Maccario R, Avanzini MA, Corradetti V, Moretta A, Libetta C, Esposito P, Bosio F, Dal Canton A, Rampino T (2013) Antineutrophil cytoplasmic antibody-associated renal vasculitis treated with autologous mesenchymal stromal cells: evaluation of the contribution of immune-mediated mechanisms. Mayo Clin Proc 88(10):1174–1179. doi: 10.1016/j.mayocp.2013.06.021 PubMedCrossRefGoogle Scholar
  199. 199.
    Davatchi F, Nikbin B, Shams H, Sadeghi Abdollahi B, Mohyeddin M, Shahram F (2013) Mesenchymal stem cell therapy unable to rescue the vision from advanced Behcet’s disease retinal vasculitis: report of three patients. Int J Rheum Dis 16(2):139–147. doi: 10.1111/1756-185X.12068 PubMedCrossRefGoogle Scholar
  200. 200.
    Lablanche S, Borot S, Wojtusciszyn A, Bayle F, Tetaz R, Badet L, Thivolet C, Morelon E, Frimat L, Penfornis A, Kessler L, Brault C, Colin C, Tauveron I, Bosco D, Berney T, Benhamou PY, Network G (2015) Five-year metabolic, functional, and safety results of patients with type 1 diabetes transplanted with allogenic islets within the Swiss-French GRAGIL network. Diabetes Care 38(9):1714–1722. doi: 10.2337/dc15-0094 PubMedCrossRefGoogle Scholar
  201. 201.
    Boumaza I, Srinivasan S, Witt WT, Feghali-Bostwick C, Dai Y, Garcia-Ocana A, Feili-Hariri M (2009) Autologous bone marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia. J Autoimmun 32(1):33–42. doi: 10.1016/j.jaut.2008.10.004 PubMedCrossRefGoogle Scholar
  202. 202.
    Xin Y, Jiang X, Wang Y, Su X, Sun M, Zhang L, Tan Y, Wintergerst KA, Li Y, Li Y (2016) Insulin-producing cells differentiated from human bone marrow mesenchymal stem cells in vitro ameliorate streptozotocin-induced diabetic hyperglycemia. PLoS One 11(1):e0145838. doi: 10.1371/journal.pone.0145838 PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Gerdoni E, Gallo B, Casazza S, Musio S, Bonanni I, Pedemonte E, Mantegazza R, Frassoni F, Mancardi G, Pedotti R, Uccelli A (2007) Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 61(3):219–227. doi: 10.1002/ana.21076 PubMedCrossRefGoogle Scholar
  204. 204.
    Kassis I, Grigoriadis N, Gowda-Kurkalli B, Mizrachi-Kol R, Ben-Hur T, Slavin S, Abramsky O, Karussis D (2008) Neuroprotection and immunomodulation with mesenchymal stem cells in chronic experimental autoimmune encephalomyelitis. Arch Neurol 65(6):753–761. doi: 10.1001/archneur.65.6.753 PubMedCrossRefGoogle Scholar
  205. 205.
    Wang D, Li SP, Fu JS, Bai L, Guo L (2016) Resveratrol augments therapeutic efficiency of mouse bone marrow mesenchymal stem cell-based therapy in experimental autoimmune encephalomyelitis. Int J Dev Neurosci 49:60–66. doi: 10.1016/j.ijdevneu.2016.01.005 PubMedCrossRefGoogle Scholar
  206. 206.
    Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, Du MQ, Luan SL, Altmann DR, Thompson AJ, Compston A, Scott MA, Miller DH, Chandran S (2012) Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol 11(2):150–156. doi: 10.1016/S1474-4422(11)70305-2 PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Lublin FD, Bowen JD, Huddlestone J, Kremenchutzky M, Carpenter A, Corboy JR, Freedman MS, Krupp L, Paulo C, Hariri RJ, Fischkoff SA (2014) Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study. Mult Scler Relat Disord 3(6):696–704. doi: 10.1016/j.msard.2014.08.002 PubMedCrossRefGoogle Scholar
  208. 208.
    Llufriu S, Sepulveda M, Blanco Y, Marin P, Moreno B, Berenguer J, Gabilondo I, Martinez-Heras E, Sola-Valls N, Arnaiz JA, Andreu EJ, Fernandez B, Bullich S, Sanchez-Dalmau B, Graus F, Villoslada P, Saiz A (2014) Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS One 9(12):e113936. doi: 10.1371/journal.pone.0113936 PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Li JF, Zhang DJ, Geng T, Chen L, Huang H, Yin HL, Zhang YZ, Lou JY, Cao B, Wang YL (2014) The potential of human umbilical cord-derived mesenchymal stem cells as a novel cellular therapy for multiple sclerosis. Cell Transplant 23(Suppl 1):S113–S122. doi: 10.3727/096368914X685005 PubMedCrossRefGoogle Scholar
  210. 210.
    Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O, Developmental Committee of the European Group for B, Marrow T (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371(9624):1579–1586. doi: 10.1016/S0140-6736(08)60690-X PubMedCrossRefGoogle Scholar
  211. 211.
    Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez M, Bueren JA (2006) Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells 24(11):2582–2591. doi: 10.1634/stemcells.2006-0228 PubMedCrossRefGoogle Scholar
  212. 212.
    Fang B, Song Y, Liao L, Zhang Y, Zhao RC (2007) Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc 39(10):3358–3362. doi: 10.1016/j.transproceed.2007.08.103 PubMedCrossRefGoogle Scholar
  213. 213.
    Kong QF, Sun B, Wang GY, Zhai DX, Mu LL, Wang DD, Wang JH, Li R, Li HL (2009) BM stromal cells ameliorate experimental autoimmune myasthenia gravis by altering the balance of Th cells through the secretion of IDO. Eur J Immunol 39(3):800–809. doi: 10.1002/eji.200838729 PubMedCrossRefGoogle Scholar
  214. 214.
    Kong QF, Sun B, Bai SS, Zhai DX, Wang GY, Liu YM, Zhang SJ, Li R, Zhao W, Sun YY, Li N, Wang Q, Peng HS, Jin LH, Li HL (2009) Administration of bone marrow stromal cells ameliorates experimental autoimmune myasthenia gravis by altering the balance of Th1/Th2/Th17/Treg cell subsets through the secretion of TGF-beta. J Neuroimmunol 207(1–2):83–91. doi: 10.1016/j.jneuroim.2008.12.005 PubMedCrossRefGoogle Scholar
  215. 215.
    Yu J, Zheng C, Ren X, Li J, Liu M, Zhang L, Liang L, Du W, Han ZC (2010) Intravenous administration of bone marrow mesenchymal stem cells benefits experimental autoimmune myasthenia gravis mice through an immunomodulatory action. Scand J Immunol 72(3):242–249. doi: 10.1111/j.1365-3083.2010.02445.x PubMedCrossRefGoogle Scholar
  216. 216.
    Tiev KP, Cabane J (2011) Digestive tract involvement in systemic sclerosis. Autoimmun Rev 11(1):68–73. doi: 10.1016/j.autrev.2010.06.002 PubMedCrossRefGoogle Scholar
  217. 217.
    Chizzolini C, Brembilla NC, Montanari E, Truchetet ME (2011) Fibrosis and immune dysregulation in systemic sclerosis. Autoimmun Rev 10(5):276–281. doi: 10.1016/j.autrev.2010.09.016 PubMedCrossRefGoogle Scholar
  218. 218.
    Almeida I, Faria R, Vita P, Vasconcelos C (2011) Systemic sclerosis refractory disease: from the skin to the heart. Autoimmun Rev 10(11):693–701. doi: 10.1016/j.autrev.2011.04.025 PubMedCrossRefGoogle Scholar
  219. 219.
    Galluccio F, Matucci-Cerinic M (2011) Two faces of the same coin: Raynaud phenomenon and digital ulcers in systemic sclerosis. Autoimmun Rev 10(5):241–243. doi: 10.1016/j.autrev.2010.09.008 PubMedCrossRefGoogle Scholar
  220. 220.
    Guiducci S, Giacomelli R, Cerinic MM (2007) Vascular complications of scleroderma. Autoimmun Rev 6(8):520–523. doi: 10.1016/j.autrev.2006.12.006 PubMedCrossRefGoogle Scholar
  221. 221.
    Lambova S, Muller-Ladner U (2010) Pulmonary arterial hypertension in systemic sclerosis. Autoimmun Rev 9(11):761–770. doi: 10.1016/j.autrev.2010.06.006 PubMedCrossRefGoogle Scholar
  222. 222.
    Chora I, Guiducci S, Manetti M, Romano E, Mazzotta C, Bellando-Randone S, Ibba-Manneschi L, Matucci-Cerinic M, Soares R (2015) Vascular biomarkers and correlation with peripheral vasculopathy in systemic sclerosis. Autoimmun Rev 14(4):314–322. doi: 10.1016/j.autrev.2014.12.001 PubMedCrossRefGoogle Scholar
  223. 223.
    Nussinovitch U, Shoenfeld Y (2011) Atherosclerosis and macrovascular involvement in systemic sclerosis: myth or reality. Autoimmun Rev 10(5):259–266. doi: 10.1016/j.autrev.2010.09.014 PubMedCrossRefGoogle Scholar
  224. 224.
    Baraut J, Michel L, Verrecchia F, Farge D (2010) Relationship between cytokine profiles and clinical outcomes in patients with systemic sclerosis. Autoimmun Rev 10(2):65–73. doi: 10.1016/j.autrev.2010.08.003 PubMedCrossRefGoogle Scholar
  225. 225.
