Interactions Between Multipotential Stromal Cells (MSCs) and Immune Cells During Bone Healing

  • Jehan J. El-Jawhari
  • Elena Jones
  • Dennis McGonagle
  • Peter V. Giannoudis
Chapter
First Online:
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

The physiological process of bone healing takes place in three sequential stages: inflammation, repair and remodelling. Multipotential stromal cells (MSCs) are the key progenitor cells for osteoblasts and chondrocytes and are also imbued with immunomodulatory capabilities. Although MSCs are well known to be involved in osteogenesis during the later stages of repair, their role during the inflammatory phase and precise interactions with immune cells remain poorly understood. This chapter describes the current knowledge on cellular interactions during the bone repair as well as cytokines and growth factors mediating these processes. The roles of emerging innate immune cell populations and innate lymphoid cells are also discussed. Based on this current knowledge, we conclude that in addition to their differentiation during later bone repair stages, MSCs are likely to have a substantial involvement in the initial stage of bone healing by controlling the fate of inflammation. An improved understanding of complex cell interactions during bone repair has broad implications on optimising the treatment of the fracture complications including non-union.

Keywords

Bone repair MSCs Immune cells Bone fracture 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Ozaki A, Tsunoda M, Kinoshita S, Saura R. Role of fracture hematoma and periosteum during fracture healing in rats: interaction of fracture hematoma and the periosteum in the initial step of the healing process. J Orthop Sci. 2000;5(1):64–70.PubMedCrossRefGoogle Scholar
  2. 2.
    Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8(11):656–64.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 1970;3(4):393–403.PubMedGoogle Scholar
  4. 4.
    Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9(5):641–50.PubMedCrossRefGoogle Scholar
  5. 5.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Colnot C. Cell sources for bone tissue engineering: insights from basic science. Tissue Eng Part B Rev. 2011;17(6):449–57.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Pitchford SC, Furze RC, Jones CP, Wengner AM, Rankin SM. Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell. 2009;4(1):62–72.PubMedCrossRefGoogle Scholar
  8. 8.
    Cuthbert R, Boxall SA, Tan HB, Giannoudis PV, McGonagle D, Jones E. Single-platform quality control assay to quantify multipotential stromal cells in bone marrow aspirates prior to bulk manufacture or direct therapeutic use. Cytotherapy. 2012;14(4):431–40.PubMedCrossRefGoogle Scholar
  9. 9.
    Alvarez-Viejo M, Menendez-Menendez Y, Otero-Hernandez J. CD271 as a marker to identify mesenchymal stem cells from diverse sources before culture. World J Stem Cells. 2015;7(2):470–6.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Nakahara H, Dennis JE, Bruder SP, Haynesworth SE, Lennon DP, Caplan AI. In vitro differentiation of bone and hypertrophic cartilage from periosteal-derived cells. Exp Cell Res. 1991;195(2):492–503.PubMedCrossRefGoogle Scholar
  11. 11.
    Kisiel AH, McDuffee LA, Masaoud E, Bailey TR, Esparza Gonzalez BP, Nino-Fong R. Isolation, characterization, and in vitro proliferation of canine mesenchymal stem cells derived from bone marrow, adipose tissue, muscle, and periosteum. Am J Vet Res. 2012;73(8):1305–17.PubMedCrossRefGoogle Scholar
  12. 12.
    Beane OS, Fonseca VC, Cooper LL, Koren G, Darling EM. Impact of aging on the regenerative properties of bone marrow-, muscle-, and adipose-derived mesenchymal stem/stromal cells. PLoS One. 2014;9(12):e115963.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol. 2014;15(11):1009–16.PubMedCrossRefGoogle Scholar
  14. 14.
    Krampera M. Mesenchymal stromal cell ‘licensing’: a multistep process. Leukemia. 2011;25(9):1408–14.PubMedCrossRefGoogle Scholar
  15. 15.
    Mizuno K, Mineo K, Tachibana T, Sumi M, Matsubara T, Hirohata K. The osteogenetic potential of fracture haematoma. Subperiosteal and intramuscular transplantation of the haematoma. J Bone Joint Surg. 1990;72(5):822–9.Google Scholar
  16. 16.
    Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol. 2012;8(3):133–43.PubMedCrossRefGoogle Scholar
  17. 17.
    Marsell R, Einhorn TA. The biology of fracture healing. Injury. 2011;42(6):551–5.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Nakahara H, Bruder SP, Haynesworth SE, Holecek JJ, Baber MA, Goldberg VM, et al. Bone and cartilage formation in diffusion chambers by subcultured cells derived from the periosteum. Bone. 1990;11(3):181–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Phillips AM. Overview of the fracture healing cascade. Injury. 2005;36 Suppl 3:S5–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Cottrell JA, Vales FM, Schachter D, Wadsworth S, Gundlapalli R, Kapadia R, et al. Osteogenic activity of locally applied small molecule drugs in a rat femur defect model. J Biomed Biotechnol. 2010;2010:597641.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337–42.PubMedCrossRefGoogle Scholar
  22. 22.
    Pettit AR, Ji H, von Stechow D, Muller R, Goldring SR, Choi Y, et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol. 2001;159(5):1689–99.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem. 2003;88(5):873–84.PubMedCrossRefGoogle Scholar
  24. 24.
    Xing Z, Lu C, Hu D, Miclau 3rd T, Marcucio RS. Rejuvenation of the inflammatory system stimulates fracture repair in aged mice. J Orthop Res. 2010;28(8):1000–6.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Richardson J, Hill AM, Johnston CJ, McGregor A, Norrish AR, Eastwood D, et al. Fracture healing in HIV-positive populations. J Bone Joint Surg. 2008;90(8):988–94.CrossRefGoogle Scholar
  26. 26.
    Aukrust P, Haug CJ, Ueland T, Lien E, Muller F, Espevik T, et al. Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J Clin Endocrinol Metab. 1999;84(1):145–50.PubMedGoogle Scholar
  27. 27.
    Timlin M, Toomey D, Condron C, Power C, Street J, Murray P, et al. Fracture hematoma is a potent proinflammatory mediator of neutrophil function. J Trauma. 2005;58(6):1223–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Xian CJ, Zhou FH, McCarty RC, Foster BK. Intramembranous ossification mechanism for bone bridge formation at the growth plate cartilage injury site. J Orthop Res. 2004;22(2):417–26.PubMedCrossRefGoogle Scholar
  29. 29.
