International Orthopaedics

, Volume 37, Issue 12, pp 2491–2498 | Cite as

Role of mesenchymal stem cells in bone regeneration and fracture repair: a review

  • Xin Wang
  • Yu Wang
  • Wenlong Gou
  • Qiang Lu
  • Jiang Peng
  • Shibi Lu
Review Article


Mesenchymal stem cells (MSCs) are non-haematopoietic stromal stem cells that have many sources, such as bone marrow, periosteum, vessel walls, adipose, muscle, tendon, peripheral circulation, umbilical cord blood, skin and dental tissues. They are capable of self-replication and of differentiating into, and contributing to the regeneration of, mesenchymal tissues, such as bone, cartilage, ligament, tendon, muscle and adipose tissue. The homing of MSCs may play an important role in the repair of bone fractures. As a composite material, the formation and growth of bone tissue is a complex process, including molecular, cell and biochemical metabolic changes. The recruitment of factors with an adequate number of MSCs and the micro-environment around the fracture are effective for fracture repair. Several studies have investigated the functional expression of various chemokine receptors, trophic factors and adhesion molecules in human MSCs. Many external factors affect MSC homing. MSCs have been used as seed cells in building tissue-engineered bone grafts. Scaffolds seeded with MSCs are most often used in tissue engineering and include biotic and abiotic materials. This knowledge provides a platform for the development of novel therapies for bone regeneration with endogenous MSCs.


Mesenchymal stem cells Homing Chemotaxis Differentiation Bone fracture 



This study was supported by a Grant from the National Technology Research and Development Program of China (2012 AA020502,2012CB518106, BWS11J025), NSFC (8107458,31240048,30930092). We thank Xiaolong Xu for technical support with the imaging work.