    Bosello S, De Luca G, Tolusso B, Lama G, Angelucci C, Sica G, Ferraccioli G (2011) B cells in systemic sclerosis: a possible target for therapy. Autoimmun Rev 10(10):624–630. doi: 10.1016/j.autrev.2011.04.013 PubMedCrossRefGoogle Scholar
  226. 226.
    Mehra S, Walker J, Patterson K, Fritzler MJ (2013) Autoantibodies in systemic sclerosis. Autoimmun Rev 12(3):340–354. doi: 10.1016/j.autrev.2012.05.011 PubMedCrossRefGoogle Scholar
  227. 227.
    Czompoly T, Simon D, Czirjak L, Nemeth P (2009) Anti-topoisomerase I autoantibodies in systemic sclerosis. Autoimmun Rev 8(8):692–696. doi: 10.1016/j.autrev.2009.02.018 PubMedCrossRefGoogle Scholar
  228. 228.
    Perosa F, Prete M, Di Lernia G, Ostuni C, Favoino E, Valentini G (2016) Anti-centromere protein A antibodies in systemic sclerosis: significance and origin. Autoimmun Rev 15(1):102–109. doi: 10.1016/j.autrev.2015.10.001 PubMedCrossRefGoogle Scholar
  229. 229.
    Cavazzana I, Ceribelli A, Airo P, Zingarelli S, Tincani A, Franceschini F (2009) Anti-RNA polymerase III antibodies: a marker of systemic sclerosis with rapid onset and skin thickening progression. Autoimmun Rev 8(7):580–584. doi: 10.1016/j.autrev.2009.02.002 PubMedCrossRefGoogle Scholar
  230. 230.
    Hachulla E, Launay D (2011) Diagnosis and classification of systemic sclerosis. Clin Rev Allergy Immunol 40(2):78–83. doi: 10.1007/s12016-010-8198-y PubMedCrossRefGoogle Scholar
  231. 231.
    Almeida C, Almeida I, Vasconcelos C (2015) Quality of life in systemic sclerosis. Autoimmun Rev 14(12):1087–1096. doi: 10.1016/j.autrev.2015.07.012 PubMedCrossRefGoogle Scholar
  232. 232.
    Bruni C, Raja J, Denton CP, Matucci-Cerinic M (2015) The clinical relevance of sexual dysfunction in systemic sclerosis. Autoimmun Rev 14(12):1111–1115. doi: 10.1016/j.autrev.2015.07.016 PubMedCrossRefGoogle Scholar
  233. 233.
    Wells AU, Steen V, Valentini G (2009) Pulmonary complications: one of the most challenging complications of systemic sclerosis. Rheumatology (Oxford) 48(Suppl 3):iii40–iii44. doi: 10.1093/rheumatology/kep109 Google Scholar
  234. 234.
    Bussone G, Mouthon L (2011) Interstitial lung disease in systemic sclerosis. Autoimmun Rev 10(5):248–255. doi: 10.1016/j.autrev.2010.09.012 PubMedCrossRefGoogle Scholar
  235. 235.
    Mouthon L, Berezne A, Bussone G, Noel LH, Villiger PM, Guillevin L (2011) Scleroderma renal crisis: a rare but severe complication of systemic sclerosis. Clin Rev Allergy Immunol 40(2):84–91. doi: 10.1007/s12016-009-8191-5 PubMedCrossRefGoogle Scholar
  236. 236.
    Carreira PE (2004) Pulmonary hypertension in autoimmune rheumatic diseases. Autoimmun Rev 3(4):313–320. doi: 10.1016/j.autrev.2003.11.004 PubMedCrossRefGoogle Scholar
  237. 237.
    Murdaca G, Contatore M, Gulli R, Mandich P, Puppo F (2016) Genetic factors and systemic sclerosis. Autoimmun Rev. doi: 10.1016/j.autrev.2016.01.016 PubMedGoogle Scholar
  238. 238.
    Dieude P, Boileau C, Allanore Y (2011) Immunogenetics of systemic sclerosis. Autoimmun Rev 10(5):282–290. doi: 10.1016/j.autrev.2010.09.017 PubMedCrossRefGoogle Scholar
  239. 239.
    Marie I, Gehanno JF, Bubenheim M, Duval-Modeste AB, Joly P, Dominique S, Bravard P, Noel D, Cailleux AF, Weber J, Lagoutte P, Benichou J, Levesque H (2014) Prospective study to evaluate the association between systemic sclerosis and occupational exposure and review of the literature. Autoimmun Rev 13(2):151–156. doi: 10.1016/j.autrev.2013.10.002 PubMedCrossRefGoogle Scholar
  240. 240.
    Bossini-Castillo L, Lopez-Isac E, Martin J (2015) Immunogenetics of systemic sclerosis: Defining heritability, functional variants and shared-autoimmunity pathways. J Autoimmun 64:53–65. doi: 10.1016/j.jaut.2015.07.005 PubMedCrossRefGoogle Scholar
  241. 241.