    Chung R, Cool JC, Scherer MA, Foster BK, Xian CJ. Roles of neutrophil-mediated inflammatory response in the bony repair of injured growth plate cartilage in young rats. J Leukoc Biol. 2006;80(6):1272–80.PubMedCrossRefGoogle Scholar
  30. 30.
    Segal AW. How neutrophils kill microbes. Annu Rev Immunol. 2005;23:197–223.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Xing Z, Lu C, Hu D, Yu YY, Wang X, Colnot C, et al. Multiple roles for CCR2 during fracture healing. Dis Model Mech. 2010;3(7-8):451–8.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Wu AC, Raggatt LJ, Alexander KA, Pettit AR. Unraveling macrophage contributions to bone repair. Bonekey Rep. 2013;2:373.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Lacey DC, Achuthan A, Fleetwood AJ, Dinh H, Roiniotis J, Scholz GM, et al. Defining GM-CSF- and macrophage-CSF-dependent macrophage responses by in vitro models. J Immunol. 2012;188(11):5752–65.PubMedCrossRefGoogle Scholar
  34. 34.
    Kon T, Cho TJ, Aizawa T, Yamazaki M, Nooh N, Graves D, et al. Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res. 2001;16(6):1004–14.PubMedCrossRefGoogle Scholar
  35. 35.
    Yu YY, Lieu S, Lu C, Miclau T, Marcucio RS, Colnot C. Immunolocalization of BMPs, BMP antagonists, receptors, and effectors during fracture repair. Bone. 2010;46(3):841–51.PubMedCrossRefGoogle Scholar
  36. 36.
    Nakase T, Yoshikawa H. Potential roles of bone morphogenetic proteins (BMPs) in skeletal repair and regeneration. J Bone Miner Metab. 2006;24(6):425–33.PubMedCrossRefGoogle Scholar
  37. 37.
    Guihard P, Danger Y, Brounais B, David E, Brion R, Delecrin J, et al. Induction of osteogenesis in mesenchymal stem cells by activated monocytes/macrophages depends on oncostatin M signaling. Stem Cells. 2012;30(4):762–72.PubMedCrossRefGoogle Scholar
  38. 38.
    Nicolaidou V, Wong MM, Redpath AN, Ersek A, Baban DF, Williams LM, et al. Monocytes induce STAT3 activation in human mesenchymal stem cells to promote osteoblast formation. PLoS One. 2012;7(7):e39871.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Ekstrom K, Omar O, Graneli C, Wang X, Vazirisani F, Thomsen P. Monocyte exosomes stimulate the osteogenic gene expression of mesenchymal stem cells. PLoS One. 2013;8(9):e75227.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Omar OM, Graneli C, Ekstrom K, Karlsson C, Johansson A, Lausmaa J, et al. The stimulation of an osteogenic response by classical monocyte activation. Biomaterials. 2011;32(32):8190–204.PubMedCrossRefGoogle Scholar
  41. 41.
    Shi FD, Ljunggren HG, La Cava A, Van Kaer L. Organ-specific features of natural killer cells. Nat Rev Immunol. 2011;11(10):658–71.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Toben D, Schroeder I, El Khassawna T, Mehta M, Hoffmann JE, Frisch JT, et al. Fracture healing is accelerated in the absence of the adaptive immune system. J Bone Miner Res. 2011;26(1):113–24.PubMedCrossRefGoogle Scholar
  43. 43.
    Thomas H, Jager M, Mauel K, Brandau S, Lask S, Flohe SB. Interaction with mesenchymal stem cells provokes natural killer cells for enhanced IL-12/IL-18-induced interferon-gamma secretion. Mediators Inflamm. 2014;2014:143463.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Gerstenfeld LC, Cho TJ, Kon T, Aizawa T, Cruceta J, Graves BD, et al. Impaired intramembranous bone formation during bone repair in the absence of tumor necrosis factor-alpha signaling. Cells Tissues Organs. 2001;169(3):285–94.PubMedCrossRefGoogle Scholar
  45. 45.
    Gerstenfeld LC, Cho TJ, Kon T, Aizawa T, Tsay A, Fitch J, et al. Impaired fracture healing in the absence of TNF-alpha signaling: the role of TNF-alpha in endochondral cartilage resorption. J Bone Miner Res. 2003;18(9):1584–92.PubMedCrossRefGoogle Scholar
  46. 46.
    Almeida CR, Vasconcelos DP, Goncalves RM, Barbosa MA. Enhanced mesenchymal stromal cell recruitment via natural killer cells by incorporation of inflammatory signals in biomaterials. J R Soc Interface. 2012;9(67):261–71.PubMedCrossRefGoogle Scholar
  47. 47.
    Soderstrom K, Stein E, Colmenero P, Purath U, Muller-Ladner U, de Matos CT, et al. Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Natl Acad Sci U S A. 2010;107(29):13028–33.PubMedCrossRefGoogle Scholar
  48. 48.
    Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. 2000;106(12):1481–8.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Spits H, Cupedo T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu Rev Immunol. 2012;30:647–75.PubMedCrossRefGoogle Scholar
  50. 50.
    Yagi R, Zhong C, Northrup DL, Yu F, Bouladoux N, Spencer S, et al. The transcription factor GATA3 is critical for the development of all IL-7Ralpha-expressing innate lymphoid cells. Immunity. 2014;40(3):378–88.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Spits H, Di Santo JP. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol. 2011;12(1):21–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Artis D, Spits H. The biology of innate lymphoid cells. Nature. 2015;517(7534):293–301.PubMedCrossRefGoogle Scholar
  53. 53.
    Fuchs A, Vermi W, Lee JS, Lonardi S, Gilfillan S, Newberry RD, et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity. 2013;38(4):769–81.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Bernink JH, Peters CP, Munneke M, te Velde AA, Meijer SL, Weijer K, et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol. 2013;14(3):221–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Price AE, Liang HE, Sullivan BM, Reinhardt RL, Eisley CJ, Erle DJ, et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A. 2010;107(25):11489–94.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010;464(7293):1367–70.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Wilhelm C, Hirota K, Stieglitz B, Van Snick J, Tolaini M, Lahl K, et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat Immunol. 2011;12(11):1071–7.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Cupedo T, Crellin NK, Papazian N, Rombouts EJ, Weijer K, Grogan JL, et al. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat Immunol. 2009;10(1):66–74.PubMedCrossRefGoogle Scholar
  59. 59.