Conflict of interest



  1. 1.
    Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822PubMedCrossRefGoogle Scholar
  2. 2.
    Aghaloo T, Jiang X, Soo C et al (2007) A study of the role of nell-1 gene modified goat bone marrow stromal cells in promoting new bone formation. Mol Ther 15:1872–1880PubMedCrossRefGoogle Scholar
  3. 3.
    Bai Y, Li P, Yin G et al (2013) BMP-2, VEGF and bFGF synergistically promote the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells. Biotechnol Lett 35:301–308PubMedCrossRefGoogle Scholar
  4. 4.
    Battula VL, Bareiss PM, Treml S et al (2007) Human placenta and bone marrow derived MSC cultured in serum-free, b-FGF-containing medium express cell surface frizzled-9 and SSEA-4 and give rise to multilineage differentiation. Differentiation 75:279–291PubMedCrossRefGoogle Scholar
  5. 5.
    Bi Y, Ehirchiou D, Kilts TM et al (2007) Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med 13:1219–1227PubMedCrossRefGoogle Scholar
  6. 6.
    Brighton CT, Krebs AG (1972) Oxygen tension of healing fractures in the rabbit. J Bone Joint Surg Am 54:323–332PubMedGoogle Scholar
  7. 7.
    Bruder SP, Kurth AA, Shea M et al (1998) Bone regeneration by implantation of purified, culture-expanded human mesenchymal stem cells. J Orthop Res 16:155–162PubMedCrossRefGoogle Scholar
  8. 8.
    Buijs JT, Henriquez NV, van Overveld PG et al (2007) TGF-beta and BMP7 interactions in tumour progression and bone metastasis. Clin Exp Metastasis 24:609–617PubMedCrossRefGoogle Scholar
  9. 9.
    Calori GM, Giannoudis PV (2011) Enhancement of fracture healing with the diamond concept: the role of the biological chamber. Injury 42:1191–1193PubMedCrossRefGoogle Scholar
  10. 10.
    Caplan AI (1991) Mesenchymal stem cells. J Orthop Res 9:641–650PubMedCrossRefGoogle Scholar
  11. 11.
    Chen WJ, Jingushi S, Aoyama I et al (2004) Effects of FGF-2 on metaphyseal fracture repair in rabbit tibiae. J Bone Miner Metab 22:303–309PubMedCrossRefGoogle Scholar
  12. 12.
    Colnot C (2009) Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration. J Bone Miner Res 24:274–282PubMedCrossRefGoogle Scholar
  13. 13.
    D’Amelio P, Cristofaro MA, Grimaldi A et al (2010) The role of circulating bone cell precursors in fracture healing. Calcif Tissue Int 86:463–469PubMedCrossRefGoogle Scholar
  14. 14.
    D’Ippolito G, Schiller PC, Ricordi C et al (1999) Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow. J Bone Miner Res 14:1115–1122PubMedCrossRefGoogle Scholar
  15. 15.
    da Silva ML, Sand TT, Harman RJ et al (2009) MSC frequency correlates with blood vessel density in equine adipose tissue. Tissue Eng Part A 15:221–229CrossRefGoogle Scholar
  16. 16.
    Di Bernardo G, Galderisi U, Fiorito C et al (2010) Dual role of parathyroid hormone in endothelial progenitor cells and marrow stromal mesenchymal stem cells. J Cell Physiol 222:474–480PubMedCrossRefGoogle Scholar
  17. 17.
    Dimitriou R, Tsiridis E, Giannoudis PV (2005) Current concepts of molecular aspects of bone healing. Injury 36:1392–1404PubMedCrossRefGoogle Scholar
  18. 18.
    Farrington-Rock C, Crofts NJ, Doherty MJ et al (2004) Chondrogenic and adipogenic potential of microvascular pericytes. Circulation 110:2226–2232PubMedCrossRefGoogle Scholar
  19. 19.
    Gamradt SC, Abe N, Bahamonde ME et al (2006) Tracking expression of virally mediated BMP-2 in gene therapy for bone repair. Clin Orthop Relat Res 450:238–245PubMedCrossRefGoogle Scholar
  20. 20.
    Gamradt SC, Lieberman JR (2004) Genetic modification of stem cells to enhance bone repair. Ann Biomed Eng 32:136–147PubMedCrossRefGoogle Scholar
  21. 21.
    Gao J, Dennis JE, Muzic RF et al (2001) The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 169:12–20PubMedCrossRefGoogle Scholar
  22. 22.
    Genetos DC, Toupadakis CA, Raheja LF et al (2010) Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts. J Cell Biochem 110:457–467PubMedGoogle Scholar
  23. 23.
    Giannelli M, Chellini F, Sassoli C et al (2013) Photoactivation of bone marrow mesenchymal stromal cells with diode laser: effects and mechanisms of action. J Cell Physiol 228:172–181PubMedCrossRefGoogle Scholar
  24. 24.
    Giannoudis PV, Einhorn TA, Marsh D (2007) Fracture healing: the diamond concept. Injury 38(Suppl 4):S3–S6CrossRefGoogle Scholar
  25. 25.
    Granero-Moltó F, Weis JA, Miga MI et al (2009) Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells 27:1887–1898PubMedCrossRefGoogle Scholar