    Wei J, Bhattacharyya S, Tourtellotte WG, Varga J (2011) Fibrosis in systemic sclerosis: emerging concepts and implications for targeted therapy. Autoimmun Rev 10(5):267–275. doi: 10.1016/j.autrev.2010.09.015 PubMedCrossRefGoogle Scholar
  242. 242.
    Cipriani P, Marrelli A, Liakouli V, Di Benedetto P, Giacomelli R (2011) Cellular players in angiogenesis during the course of systemic sclerosis. Autoimmun Rev 10(10):641–646. doi: 10.1016/j.autrev.2011.04.016 PubMedCrossRefGoogle Scholar
  243. 243.
    Liakouli V, Cipriani P, Marrelli A, Alvaro S, Ruscitti P, Giacomelli R (2011) Angiogenic cytokines and growth factors in systemic sclerosis. Autoimmun Rev 10(10):590–594. doi: 10.1016/j.autrev.2011.04.019 PubMedCrossRefGoogle Scholar
  244. 244.
    Servettaz A, Guilpain P, Goulvestre C, Chereau C, Hercend C, Nicco C, Guillevin L, Weill B, Mouthon L, Batteux F (2007) Radical oxygen species production induced by advanced oxidation protein products predicts clinical evolution and response to treatment in systemic sclerosis. Ann Rheum Dis 66(9):1202–1209. doi: 10.1136/ard.2006.067504 PubMedPubMedCentralCrossRefGoogle Scholar
  245. 245.
    Launay D, Savale L, Berezne A, Le Pavec J, Hachulla E, Mouthon L, Sitbon O, Lambert B, Gaudric M, Jais X, Stephan F, Hatron PY, Lamblin N, Vignaux O, Cottin V, Farge D, Wallaert B, Guillevin L, Simonneau G, Mercier O, Fadel E, Dartevelle P, Humbert M, Mussot S, Working Group on Heart/Lung transplantation in systemic sclerosis of the French Network on Pulmonary H (2014) Lung and heart-lung transplantation for systemic sclerosis patients. A monocentric experience of 13 patients, review of the literature and position paper of a multidisciplinary Working Group. Presse Med 43(10 Pt 2):e345–e363. doi: 10.1016/j.lpm.2014.01.020 PubMedCrossRefGoogle Scholar
  246. 246.
    Sobanski V, Launay D, Hachulla E, Humbert M (2016) Current approaches to the treatment of systemic-sclerosis-associated pulmonary arterial hypertension (SSc-PAH). Curr Rheumatol Rep 18(2):10. doi: 10.1007/s11926-015-0560-x PubMedCrossRefGoogle Scholar
  247. 247.
    Elhai M, Meune C, Avouac J, Kahan A, Allanore Y (2012) Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford) 51(6):1017–1026. doi: 10.1093/rheumatology/ker269 CrossRefGoogle Scholar
  248. 248.
    Vonk MC, Marjanovic Z, van den Hoogen FH, Zohar S, Schattenberg AV, Fibbe WE, Larghero J, Gluckman E, Preijers FW, van Dijk AP, Bax JJ, Roblot P, van Riel PL, van Laar JM, Farge D (2008) Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis 67(1):98–104. doi: 10.1136/ard.2007.071464 PubMedCrossRefGoogle Scholar
  249. 249.
    Binks M, Passweg JR, Furst D, McSweeney P, Sullivan K, Besenthal C, Finke J, Peter HH, van Laar J, Breedveld FC, Fibbe WE, Farge D, Gluckman E, Locatelli F, Martini A, van den Hoogen F, van de Putte L, Schattenberg AV, Arnold R, Bacon PA, Emery P, Espigado I, Hertenstein B, Hiepe F, Kashyap A, Kotter I, Marmont A, Martinez A, Pascual MJ, Gratwohl A, Prentice HG, Black C, Tyndall A (2001) Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis 60(6):577–584PubMedPubMedCentralCrossRefGoogle Scholar
  250. 250.
    van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, Schuerwegh AJ, Marijt EW, Vonk MC, Schattenberg AV, Matucci-Cerinic M, Voskuyl AE, van de Loosdrecht AA, Daikeler T, Kotter I, Schmalzing M, Martin T, Lioure B, Weiner SM, Kreuter A, Deligny C, Durand JM, Emery P, Machold KP, Sarrot-Reynauld F, Warnatz K, Adoue DF, Constans J, Tony HP, Del Papa N, Fassas A, Himsel A, Launay D, Lo Monaco A, Philippe P, Quere I, Rich E, Westhovens R, Griffiths B, Saccardi R, van den Hoogen FH, Fibbe WE, Socie G, Gratwohl A, Tyndall A, Group EESS (2014) Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 311(24):2490–2498. doi: 10.1001/jama.2014.6368 PubMedCrossRefGoogle Scholar
  251. 251.