    Sawa S, Lochner M, Satoh-Takayama N, Dulauroy S, Berard M, Kleinschek M, et al. RORgammat + innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat Immunol. 2011;12(4):320–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Dudakov JA, Hanash AM, Jenq RR, Young LF, Ghosh A, Singer NV, et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science. 2012;336(6077):91–5.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Scandella E, Bolinger B, Lattmann E, Miller S, Favre S, Littman DR, et al. Restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the T cell zone. Nat Immunol. 2008;9(6):667–75.PubMedCrossRefGoogle Scholar
  62. 62.
    Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG, Doering TA, et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol. 2011;12(11):1045–54.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Nam D, Mau E, Wang Y, Wright D, Silkstone D, Whetstone H, et al. T-lymphocytes enable osteoblast maturation via IL-17F during the early phase of fracture repair. PLoS One. 2012;7(6):e40044.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Yasser El-Sherbiny AE, Evangelos MF, Richard C, Thomas B, Elena J, Dennis McG. IL-22 drives the proliferation and differentiation of human bone marrow mesenchymal stem cells (MSCs); a novel pathway that may contribute to aberrant new bone formation in human Spa and beyond. 2015 ACR/ARHP Annual Meeting. ACR Poster Session B (Innate Immunity and Rheumatic Disease Poster II), 2015Google Scholar
  65. 65.
    Askalonov AA, Gordienko SM, Avdyunicheva OE, Bondarenko AV, Voronkov SF. The role of T-system immunity in reparatory regeneration of the bone tissue in animals. J Hyg Epidemiol Microbiol Immunol. 1987;31(2):219–24.PubMedGoogle Scholar
  66. 66.
    Askalonov AA. Changes in some indices of cellular immunity in patients with uncomplicated and complicated healing of bone fractures. J Hyg Epidemiol Microbiol Immunol. 1981;25(3):307–10.PubMedGoogle Scholar
  67. 67.
    Hauser CJ, Zhou X, Joshi P, Cuchens MA, Kregor P, Devidas M, et al. The immune microenvironment of human fracture/soft-tissue hematomas and its relationship to systemic immunity. J Trauma. 1997;42(5):895–903. discussion-4.PubMedCrossRefGoogle Scholar
  68. 68.
    Andrew JG, Andrew SM, Freemont AJ, Marsh DR. Inflammatory cells in normal human fracture healing. Acta Orthop Scand. 1994;65(4):462–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999;402(6759):304–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Connor JR, Dodds RA, James IE, Gowen M. Human osteoclast and giant cell differentiation: the apparent switch from nonspecific esterase to tartrate resistant acid phosphatase activity coincides with the in situ expression of osteopontin mRNA. J Histochem Cytochem. 1995;43(12):1193–201.PubMedCrossRefGoogle Scholar
  71. 71.
    Grassi F, Cattini L, Gambari L, Manferdini C, Piacentini A, Gabusi E, et al. T cell subsets differently regulate osteogenic differentiation of human mesenchymal stromal cells in vitro. J Tissue Eng Regen Med. 2013;10(4):305–14.PubMedCrossRefGoogle Scholar
  72. 72.
    Ng F, Boucher S, Koh S, Sastry KS, Chase L, Lakshmipathy U, et al. PDGF, TGF-beta, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages. Blood. 2008;112(2):295–307.PubMedCrossRefGoogle Scholar
  73. 73.
    Cho TJ, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res. 2002;17(3):513–20.PubMedCrossRefGoogle Scholar
  74. 74.
    Manabe N, Kawaguchi H, Chikuda H, Miyaura C, Inada M, Nagai R, et al. Connection between B lymphocyte and osteoclast differentiation pathways. J Immunol. 2001;167(5):2625–31.PubMedCrossRefGoogle Scholar
  75. 75.
    Weitzmann MN, Cenci S, Haug J, Brown C, DiPersio J, Pacifici R. B lymphocytes inhibit human osteoclastogenesis by secretion of TGFbeta. J Cell Biochem. 2000;78(2):318–24.PubMedCrossRefGoogle Scholar
  76. 76.
    Raggatt LJ, Alexander KA, Kaur S, Wu AC, MacDonald KPA, Pettit AR. Absence of B cells does not compromise intramembranous bone formation during healing in a tibial injury model. Am J Pathol. 2013;182(5):1501–8.PubMedCrossRefGoogle Scholar
  77. 77.
    McKibbin B. The biology of fracture healing in long bones. J Bone Joint Surg. 1978;60-B(2):150–62.Google Scholar
  78. 78.
    Kumagai K, Vasanji A, Drazba JA, Butler RS, Muschler GF. Circulating cells with osteogenic potential are physiologically mobilized into the fracture healing site in the parabiotic mice model. J Orthop Res. 2008;26(2):165–75.PubMedCrossRefGoogle Scholar
  79. 79.
    Malizos KN, Papatheodorou LK. The healing potential of the periosteum molecular aspects. Injury. 2005;36 Suppl 3:S13–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Colnot C, Huang S, Helms J. Analyzing the cellular contribution of bone marrow to fracture healing using bone marrow transplantation in mice. Biochem Biophys Res Commun. 2006;350(3):557–61.PubMedCrossRefGoogle Scholar
  81. 81.
    Yu YY, Lieu S, Lu C, Colnot C. Bone morphogenetic protein 2 stimulates endochondral ossification by regulating periosteal cell fate during bone repair. Bone. 2010;47(1):65–73.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Liu R, Birke O, Morse A, Peacock L, Mikulec K, Little DG, et al. Myogenic progenitors contribute to open but not closed fracture repair. BMC Musculoskelet Disord. 2011;12:288.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Kitaori T, Ito H, Schwarz EM, Tsutsumi R, Yoshitomi H, Oishi S, et al. Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum. 2009;60(3):813–23.PubMedCrossRefGoogle Scholar
  84. 84.