  26. 26.
    Griffin M, Iqbal SA, Sebastian A et al (2011) Degenerate wave and capacitive coupling increase human MSC invasion and proliferation while reducing cytotoxicity in an in vitro wound healing model. PLoS One 6:e23404PubMedCrossRefGoogle Scholar
  27. 27.
    Gu Q, Cai Y, Huang C et al (2012) Curcumin increases rat mesenchymal stem cell osteoblast differentiation but inhibits adipocyte differentiation. Pharmacogn Mag 8:202–208PubMedGoogle Scholar
  28. 28.
    Hoffmann A, Gross G (2007) Tendon and ligament engineering in the adult organism: mesenchymal stem cells and gene-therapeutic approaches. Int Orthop 31:791–797PubMedCrossRefGoogle Scholar
  29. 29.
    Honczarenko M, Le Y, Swierkowski M et al (2006) Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells 24:1030–1041PubMedCrossRefGoogle Scholar
  30. 30.
    Horwitz EM, Gordon PL, Koo WK et al (2002) Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc Natl Acad Sci U S A 99:8932–8937PubMedCrossRefGoogle Scholar
  31. 31.
    Huang XP, Sun Z, Miyagi Y et al (2010) Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair. Circulation 122:2419–2429PubMedCrossRefGoogle Scholar
  32. 32.
    Hui CF, Chan CW, Yeung HY et al (2011) Low-intensity pulsed ultrasound enhances posterior spinal fusion implanted with mesenchymal stem cells-calcium phosphate composite without bone grafting. Spine (Phila Pa 1976) 36:1010–1016Google Scholar
  33. 33.
    Ivkovic A, Marijanovic I, Hudetz D et al (2011) Regenerative medicine and tissue engineering in orthopaedic surgery. Front Biosci (Elite Ed) 3:923–944Google Scholar
  34. 34.
    Javazon EH, Beggs KJ, Flake AW (2004) Mesenchymal stem cells: paradoxes of passaging. Exp Hematol 32:414–425PubMedCrossRefGoogle Scholar
  35. 35.
    Jones EA, English A, Henshaw K et al (2004) Enumeration and phenotypic characterization of synovial fluid multipotential mesenchymal progenitor cells in inflammatory and degenerative arthritis. Arthritis Rheum 50:817–827PubMedCrossRefGoogle Scholar
  36. 36.
    Kawate K, Yajima H, Ohgushi H et al (2006) Tissue-engineered approach for the treatment of steroid-induced osteonecrosis of the femoral head: transplantation of autologous mesenchymal stem cells cultured with beta-tricalcium phosphate ceramics and free vascularized fibula. Artif Organs 30:960–962PubMedCrossRefGoogle Scholar
  37. 37.
    Kim SH, Kim YS, Lee SY et al (2011) Gene expression profile in mesenchymal stem cells derived from dental tissues and bone marrow. J Periodontal Implant Sci 41:192–200PubMedCrossRefGoogle Scholar
  38. 38.
    Kitaori T, Ito H, Schwarz EM et al (2009) 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 60:813–823PubMedCrossRefGoogle Scholar
  39. 39.
    Klyushnenkova E, Mosca JD, Zernetkina V et al (2005) T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci 12:47–57PubMedCrossRefGoogle Scholar
  40. 40.
    Kodama A, Kamei N, Kamei G et al (2012) In vivo bioluminescence imaging of transplanted bone marrow mesenchymal stromal cells using a magnetic delivery system in a rat fracture model. J Bone Joint Surg Br 94:998–1006PubMedGoogle Scholar
  41. 41.
    Kotobuki N, Katsube Y, Katou Y et al (2008) In vivo survival and osteogenic differentiation of allogeneic rat bone marrow mesenchymal stem cells (MSCs). Cell Transplant 17:705–712PubMedCrossRefGoogle Scholar
  42. 42.
    Kumagai K, Vasanji A, Drazba JA et al (2008) Circulating cells with osteogenic potential are physiologically mobilized into the fracture healing site in the parabiotic mice model. J Orthop Res 26:165–175PubMedCrossRefGoogle Scholar
  43. 43.
    Lavoie JF, Biernaskie JA, Chen Y et al (2009) Skin-derived precursors differentiate into skeletogenic cell types and contribute to bone repair. Stem Cells Dev 18:893–906PubMedCrossRefGoogle Scholar
  44. 44.
    Lee OK, Kuo TK, Chen WM et al (2004) Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 103:1669–1675PubMedCrossRefGoogle Scholar
  45. 45.
    Liu C, Chen Z, Zhang T et al (2006) Multiple tumor types may originate from bone marrow-derived cells. Neoplasia 8:716–724PubMedCrossRefGoogle Scholar
  46. 46.
    Lu SS, Zhang X, Soo C et al (2007) The osteoinductive properties of Nell-1 in a rat spinal fusion model. Spine J 7:50–60PubMedCrossRefGoogle Scholar
  47. 47.