    Farge D, Marolleau JP, Zohar S, Marjanovic Z, Cabane J, Mounier N, Hachulla E, Philippe P, Sibilia J, Rabian C, Chevret S, Gluckman E, Intensification et Autogreffe dans les Maladies Auto Immunes Resistantes Study G (2002) Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: early results from a French multicentre phase I-II study. Br J Haematol 119(3):726–739PubMedCrossRefGoogle Scholar
  252. 252.
    Farge D, Passweg J, van Laar JM, Marjanovic Z, Besenthal C, Finke J, Peter HH, Breedveld FC, Fibbe WE, Black C, Denton C, Koetter I, Locatelli F, Martini A, Schattenberg AV, van den Hoogen F, van de Putte L, Lanza F, Arnold R, Bacon PA, Bingham S, Ciceri F, Didier B, Diez-Martin JL, Emery P, Feremans W, Hertenstein B, Hiepe F, Luosujarvi R, Leon Lara A, Marmont A, Martinez AM, Pascual Cascon H, Bocelli-Tyndall C, Gluckman E, Gratwohl A, Tyndall A, EE Registry (2004) Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry. Ann Rheum Dis 63(8):974–981. doi: 10.1136/ard.2003.011205 PubMedPubMedCentralCrossRefGoogle Scholar
  253. 253.
    van Laar JM, Naraghi K, Tyndall A (2015) Haematopoietic stem cell transplantation for poor-prognosis systemic sclerosis. Rheumatology 54(12):2126–2133. doi: 10.1093/rheumatology/kev117 PubMedCrossRefGoogle Scholar
  254. 254.
    Tyndall A (2011) Successes and failures of stem cell transplantation in autoimmune diseases. Hematology / Educ Program Am Soc Hematol Am Soc Hemat Educ Program 2011:280–284. doi: 10.1182/asheducation-2011.1.280 Google Scholar
  255. 255.
    Tyndall A (2014) Mesenchymal stem cell treatments in rheumatology: a glass half full? Nat Rev Rheumatol 10(2):117–124. doi: 10.1038/nrrheum.2013.166 PubMedCrossRefGoogle Scholar
  256. 256.
    Larghero J, Farge D, Braccini A, Lecourt S, Scherberich A, Fois E, Verrecchia F, Daikeler T, Gluckman E, Tyndall A, Bocelli-Tyndall C (2008) Phenotypical and functional characteristics of in vitro expanded bone marrow mesenchymal stem cells from patients with systemic sclerosis. Ann Rheum Dis 67(4):443–449. doi: 10.1136/ard.2007.071233 PubMedCrossRefGoogle Scholar
  257. 257.
    Bocelli-Tyndall C, Bracci L, Spagnoli G, Braccini A, Bouchenaki M, Ceredig R, Pistoia V, Martin I, Tyndall A (2007) Bone marrow mesenchymal stromal cells (BM-MSCs) from healthy donors and auto-immune disease patients reduce the proliferation of autologous- and allogeneic-stimulated lymphocytes in vitro. Rheumatology (Oxford) 46(3):403–408. doi: 10.1093/rheumatology/kel267 CrossRefGoogle Scholar
  258. 258.
    Del Papa N, Quirici N, Soligo D, Scavullo C, Cortiana M, Borsotti C, Maglione W, Comina DP, Vitali C, Fraticelli P, Gabrielli A, Cortelezzi A, Lambertenghi-Deliliers G (2006) Bone marrow endothelial progenitors are defective in systemic sclerosis. Arthritis Rheum 54(8):2605–2615. doi: 10.1002/art.22035 PubMedCrossRefGoogle Scholar
  259. 259.
    Cipriani P, Guiducci S, Miniati I, Cinelli M, Urbani S, Marrelli A, Dolo V, Pavan A, Saccardi R, Tyndall A, Giacomelli R, Cerinic MM (2007) Impairment of endothelial cell differentiation from bone marrow-derived mesenchymal stem cells: new insight into the pathogenesis of systemic sclerosis. Arthritis Rheum 56(6):1994–2004. doi: 10.1002/art.22698 PubMedCrossRefGoogle Scholar
  260. 260.
    Cipriani P, Di Benedetto P, Liakouli V, Del Papa B, Di Padova M, Di Ianni M, Marrelli A, Alesse E, Giacomelli R (2013) Mesenchymal stem cells (MSCs) from scleroderma patients (SSc) preserve their immunomodulatory properties although senescent and normally induce T regulatory cells (Tregs) with a functional phenotype: implications for cellular-based therapy. Clin Exp Immunol 173(2):195–206. doi: 10.1111/cei.12111 PubMedPubMedCentralCrossRefGoogle Scholar
  261. 261.