    Liu X, Duan B, Cheng Z, Jia X, Mao L, Fu H, et al. SDF-1/CXCR4 axis modulates bone marrow mesenchymal stem cell apoptosis, migration and cytokine secretion. Protein Cell. 2011;2(10):845–54.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Guiducci S, Manetti M, Romano E, Mazzanti B, Ceccarelli C, Dal Pozzo S, et al. Bone marrow-derived mesenchymal stem cells from early diffuse systemic sclerosis exhibit a paracrine machinery and stimulate angiogenesis in vitro. Ann Rheum Dis. 2011;70(11):2011–21.PubMedCrossRefGoogle Scholar
  86. 86.
    Hosogane N, Huang Z, Rawlins BA, Liu X, Boachie-Adjei O, Boskey AL, et al. Stromal derived factor-1 regulates bone morphogenetic protein 2-induced osteogenic differentiation of primary mesenchymal stem cells. Int J Biochem Cell Biol. 2010;42(7):1132–41.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Bocker W, Docheva D, Prall WC, Egea V, Pappou E, Rossmann O, et al. IKK-2 is required for TNF-alpha-induced invasion and proliferation of human mesenchymal stem cells. J Mol Med. 2008;86(10):1183–92.PubMedCrossRefGoogle Scholar
  88. 88.
    Tso GH, Law HK, Tu W, Chan GC, Lau YL. Phagocytosis of apoptotic cells modulates mesenchymal stem cells osteogenic differentiation to enhance IL-17 and RANKL expression on CD4+ T cells. Stem Cells. 2010;28(5):939–54.PubMedGoogle Scholar
  89. 89.
    Mbalaviele G, Jaiswal N, Meng A, Cheng L, Van Den Bos C, Thiede M. Human mesenchymal stem cells promote human osteoclast differentiation from CD34+ bone marrow hematopoietic progenitors. Endocrinology. 1999;140(8):3736–43.PubMedGoogle Scholar
  90. 90.
    Croitoru-Lamoury J, Lamoury FM, Caristo M, Suzuki K, Walker D, Takikawa O, et al. Interferon-gamma regulates the proliferation and differentiation of mesenchymal stem cells via activation of indoleamine 2,3 dioxygenase (IDO). PLoS One. 2011;6(2):e14698.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Ren G, Zhao X, Zhang L, Zhang J, L’Huillier A, Ling W, et al. Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J Immunol. 2010;184(5):2321–8.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Dorronsoro A, Ferrin I, Salcedo JM, Jakobsson E, Fernandez-Rueda J, Lang V, et al. Human mesenchymal stromal cells modulate T-cell responses through TNF-alpha-mediated activation of NF-kappaB. Eur J Immunol. 2014;44(2):480–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Fan H, Zhao G, Liu L, Liu F, Gong W, Liu X, et al. Pre-treatment with IL-1beta enhances the efficacy of MSC transplantation in DSS-induced colitis. Cell Mol Immunol. 2012;9(6):473–81.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Delarosa O, Dalemans W, Lombardo E. Toll-like receptors as modulators of mesenchymal stem cells. Front Immunol. 2012;3:182.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Han X, Yang Q, Lin L, Xu C, Zheng C, Chen X, et al. Interleukin-17 enhances immunosuppression by mesenchymal stem cells. Cell Death Differ. 2014;21(11):1758–68.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Crane JL, Cao X. Bone marrow mesenchymal stem cells and TGF-beta signaling in bone remodeling. J Clin Invest. 2014;124(2):466–72.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Xu C, Yu P, Han X, Du L, Gan J, Wang Y, et al. TGF-beta promotes immune responses in the presence of mesenchymal stem cells. J Immunol. 2014;192(1):103–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Renner P, Eggenhofer E, Rosenauer A, Popp FC, Steinmann JF, Slowik P, et al. Mesenchymal stem cells require a sufficient, ongoing immune response to exert their immunosuppressive function. Transplant Proc. 2009;41(6):2607–11.PubMedCrossRefGoogle Scholar
  99. 99.
    Granero-Molto F, Weis JA, Miga MI, Landis B, Myers TJ, O’Rear L, et al. Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells. 2009;27(8):1887–98.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Klyushnenkova E, Mosca JD, McIntosh KR. Human mesenchymal stem cells suppress allogeneic T cell responses in vitro: Implications for allogeneic transplantation. Blood. 1998;92(10):642a.Google Scholar
  101. 101.
    Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30(1):42–8.PubMedCrossRefGoogle Scholar
  102. 102.
    Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L. 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. 2006;107(4):1484–90.PubMedCrossRefGoogle Scholar
  103. 103.
    Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood. 2008;111(3):1327–33.PubMedCrossRefGoogle Scholar
  104. 104.
    Luz-Crawford P, Kurte M, Bravo-Alegria J, Contreras R, Nova-Lamperti E, Tejedor G, et al. 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. 2013;4(3):65.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Deng Y, Yi S, Wang G, Cheng J, Zhang Y, Chen W, et al. Umbilical cord-derived mesenchymal stem cells instruct dendritic cells to acquire tolerogenic phenotypes through the IL-6-mediated upregulation of SOCS1. Stem Cells Dev. 2014;23(17):2080–92.PubMedCrossRefGoogle Scholar
  106. 106.
    Akiyama K, Chen C, Wang D, Xu X, Qu C, Yamaza T, et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell. 2012;10(5):544–55.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107(1):367–72.PubMedCrossRefGoogle Scholar
  108. 108.
    Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15(1):42–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Nemeth K, Keane-Myers A, Brown JM, Metcalfe DD, Gorham JD, Bundoc VG, et al. Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma. Proc Natl Acad Sci U S A. 2010;107(12):5652–7.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    DelaRosa O, Lombardo E, Beraza A, Mancheno-Corvo P, Ramirez C, Menta R, et al. Requirement of IFN-gamma-mediated indoleamine 2,3-dioxygenase expression in the modulation of lymphocyte proliferation by human adipose-derived stem cells. Tissue Eng Part A. 2009;15(10):2795–806.PubMedCrossRefGoogle Scholar
  111. 111.
    Rafei M, Campeau PM, Aguilar-Mahecha A, Buchanan M, Williams P, Birman E, et al. Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. J Immunol. 2009;182(10):5994–6002.PubMedCrossRefGoogle Scholar
  112. 112.