    Ma X, Zhang X, Jia Y et al (2013) Dexamethasone induces osteogenesis via regulation of hedgehog signalling molecules in rat mesenchymal stem cells. Int Orthop 37:1399–1404PubMedCrossRefGoogle Scholar
  48. 48.
    Mendelson A, Frank E, Allred C et al (2011) Chondrogenesis by chemotactic homing of synovium, bone marrow, and adipose stem cells in vitro. FASEB J 25:3496–3504PubMedCrossRefGoogle Scholar
  49. 49.
    Myers TJ, Yan Y, Granero-Molto F et al (2012) Systemically delivered insulin-like growth factor-I enhances mesenchymal stem cell-dependent fracture healing. Growth Factors 30:230–241PubMedCrossRefGoogle Scholar
  50. 50.
    Nakahara H, Goldberg VM, Caplan AI (1991) Culture-expanded human periosteal-derived cells exhibit osteochondral potential in vivo. J Orthop Res 9:465–476PubMedCrossRefGoogle Scholar
  51. 51.
    Nohmi S, Yamamoto Y, Mizukami H et al (2012) Post injury changes in the properties of mesenchymal stem cells derived from human anterior cruciate ligaments. Int Orthop 36:1515–1522PubMedCrossRefGoogle Scholar
  52. 52.
    Nunes SP, Galembeck F (1985) Percoll and Ficoll self-generated density gradients by low-speed osmocentrifugation. Anal Biochem 146:48–51PubMedCrossRefGoogle Scholar
  53. 53.
    Ode A, Kopf J, Kurtz A et al (2011) CD73 and CD29 concurrently mediate the mechanically induced decrease of migratory capacity of mesenchymal stromal cells. Eur Cell Mater 22:26–42PubMedGoogle Scholar
  54. 54.
    Otto WR, Rao J (2004) Tomorrow’s skeleton staff: mesenchymal stem cells and the repair of bone and cartilage. Cell Prolif 37:97–110PubMedCrossRefGoogle Scholar
  55. 55.
    Raheja LF, Genetos DC, Yellowley CE (2010) The effect of oxygen tension on the long-term osteogenic differentiation and MMP/TIMP expression of human mesenchymal stem cells. Cells Tissues Organs 191:175–184PubMedCrossRefGoogle Scholar
  56. 56.
    Rodríguez-Lozano FJ, Bueno C, Insausti CL et al (2011) Mesenchymal stem cells derived from dental tissues. Int Endod J 44:800–806PubMedCrossRefGoogle Scholar
  57. 57.
    Rombouts WJ, Ploemacher RE (2003) Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia 17:160–170PubMedCrossRefGoogle Scholar
  58. 58.
    Rubin C, Turner AS, Bain S et al (2001) Anabolism. Low mechanical signals strengthen long bones. Nature 412:603–604PubMedCrossRefGoogle Scholar
  59. 59.
    Rui YF, Lui PP, Lee YW et al (2012) Higher BMP receptor expression and BMP-2-induced osteogenic differentiation in tendon-derived stem cells compared with bone-marrow-derived mesenchymal stem cells. Int Orthop 36:1099–1107PubMedCrossRefGoogle Scholar
  60. 60.
    Scadden DT (2006) The stem-cell niche as an entity of action. Nature 441:1075–1079PubMedCrossRefGoogle Scholar
  61. 61.
    Schindeler A, McDonald MM, Bokko P et al (2008) Bone remodeling during fracture repair: the cellular picture. Semin Cell Dev Biol 19:459–466PubMedCrossRefGoogle Scholar
  62. 62.
    Schrepfer S, Deuse T, Reichenspurner H et al (2007) Stem cell transplantation: the lung barrier. Transplant Proc 39:573–576PubMedCrossRefGoogle Scholar
  63. 63.
    Schuh EM, Friedman MS, Carrade DD et al (2009) Identification of variables that optimize isolation and culture of multipotent mesenchymal stem cells from equine umbilical-cord blood. Am J Vet Res 70:1526–1535PubMedCrossRefGoogle Scholar
  64. 64.
    Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88:1474–1480PubMedGoogle Scholar
  65. 65.
    Shinohara K, Greenfield S, Pan H et al (2011) Stromal cell-derived factor-1 and monocyte chemotactic protein-3 improve recruitment of osteogenic cells into sites of musculoskeletal repair. J Orthop Res 29:1064–1069PubMedCrossRefGoogle Scholar
  66. 66.
    Siu RK, Lu SS, Li W et al (2011) Nell-1 protein promotes bone formation in a sheep spinal fusion model. Tissue Eng Part A 17:1123–1135PubMedCrossRefGoogle Scholar
  67. 67.
    Takeuchi M, Takeuchi K, Kohara A et al (2007) Chromosomal instability in human mesenchymal stem cells immortalized with human papilloma virus E6, E7, and hTERT genes. In Vitro Cell Dev Biol Anim 43:129–138PubMedCrossRefGoogle Scholar
  68. 68.
    Tian LL, Yue W, Zhu F et al (2011) Human mesenchymal stem cells play a dual role on tumor cell growth in vitro and in vivo. J Cell Physiol 226:1860–1867PubMedCrossRefGoogle Scholar
  69. 69.
    Tintut Y, Alfonso Z, Saini T et al (2003) Multilineage potential of cells from the artery wall. Circulation 108:2505–2510PubMedCrossRefGoogle Scholar
  70. 70.