    Guiducci S, Manetti M, Romano E, Mazzanti B, Ceccarelli C, Dal Pozzo S, Milia AF, Bellando-Randone S, Fiori G, Conforti ML, Saccardi R, Ibba-Manneschi L, Matucci-Cerinic M (2011) Bone marrow-derived mesenchymal stem cells from early diffuse systemic sclerosis exhibit a paracrine machinery and stimulate angiogenesis in vitro. Ann Rheum Dis 70(11):2011–2021. doi: 10.1136/ard.2011.150607 PubMedCrossRefGoogle Scholar
  262. 262.
    Vanneaux V, Farge-Bancel D, Lecourt S, Baraut J, Cras A, Jean-Louis F, Brun C, Verrecchia F, Larghero J, Michel L (2013) Expression of transforming growth factor beta receptor II in mesenchymal stem cells from systemic sclerosis patients. BMJ Open 3(1):e001890. doi: 10.1136/bmjopen-2012-001890 PubMedPubMedCentralCrossRefGoogle Scholar
  263. 263.
    Scuderi N, Ceccarelli S, Onesti MG, Fioramonti P, Guidi C, Romano F, Frati L, Angeloni A, Marchese C (2013) Human adipose-derived stromal cells for cell-based therapies in the treatment of systemic sclerosis. Cell Transplant 22(5):779–795. doi: 10.3727/096368912X639017 PubMedCrossRefGoogle Scholar
  264. 264.
    Batteux F, Kavian N, Servettaz A (2011) New insights on chemically induced animal models of systemic sclerosis. Curr Opin Rheumatol 23(6):511–518. doi: 10.1097/BOR.0b013e32834b1606 PubMedCrossRefGoogle Scholar
  265. 265.
    Inamdar AC, Inamdar AA (2013) Mesenchymal stem cell therapy in lung disorders: pathogenesis of lung diseases and mechanism of action of mesenchymal stem cell. Exp Lung Res 39(8):315–327. doi: 10.3109/01902148.2013.816803 PubMedCrossRefGoogle Scholar
  266. 266.
    Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, Brigham KL (2005) Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 33(2):145–152. doi: 10.1165/rcmb.2004-0330OC PubMedPubMedCentralCrossRefGoogle Scholar
  267. 267.
    Kumamoto M, Nishiwaki T, Matsuo N, Kimura H, Matsushima K (2009) Minimally cultured bone marrow mesenchymal stem cells ameliorate fibrotic lung injury. Eur Respir J 34(3):740–748. doi: 10.1183/09031936.00128508 PubMedCrossRefGoogle Scholar
  268. 268.
    Cargnoni A, Gibelli L, Tosini A, Signoroni PB, Nassuato C, Arienti D, Lombardi G, Albertini A, Wengler GS, Parolini O (2009) Transplantation of allogeneic and xenogeneic placenta-derived cells reduces bleomycin-induced lung fibrosis. Cell Transplant 18(4):405–422. doi: 10.3727/096368909788809857 PubMedCrossRefGoogle Scholar
  269. 269.
    Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG (2007) Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 104(26):11002–11007. doi: 10.1073/pnas.0704421104 PubMedPubMedCentralCrossRefGoogle Scholar
  270. 270.
    Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Semprun-Prieto L, Delafontaine P, Prockop DJ (2009) Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 5(1):54–63. doi: 10.1016/j.stem.2009.05.003 PubMedPubMedCentralCrossRefGoogle Scholar
  271. 271.
    Lee SH, Jang AS, Kim YE, Cha JY, Kim TH, Jung S, Park SK, Lee YK, Won JH, Kim YH, Park CS (2010) Modulation of cytokine and nitric oxide by mesenchymal stem cell transfer in lung injury/fibrosis. Respir Res 11:16. doi: 10.1186/1465-9921-11-16 PubMedPubMedCentralCrossRefGoogle Scholar
  272. 272.
    Conese M, Carbone A, Castellani S, Di Gioia S (2013) Paracrine effects and heterogeneity of marrow-derived stem/progenitor cells: relevance for the treatment of respiratory diseases. Cells Tissues Organs 197(6):445–473. doi: 10.1159/000348831 PubMedCrossRefGoogle Scholar
  273. 273.
    Servettaz A, Goulvestre C, Kavian N, Nicco C, Guilpain P, Chereau C, Vuiblet V, Guillevin L, Mouthon L, Weill B, Batteux F (2009) Selective oxidation of DNA topoisomerase 1 induces systemic sclerosis in the mouse. J Immunol 182(9):5855–5864. doi: 10.4049/jimmunol.0803705 PubMedCrossRefGoogle Scholar
  274. 274.
    Hua-Huy T, Le-Dong NN, Duong-Quy S, Bei Y, Riviere S, Tiev KP, Nicco C, Chereau C, Batteux F, Dinh-Xuan AT (2015) Increased exhaled nitric oxide precedes lung fibrosis in two murine models of systemic sclerosis. J Breath Res 9(3):036007. doi: 10.1088/1752-7155/9/3/036007 PubMedCrossRefGoogle Scholar
  275. 275.