    Shi Y, Hu G, Su J, Li W, Chen Q, Shou P, et al. Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res. 2010;20(5):510–8.PubMedCrossRefGoogle Scholar
  113. 113.
    Barnes GL, Kostenuik PJ, Gerstenfeld LC, Einhorn TA. Growth factor regulation of fracture repair. J Bone Miner Res. 1999;14(11):1805–15.PubMedCrossRefGoogle Scholar
  114. 114.
    Schindeler A, McDonald MM, Bokko P, Little DG. Bone remodeling during fracture repair: the cellular picture. Semin Cell Dev Biol. 2008;19(5):459–66.PubMedCrossRefGoogle Scholar
  115. 115.
    Knight MN, Hankenson KD. Mesenchymal stem cells in bone regeneration. Adv Wound Care. 2013;2(6):306–16.CrossRefGoogle Scholar
  116. 116.
    Gerstenfeld LC, Alkhiary YM, Krall EA, Nicholls FH, Stapleton SN, Fitch JL, et al. Three-dimensional reconstruction of fracture callus morphogenesis. J Histochem Cytochem. 2006;54(11):1215–28.PubMedCrossRefGoogle Scholar
  117. 117.
    Zelzer E, Glotzer DJ, Hartmann C, Thomas D, Fukai N, Soker S, et al. Tissue specific regulation of VEGF expression during bone development requires Cbfa1/Runx2. Mech Dev. 2001;106(1–2):97–106.PubMedCrossRefGoogle Scholar
  118. 118.
    Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007;25(10):2648–59.PubMedCrossRefGoogle Scholar
  119. 119.
    Blumer MJ, Longato S, Fritsch H. Localization of tartrate-resistant acid phosphatase (TRAP), membrane type-1 matrix metalloproteinases (MT1-MMP) and macrophages during early endochondral bone formation. J Anat. 2008;213(4):431–41.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Huang WC, Sala-Newby GB, Susana A, Johnson JL, Newby AC. Classical macrophage activation up-regulates several matrix metalloproteinases through mitogen activated protein kinases and nuclear factor-kappaB. PLoS One. 2012;7(8):e42507.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Dreier R, Wallace S, Fuchs S, Bruckner P, Grassel S. Paracrine interactions of chondrocytes and macrophages in cartilage degradation: articular chondrocytes provide factors that activate macrophage-derived pro-gelatinase B (pro-MMP-9). J Cell Sci. 2001;114(Pt 21):3813–22.PubMedGoogle Scholar
  122. 122.
    Colnot C, Thompson Z, Miclau T, Werb Z, Helms JA. Altered fracture repair in the absence of MMP9. Development. 2003;130(17):4123–33.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Kosaki N, Takaishi H, Kamekura S, Kimura T, Okada Y, Minqi L, et al. Impaired bone fracture healing in matrix metalloproteinase-13 deficient mice. Biochem Biophys Res Commun. 2007;354(4):846–51.PubMedCrossRefGoogle Scholar
  124. 124.
    McDonald MM, Morse A, Mikulec K, Peacock L, Baldock PA, Kostenuik PJ, et al. Matrix metalloproteinase-driven endochondral fracture union proceeds independently of osteoclast activity. J Bone Miner Res. 2013;28(7):1550–60.PubMedCrossRefGoogle Scholar
  125. 125.
    Fajardo M, Liu CJ, Ilalov K, Egol KA. Matrix metalloproteinases that associate with and cleave bone morphogenetic protein-2 in vitro are elevated in hypertrophic fracture nonunion tissue. J Orthop Trauma. 2010;24(9):557–63.PubMedCrossRefGoogle Scholar
  126. 126.
    Alexander KA, Chang MK, Maylin ER, Kohler T, Muller R, Wu AC, et al. Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model. J Bone Miner Res. 2011;26(7):1517–32.PubMedCrossRefGoogle Scholar
  127. 127.
    Hankemeier S, Grassel S, Plenz G, Spiegel HU, Bruckner P, Probst A. Alteration of fracture stability influences chondrogenesis, osteogenesis and immigration of macrophages. J Orthop Res. 2001;19(4):531–8.PubMedCrossRefGoogle Scholar
  128. 128.
    Konnecke I, Serra A, El Khassawna T, Schlundt C, Schell H, Hauser A, et al. T and B cells participate in bone repair by infiltrating the fracture callus in a two-wave fashion. Bone. 2014;64:155–65.PubMedCrossRefGoogle Scholar
  129. 129.
    Mountziaris PM, Mikos AG. Modulation of the inflammatory response for enhanced bone tissue regeneration. Tissue Eng Part B Rev. 2008;14(2):179–86.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Chen G, Deng C, Li YP. TGF-beta and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci. 2012;8(2):272–88.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Lienau J, Schmidt-Bleek K, Peters A, Weber H, Bail HJ, Duda GN, et al. Insight into the molecular pathophysiology of delayed bone healing in a sheep model. Tissue Eng Part A. 2010;16(1):191–9.PubMedCrossRefGoogle Scholar
  132. 132.
    Hak DJ, Makino T, Niikura T, Hazelwood SJ, Curtiss S, Reddi AH. Recombinant human BMP-7 effectively prevents non-union in both young and old rats. J Orthop Res. 2006;24(1):11–20.PubMedCrossRefGoogle Scholar
  133. 133.
    Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L, et al. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet. 2006;38(12):1424–9.PubMedCrossRefGoogle Scholar
  134. 134.
    Bandyopadhyay A, Tsuji K, Cox K, Harfe BD, Rosen V, Tabin CJ. Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet. 2006;2(12):e216.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Lehmann W, Edgar CM, Wang K, Cho TJ, Barnes GL, Kakar S, et al. Tumor necrosis factor alpha (TNF-alpha) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing. Bone. 2005;36(2):300–10.PubMedCrossRefGoogle Scholar
  136. 136.
    Aizawa T, Kon T, Einhorn TA, Gerstenfeld LC. Induction of apoptosis in chondrocytes by tumor necrosis factor-alpha. J Orthop Res. 2001;19(5):785–96.PubMedCrossRefGoogle Scholar
  137. 137.