    Toupadakis CA, Wong A, Genetos DC et al (2012) Long-term administration of AMD3100, an antagonist of SDF-1/CXCR4 signaling, alters fracture repair. J Orthop Res 30:1853–1859PubMedCrossRefGoogle Scholar
  71. 71.
    Tsai MT, Lin DJ, Huang S et al (2012) Osteogenic differentiation is synergistically influenced by osteoinductive treatment and direct cell-cell contact between murine osteoblasts and mesenchymal stem cells. Int Orthop 36:199–205PubMedCrossRefGoogle Scholar
  72. 72.
    Ueno M, Urabe K, Naruse K et al (2011) Influence of internal fixator stiffness on murine fracture healing: two types of fracture healing lead to two distinct cellular events and FGF-2 expressions. Exp Anim 60:79–87PubMedCrossRefGoogle Scholar
  73. 73.
    Usas A, Huard J (2007) Muscle-derived stem cells for tissue engineering and regenerative therapy. Biomaterials 28:5401–5406PubMedCrossRefGoogle Scholar
  74. 74.
    Weaver AS, Su YP, Begun DL et al (2010) The effects of axial displacement on fracture callus morphology and MSC homing depend on the timing of application. Bone 47:41–48PubMedCrossRefGoogle Scholar
  75. 75.
    Wislet-Gendebien S, Poulet C, Neirinckx V et al (2012) In vivo tumorigenesis was observed after injection of in vitro expanded neural crest stem cells isolated from adult bone marrow. PLoS One 7:e46425PubMedCrossRefGoogle Scholar
  76. 76.
    Wynn RF, Hart CA, Corradi-Perini C et al (2004) A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood 104:2643–2645PubMedCrossRefGoogle Scholar
  77. 77.
    Xia L, Xu Y, Chang Q et al (2011) Maxillary sinus floor elevation using BMP-2 and Nell-1 gene-modified bone marrow stromal cells and TCP in rabbits. Calcif Tissue Int 89:53–64PubMedCrossRefGoogle Scholar
  78. 78.
    Xue J, Peng J, Yuan M et al (2011) NELL1 promotes high-quality bone regeneration in rat femoral distraction osteogenesis model. Bone 48:485–495PubMedCrossRefGoogle Scholar
  79. 79.
    Yu Z, Zhu T, Li C et al (2012) Improvement of intertrochanteric bone quality in osteoporotic female rats after injection of polylactic acid-polyglycolic acid copolymer/collagen type I microspheres combined with bone mesenchymal stem cells. Int Orthop 36:2163–2171PubMedCrossRefGoogle Scholar
  80. 80.
    Zangi L, Margalit R, Reich-Zeliger S et al (2009) Direct imaging of immune rejection and memory induction by allogeneic mesenchymal stromal cells. Stem Cells 27:2865–2874PubMedCrossRefGoogle Scholar
  81. 81.
    Zhang X, Zara J, Siu RK et al (2010) The role of NELL-1, a growth factor associated with craniosynostosis, in promoting bone regeneration. J Dent Res 89:865–878PubMedCrossRefGoogle Scholar
  82. 82.
    Zhang Y, Wang F, Chen J et al (2012) Bone marrow-derived mesenchymal stem cells versus bone marrow nucleated cells in the treatment of chondral defects. Int Orthop 36:1079–1086PubMedCrossRefGoogle Scholar
  83. 83.
    Zhao Z, Watt C, Karystinou A et al (2011) Directed migration of human bone marrow mesenchymal stem cells in a physiological direct current electric field. Eur Cell Mater 22:344–358PubMedGoogle Scholar
  84. 84.
    Zhi L, Chen C, Pang X et al (2011) Synergistic effect of recombinant human bone morphogenic protein-7 and osteogenic differentiation medium on human bone-marrow-derived mesenchymal stem cells in vitro. Int Orthop 35:1889–1895PubMedCrossRefGoogle Scholar
  85. 85.
    Zhu H, Liu YL, Chen JD et al (2012) Effect of osteogenically and adipogenically differentiated bone mesenchymal stem cells from mouse on osteoclast formation. Zhongguo Shi Yan Xue Ye Xue Za Zhi 20:1187–1190PubMedGoogle Scholar
  86. 86.
    Zhu S, Song D, Jiang X et al (2011) Combined effects of recombinant human BMP-2 and Nell-1 on bone regeneration in rapid distraction osteogenesis of rabbit tibia. Injury 42:1467–1473PubMedCrossRefGoogle Scholar
  87. 87.
    Zuk PA, Zhu M, Ashjian P et al (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13:4279–4295PubMedCrossRefGoogle Scholar
  88. 88.
    Zuo Q, Cui W, Liu F et al (2013) Co-cultivated mesenchymal stem cells support chondrocytic differentiation of articular chondrocytes. Int Orthop 37:747–752PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Xin Wang
    • 1
  • Yu Wang
    • 1
  • Wenlong Gou
    • 1
  • Qiang Lu
    • 1
  • Jiang Peng
    • 1
  • Shibi Lu
    • 1
  1. 1.Key Laboratory of Peoples Liberation Army, Institute of OrthopedicsChinese PLA General HospitalBeijingPeople’s Republic of China

Personalised recommendations