    Kavian N, Marut W, Servettaz A, Nicco C, Chereau C, Lemarechal H, Borderie D, Dupin N, Weill B, Batteux F (2012) Reactive oxygen species-mediated killing of activated fibroblasts by arsenic trioxide ameliorates fibrosis in a murine model of systemic sclerosis. Arthritis Rheum 64(10):3430–3440. doi: 10.1002/art.34534 PubMedCrossRefGoogle Scholar
  276. 276.
    Kavian N, Servettaz A, Marut W, Nicco C, Chereau C, Weill B, Batteux F (2012) Sunitinib inhibits the phosphorylation of platelet-derived growth factor receptor beta in the skin of mice with scleroderma-like features and prevents the development of the disease. Arthritis Rheum 64(6):1990–2000. doi: 10.1002/art.34354 PubMedCrossRefGoogle Scholar
  277. 277.
    Kavian N, Servettaz A, Mongaret C, Wang A, Nicco C, Chereau C, Grange P, Vuiblet V, Birembaut P, Diebold MD, Weill B, Dupin N, Batteux F (2010) Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model. Arthritis Rheum 62(11):3477–3487. doi: 10.1002/art.27626 PubMedCrossRefGoogle Scholar
  278. 278.
    Marut W, Jamier V, Kavian N, Servettaz A, Winyard PG, Eggleton P, Anwar A, Nicco C, Jacob C, Chereau C, Weill B, Batteux F (2013) The natural organosulfur compound dipropyltetrasulfide prevents HOCl-induced systemic sclerosis in the mouse. Arthritis Res Ther 15(5):R167. doi: 10.1186/ar4351 PubMedPubMedCentralCrossRefGoogle Scholar
  279. 279.
    Marut W, Kavian N, Servettaz A, Hua-Huy T, Nicco C, Chereau C, Weill B, Dinh-Xuan AT, Batteux F (2013) Amelioration of systemic fibrosis in mice by angiotensin II receptor blockade. Arthritis Rheum 65(5):1367–1377. doi: 10.1002/art.37873 PubMedCrossRefGoogle Scholar
  280. 280.
    Marut WK, Kavian N, Servettaz A, Nicco C, Ba LA, Doering M, Chereau C, Jacob C, Weill B, Batteux F (2012) The organotelluride catalyst (PHTE)(2)NQ prevents HOCl-induced systemic sclerosis in mouse. J Invest Dermatol 132(4):1125–1132. doi: 10.1038/jid.2011.455 PubMedCrossRefGoogle Scholar
  281. 281.
    Servettaz A, Kavian N, Nicco C, Deveaux V, Chereau C, Wang A, Zimmer A, Lotersztajn S, Weill B, Batteux F (2010) Targeting the cannabinoid pathway limits the development of fibrosis and autoimmunity in a mouse model of systemic sclerosis. Am J Pathol 177(1):187–196. doi: 10.2353/ajpath.2010.090763 PubMedPubMedCentralCrossRefGoogle Scholar
  282. 282.
    Bagnato G, Bitto A, Irrera N, Pizzino G, Sangari D, Cinquegrani M, Roberts W, Atteritano M, Altavilla D, Squadrito F, Bagnato G, Saitta A (2013) Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis. Arthritis Res Ther 15(5):R120. doi: 10.1186/ar4300 PubMedPubMedCentralCrossRefGoogle Scholar
  283. 283.
    Bagnato G, Bitto A, Pizzino G, Irrera N, Sangari D, Cinquegrani M, Roberts WN, Matucci Cerinic M, Squadrito F, Altavilla D, Bagnato G, Saitta A (2013) Simvastatin attenuates the development of pulmonary and cutaneous fibrosis in a murine model of systemic sclerosis. Rheumatology 52(8):1377–1386. doi: 10.1093/rheumatology/ket144 PubMedCrossRefGoogle Scholar
  284. 284.
    Maria A, Toupet K, Maumus M, Fonteneau G, Le Quellec A, Jorgensen C, Guilpain P, Noël D (2016) Human adipose mesenchymal stem cells as potent anti-fibrosis therapy for systemic sclerosis. J Autoimmunity 70:31–39Google Scholar
  285. 285.
    Naderi N, Combellack EJ, Griffin M, Sedaghati T, Javed M, Findlay MW, Wallace CG, Mosahebi A, Butler PE, Seifalian AM, Whitaker IS (2016) The regenerative role of adipose-derived stem cells (ADSC) in plastic and reconstructive surgery. Int Wound J. doi: 10.1111/iwj.12569 PubMedGoogle Scholar
  286. 286.