    Wan C, Shao J, Gilbert SR, Riddle RC, Long F, Johnson RS, et al. Role of HIF-1alpha in skeletal development. Ann N Y Acad Sci. 2010;1192:322–6.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Kondo M, Yamaoka K, Sonomoto K, Fukuyo S, Oshita K, Okada Y, et al. IL-17 inhibits chondrogenic differentiation of human mesenchymal stem cells. PLoS One. 2013;8(11):e79463.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Mulari MT, Qu Q, Harkonen PL, Vaananen HK. Osteoblast-like cells complete osteoclastic bone resorption and form new mineralized bone matrix in vitro. Calcif Tissue Int. 2004;75(3):253–61.PubMedCrossRefGoogle Scholar
  140. 140.
    Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289(5484):1504–8.PubMedCrossRefGoogle Scholar
  141. 141.
    Taguchi K, Ogawa R, Migita M, Hanawa H, Ito H, Orimo H. The role of bone marrow-derived cells in bone fracture repair in a green fluorescent protein chimeric mouse model. Biochem Biophys Res Commun. 2005;331(1):31–6.PubMedCrossRefGoogle Scholar
  142. 142.
    James AW. Review of signaling pathways governing MSC osteogenic and adipogenic differentiation. Scientifica. 2013;2013:684736.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    De Boer J, Wang HJ, Van Blitterswijk C. Effects of Wnt signaling on proliferation and differentiation of human mesenchymal stem cells. Tissue Eng. 2004;10(3–4):393–401.PubMedCrossRefGoogle Scholar
  144. 144.
    Baksh D, Tuan RS. Canonical and non-canonical Wnts differentially affect the development potential of primary isolate of human bone marrow mesenchymal stem cells. J Cell Physiol. 2007;212(3):817–26.PubMedCrossRefGoogle Scholar
  145. 145.
    Cawthorn WP, Bree AJ, Yao Y, Du B, Hemati N, Martinez-Santibanez G, et al. Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a beta-catenin-dependent mechanism. Bone. 2012;50(2):477–89.PubMedCrossRefGoogle Scholar
  146. 146.
    Zhang X, Schwarz EM, Young DA, Puzas JE, Rosier RN, O’Keefe RJ. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest. 2002;109(11):1405–15.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Naik AA, Xie C, Zuscik MJ, Kingsley P, Schwarz EM, Awad H, et al. Reduced COX-2 expression in aged mice is associated with impaired fracture healing. J Bone Miner Res. 2009;24(2):251–64.PubMedCrossRefGoogle Scholar
  148. 148.
    Oshita K, Yamaoka K, Udagawa N, Fukuyo S, Sonomoto K, Maeshima K, et al. Human mesenchymal stem cells inhibit osteoclastogenesis through osteoprotegerin production. Arthritis Rheum. 2011;63(6):1658–67.PubMedCrossRefGoogle Scholar
  149. 149.
    Walsh NC, Gravallese EM. Bone remodeling in rheumatic disease: a question of balance. Immunol Rev. 2010;233(1):301–12.PubMedCrossRefGoogle Scholar
  150. 150.
    Chen Y, Whetstone HC, Lin AC, Nadesan P, Wei Q, Poon R, et al. Beta-catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing. PLoS Med. 2007;4(7):e249.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Laird RK, Pavlos NJ, Xu J, Brankov B, White B, Fan Y, et al. Bone allograft non-union is related to excessive osteoclastic bone resorption: a sheep model study. Histol Histopathol. 2006;21(12):1277–85.PubMedGoogle Scholar
  152. 152.
    Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203(12):2673–82.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Huang H, Kim HJ, Chang EJ, Lee ZH, Hwang SJ, Kim HM, et al. IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ. 2009;16(10):1332–43.PubMedCrossRefGoogle Scholar
  154. 154.
    Lee Y. The role of interleukin-17 in bone metabolism and inflammatory skeletal diseases. BMB Rep. 2013;46(10):479–83.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Fan X, Biskobing DM, Fan D, Hofstetter W, Rubin J. Macrophage colony stimulating factor down-regulates MCSF-receptor expression and entry of progenitors into the osteoclast lineage. J Bone Miner Res. 1997;12(9):1387–95.PubMedCrossRefGoogle Scholar
  156. 156.
    Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397(6717):315–23.PubMedCrossRefGoogle Scholar
  157. 157.
    Champagne CM, Takebe J, Offenbacher S, Cooper LF. Macrophage cell lines produce osteoinductive signals that include bone morphogenetic protein-2. Bone. 2002;30(1):26–31.PubMedCrossRefGoogle Scholar
  158. 158.
    Bhat A, Wooten RM, Jayasuriya AC. Secretion of growth factors from macrophages when cultured with microparticles. J Biomed Mater Res A. 2013;101(11):3170–80.PubMedPubMedCentralGoogle Scholar
  159. 159.
    Stewart A, Guan H, Yang K. BMP-3 promotes mesenchymal stem cell proliferation through the TGF-beta/activin signaling pathway. J Cell Physiol. 2010;223(3):658–66.PubMedGoogle Scholar
  160. 160.
    Guo X, Wang XF. Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res. 2009;19(1):71–88.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Lin GL, Hankenson KD. Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. J Cell Biochem. 2011;112(12):3491–501.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Bhandari M, Tornetta 3rd P, Sprague S, Najibi S, Petrisor B, Griffith L, et al. Predictors of reoperation following operative management of fractures of the tibial shaft. J Orthop Trauma. 2003;17(5):353–61.PubMedCrossRefGoogle Scholar
  163. 163.
    Bajada S, Marshall MJ, Wright KT, Richardson JB, Johnson WE. Decreased osteogenesis, increased cell senescence and elevated Dickkopf-1 secretion in human fracture non union stromal cells. Bone. 2009;45(4):726–35.PubMedCrossRefGoogle Scholar
  164. 164.
    Seebach C, Henrich D, Tewksbury R, Wilhelm K, Marzi I. Number and proliferative capacity of human mesenchymal stem cells are modulated positively in multiple trauma patients and negatively in atrophic nonunions. Calcif Tissue Int. 2007;80(4):294–300.PubMedCrossRefGoogle Scholar
  165. 165.
    Mathieu M, Rigutto S, Ingels A, Spruyt D, Stricwant N, Kharroubi I, et al. Decreased pool of mesenchymal stem cells is associated with altered chemokines serum levels in atrophic nonunion fractures. Bone. 2013;53(2):391–8.PubMedCrossRefGoogle Scholar
  166. 166.
    Bajada S, Harrison PE, Ashton BA, Cassar-Pullicino VN, Ashammakhi N, Richardson JB. Successful treatment of refractory tibial nonunion using calcium sulphate and bone marrow stromal cell implantation. J Bone Joint Surg. 2007;89(10):1382–6.CrossRefGoogle Scholar
  167. 167.
    Tawonsawatruk T, Kelly M, Simpson H. Evaluation of native mesenchymal stem cells from bone marrow and local tissue in an atrophic nonunion model. Tissue Eng Part C Methods. 2014;20(6):524–32.PubMedCrossRefGoogle Scholar
  168. 168.
    Qu G, von Schroeder HP. The osteogenic potential of pseudoarthrosis tissue and bone from human scaphoid non-unions. J Hand Surg Eur Vol. 2008;33(4):449–56.PubMedCrossRefGoogle Scholar
  169. 169.
    Gomez-Barrena E, Rosset P, Lozano D, Stanovici J, Ermthaller C, Gerbhard F. Bone fracture healing: cell therapy in delayed unions and nonunions. Bone. 2015;70:93–101.PubMedCrossRefGoogle Scholar
  170. 170.
    Gokturk E, Turgut A, Baycu C, Gunal I, Seber S, Gulbas Z. Oxygen-free radicals impair fracture healing in rats. Acta Orthop Scand. 1995;66(5):473–5.PubMedCrossRefGoogle Scholar
  171. 171.
    Grogaard B, Gerdin B, Reikeras O. The polymorphonuclear leukocyte: has it a role in fracture healing? Arch Orthop Trauma Surg. 1990;109(5):268–71.PubMedCrossRefGoogle Scholar
  172. 172.
    Herman S, Muller RB, Kronke G, Zwerina J, Redlich K, Hueber AJ, et al. Induction of osteoclast-associated receptor, a key osteoclast costimulation molecule, in rheumatoid arthritis. Arthritis Rheum. 2008;58(10):3041–50.PubMedCrossRefGoogle Scholar
  173. 173.
    Crop MJ, Korevaar SS, de Kuiper R, IJzermans JN, van Besouw NM, Baan CC, et al. Human mesenchymal stem cells are susceptible to lysis by CD8(+) T cells and NK cells. Cell Transplant. 2011;20(10):1547–59.PubMedCrossRefGoogle Scholar
  174. 174.
    Gotherstrom C, Lundqvist A, Duprez IR, Childs R, Berg L, le Blanc K. Fetal and adult multipotent mesenchymal stromal cells are killed by different pathways. Cytotherapy. 2011;13(3):269–78.PubMedCrossRefGoogle Scholar
  175. 175.
    Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells. 2006;24(1):74–85.PubMedCrossRefGoogle Scholar
  176. 176.
    Poggi A, Prevosto C, Massaro AM, Negrini S, Urbani S, Pierri I, et al. Interaction between human NK cells and bone marrow stromal cells induces NK cell triggering: role of NKp30 and NKG2D receptors. J Immunol. 2005;175(10):6352–60.PubMedCrossRefGoogle Scholar
  177. 177.
    Schmidt-Bleek K, Schell H, Schulz N, Hoff P, Perka C, Buttgereit F, et al. Inflammatory phase of bone healing initiates the regenerative healing cascade. Cell Tissue Res. 2012;347(3):567–73.PubMedCrossRefGoogle Scholar
  178. 178.
    Colburn NT, Zaal KJ, Wang F, Tuan RS. A role for gamma/delta T cells in a mouse model of fracture healing. Arthritis Rheum. 2009;60(6):1694–703.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Harre U, Georgess D, Bang H, Bozec A, Axmann R, Ossipova E, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest. 2012;122(5):1791–802.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Reinke S, Geissler S, Taylor WR, Schmidt-Bleek K, Juelke K, Schwachmeyer V, et al. Terminally differentiated CD8(+) T cells negatively affect bone regeneration in humans. Sci Transl Med. 2013;5(177):177ra36.PubMedCrossRefGoogle Scholar
  181. 181.
    Dighe AS, Yang S, Madhu V, Balian G, Cui Q. Interferon gamma and T cells inhibit osteogenesis induced by allogeneic mesenchymal stromal cells. J Orthop Res. 2013;31(2):227–34.PubMedCrossRefGoogle Scholar
  182. 182.
    Liu Y, Wang L, Kikuiri T, Akiyama K, Chen C, Xu X, et al. Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-gamma and TNF-alpha. Nat Med. 2011;17(12):1594–601.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Baboolal TG, Boxall SA, El-Sherbiny YM, Moseley TA, Cuthbert RJ, Giannoudis PV, et al. Multipotential stromal cell abundance in cellular bone allograft: comparison with fresh age-matched iliac crest bone and bone marrow aspirate. Regen Med. 2014;9(5):593–607.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Kerr 3rd EJ, Jawahar A, Wooten T, Kay S, Cavanaugh DA, Nunley PD. The use of osteo-conductive stem-cells allograft in lumbar interbody fusion procedures: an alternative to recombinant human bone morphogenetic protein. J Surg Orthop Adv. 2011;20(3):193–7.PubMedGoogle Scholar
  185. 185.
    Struijs PA, Poolman RW, Bhandari M. Infected nonunion of the long bones. J Orthop Trauma. 2007;21(7):507–11.PubMedCrossRefGoogle Scholar
  186. 186.
    Kayal RA, Siqueira M, Alblowi J, McLean J, Krothapalli N, Faibish D, et al. TNF-alpha mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO1. J Bone Miner Res. 2010;25(7):1604–15.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Alblowi J, Kayal RA, Siqueira M, McKenzie E, Krothapalli N, McLean J, et al. High levels of tumor necrosis factor-alpha contribute to accelerated loss of cartilage in diabetic fracture healing. Am J Pathol. 2009;175(4):1574–85.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13(2):156–63.PubMedCrossRefGoogle Scholar
  189. 189.
    Tsukasaki M, Yamada A, Suzuki D, Aizawa R, Miyazono A, Miyamoto Y, et al. Expression of POEM, a positive regulator of osteoblast differentiation, is suppressed by TNF-alpha. Biochem Biophys Res Commun. 2011;410(4):766–70.PubMedCrossRefGoogle Scholar
  190. 190.