    Lataillade JJ, Doucet C, Bey E, Carsin H, Huet C, Clairand I, Bottollier-Depois JF, Chapel A, Ernou I, Gourven M, Boutin L, Hayden A, Carcamo C, Buglova E, Joussemet M, de Revel T, Gourmelon P (2007) New approach to radiation burn treatment by dosimetry-guided surgery combined with autologous mesenchymal stem cell therapy. Regen Med 2(5):785–794. doi: 10.2217/17460751.2.5.785 PubMedCrossRefGoogle Scholar
  287. 287.
    Bey E, Prat M, Duhamel P, Benderitter M, Brachet M, Trompier F, Battaglini P, Ernou I, Boutin L, Gourven M, Tissedre F, Crea S, Mansour CA, de Revel T, Carsin H, Gourmelon P, Lataillade JJ (2010) Emerging therapy for improving wound repair of severe radiation burns using local bone marrow-derived stem cell administrations. Wound Repair Regen 18(1):50–58. doi: 10.1111/j.1524-475X.2009.00562.x PubMedCrossRefGoogle Scholar
  288. 288.
    Leclerc T, Thepenier C, Jault P, Bey E, Peltzer J, Trouillas M, Duhamel P, Bargues L, Prat M, Bonderriter M, Lataillade JJ (2011) Cell therapy of burns. Cell Prolif 44(Suppl 1):48–54. doi: 10.1111/j.1365-2184.2010.00727.x PubMedCrossRefGoogle Scholar
  289. 289.
    Linard C, Busson E, Holler V, Strup-Perrot C, Lacave-Lapalun JV, Lhomme B, Prat M, Devauchelle P, Sabourin JC, Simon JM, Bonneau M, Lataillade JJ, Benderitter M (2013) Repeated autologous bone marrow-derived mesenchymal stem cell injections improve radiation-induced proctitis in pigs. Stem Cells Transl Med 2(11):916–927. doi: 10.5966/sctm.2013-0030 PubMedPubMedCentralCrossRefGoogle Scholar
  290. 290.
    Linard C, Tissedre F, Busson E, Holler V, Leclerc T, Strup-Perrot C, Couty L, L’Homme B, Benderitter M, Lafont A, Lataillade JJ, Coulomb B (2015) Therapeutic potential of gingival fibroblasts for cutaneous radiation syndrome: comparison to bone marrow-mesenchymal stem cell grafts. Stem Cells Dev 24(10):1182–1193. doi: 10.1089/scd.2014.0486 PubMedPubMedCentralCrossRefGoogle Scholar
  291. 291.
    Christopeit M, Schendel M, Foll J, Muller LP, Keysser G, Behre G (2008) Marked improvement of severe progressive systemic sclerosis after transplantation of mesenchymal stem cells from an allogeneic haploidentical-related donor mediated by ligation of CD137L. Leukemia 22(5):1062–1064. doi: 10.1038/sj.leu.2404996 PubMedCrossRefGoogle Scholar
  292. 292.
    Keyszer G, Christopeit M, Fick S, Schendel M, Taute BM, Behre G, Muller LP, Schmoll HJ (2011) Treatment of severe progressive systemic sclerosis with transplantation of mesenchymal stromal cells from allogeneic related donors: report of five cases. Arthritis Rheum 63(8):2540–2542. doi: 10.1002/art.30431 PubMedCrossRefGoogle Scholar
  293. 293.
    Guiducci S, Porta F, Saccardi R, Guidi S, Ibba-Manneschi L, Manetti M, Mazzanti B, Dal Pozzo S, Milia AF, Bellando-Randone S, Miniati I, Fiori G, Fontana R, Amanzi L, Braschi F, Bosi A, Matucci-Cerinic M (2010) Autologous mesenchymal stem cells foster revascularization of ischemic limbs in systemic sclerosis: a case report. Ann Intern Med 153(10):650–654. doi: 10.7326/0003-4819-153-10-201011160-00007 PubMedCrossRefGoogle Scholar
  294. 294.
    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 (2015) 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 74(12):2175–2182. doi: 10.1136/annrheumdis-2014-205681 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Alexandre T. J. Maria
    • 1
    • 2
    • 3
  • Marie Maumus
    • 1
    • 2
  • Alain Le Quellec
    • 2
    • 3
  • Christian Jorgensen
    • 1
    • 2
    • 4
  • Danièle Noël
    • 1
    • 2
    • 4
  • Philippe Guilpain
    • 1
    • 2
    • 3
  1. 1.Inserm, U 1183Hôpital Saint-EloiMontpellierFrance
  2. 2.Medical SchoolMontpellier UniversityMontpellierFrance
  3. 3.Department of Internal Medicine, Multiorganic DiseasesSaint-Eloi HospitalMontpellierFrance
  4. 4.Clinical Immunology and Osteoarticular Diseases Therapeutic UnitLapeyronie HospitalMontpellierFrance

Personalised recommendations