    Kitaura H, Zhou P, Kim HJ, Novack DV, Ross FP, Teitelbaum SL. M-CSF mediates TNF-induced inflammatory osteolysis. J Clin Invest. 2005;115(12):3418–27.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Huang H, Zhao N, Xu X, Xu Y, Li S, Zhang J, et al. Dose-specific effects of tumor necrosis factor alpha on osteogenic differentiation of mesenchymal stem cells. Cell Prolif. 2011;44(5):420–7.PubMedCrossRefGoogle Scholar
  192. 192.
    Lacey DC, Simmons PJ, Graves SE, Hamilton JA. Proinflammatory cytokines inhibit osteogenic differentiation from stem cells: implications for bone repair during inflammation. Osteoarthritis Cartilage. 2009;17(6):735–42.PubMedCrossRefGoogle Scholar
  193. 193.
    Gao Y, Grassi F, Ryan MR, Terauchi M, Page K, Yang X, et al. IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. J Clin Invest. 2007;117(1):122–32.PubMedCrossRefGoogle Scholar
  194. 194.
    Axmann R, Bohm C, Kronke G, Zwerina J, Smolen J, Schett G. Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum. 2009;60(9):2747–56.PubMedCrossRefGoogle Scholar
  195. 195.
    Zwerina J, Redlich K, Polzer K, Joosten L, Kronke G, Distler J, et al. TNF-induced structural joint damage is mediated by IL-1. Proc Natl Acad Sci U S A. 2007;104(28):11742–7.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Fajardo M, Liu CJ, Egol K. Levels of expression for BMP-7 and several BMP antagonists may play an integral role in a fracture nonunion: a pilot study. Clin Orthop Relat Res. 2009;467(12):3071–8.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Hofmann A, Ritz U, Hessmann MH, Schmid C, Tresch A, Rompe JD, et al. Cell viability, osteoblast differentiation, and gene expression are altered in human osteoblasts from hypertrophic fracture non-unions. Bone. 2008;42(5):894–906.PubMedCrossRefGoogle Scholar
  198. 198.
    Chan JL, Tang KC, Patel AP, Bonilla LM, Pierobon N, Ponzio NM, et al. Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma. Blood. 2006;107(12):4817–24.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Li W, Ren G, Huang Y, Su J, Han Y, Li J, et al. Mesenchymal stem cells: a double-edged sword in regulating immune responses. Cell Death Differ. 2012;19(9):1505–13.PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Prigozhina TB, Khitrin S, Elkin G, Eizik O, Morecki S, Slavin S. Mesenchymal stromal cells lose their immunosuppressive potential after allotransplantation. Exp Hematol. 2008;36(10):1370–6.PubMedCrossRefGoogle Scholar
  201. 201.
    Okuno M, Muneta T, Koga H, Ozeki N, Nakagawa Y, Tsuji K, et al. Meniscus regeneration by syngeneic, minor mismatched, and major mismatched transplantation of synovial mesenchymal stem cells in a rat model. J Orthop Res. 2014;32(7):928–36.PubMedCrossRefGoogle Scholar
  202. 202.
    Isakova IA, Lanclos C, Bruhn J, Kuroda MJ, Baker KC, Krishnappa V, et al. Allo-reactivity of mesenchymal stem cells in rhesus macaques is dose and haplotype dependent and limits durable cell engraftment in vivo. PLoS One. 2014;9(1):e87238.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Reinders ME, Hoogduijn MJ. NK cells and MSCs: possible implications for MSC therapy in renal transplantation. J Stem Cell Res Ther. 2014;4(2):1000166.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Arinzeh TL, Peter SJ, Archambault MP, van den Bos C, Gordon S, Kraus K, et al. Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect. J Bone Joint Surg Am. 2003;85-A(10):1927–35.PubMedGoogle Scholar
  205. 205.
    Guo SQ, Xu JZ, Zou QM, Jiang DM. Immunological study of allogeneic mesenchymal stem cells during bone formation. J Int Med Res. 2009;37(6):1750–9.PubMedCrossRefGoogle Scholar
  206. 206.
    Udehiya RK, Amarpal, Aithal HP, Kinjavdekar P, Pawde AM, Singh R, et al. Comparison of autogenic and allogenic bone marrow derived mesenchymal stem cells for repair of segmental bone defects in rabbits. Res Vet Sci. 2013;94(3):743–52.PubMedCrossRefGoogle Scholar
  207. 207.
    Streckbein P, Jackel S, Malik CY, Obert M, Kahling C, Wilbrand JF, et al. Reconstruction of critical-size mandibular defects in immunoincompetent rats with human adipose-derived stromal cells. J Craniomaxillofac Surg. 2013;41(6):496–503.PubMedCrossRefGoogle Scholar
  208. 208.
    Gu H, Xiong Z, Yin X, Li B, Mei N, Li G, et al. Bone regeneration in a rabbit ulna defect model: use of allogeneic adipose-derived stem cells with low immunogenicity. Cell Tissue Res. 2014;358(2):453–64.PubMedCrossRefGoogle Scholar
  209. 209.
    Xie F, Teng L, Wang Q, Sun XJ, Cai L, Zeng HF, et al. Ectopic osteogenesis of allogeneic bone mesenchymal stem cells loading on beta-tricalcium phosphate in canines. Plast Reconstr Surg. 2014;133(2):142e–53.PubMedCrossRefGoogle Scholar
  210. 210.
    Chen L, Tredget EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008;3(4):e1886.PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Mountziaris PM, Spicer PP, Kasper FK, Mikos AG. Harnessing and modulating inflammation in strategies for bone regeneration. Tissue Eng Part B Rev. 2011;17(6):393–402.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Jehan J. El-Jawhari
    • 1
    • 2
  • Elena Jones
    • 1
    • 2
  • Dennis McGonagle
    • 1
    • 2
  • Peter V. Giannoudis
    • 1
    • 2
  1. 1.Leeds Institute of Rheumatic and Musculoskeletal Medicine, St. James University HospitalUniversity of LeedsLeedsUK
  2. 2.NIHR, Leeds Biomedical Research Unit, Chapel Allerton HospitalUniversity of LeedsLeedsUK

Personalised recommendations