Bone Marrow Mesenchymal Cells: How Do They Contribute to Tissue Repair and Are They Really Stem Cells?

  • Yasumasa Kuroda
  • Masaaki Kitada
  • Shohei Wakao
  • Mari Dezawa


Adult stem cells typically generate the cell types of the tissue in which they reside, and thus the range of their differentiation is considered limited. Bone marrow mesenchymal stem cells (MSCs) are different from other somatic stem cells in that they differentiate not only into the same mesodermal-lineage such as bone, cartilage, and adipocytes but also into other lineages of ectodermal and endodermal cells. Thus, MSCs are a unique type of adult stem cells. In addition, MSCs home to damaged sites, differentiate into cells specific to the tissue and contribute to tissue repair. Therefore, application of MSCs in the treatment of various diseases, including liver dysfunction, myocardial infarction, and central nervous system repair, has been initiated. Because MSCs are generally harvested as adherent cells from bone marrow aspirates, however, they comprise heterogeneous cell populations and their wide-ranging differentiation ability and repair functions are not yet clear. Recent evidence suggests that a very small subpopulation of cells that assume a repair function with the ability to differentiate into trilineage cells resides among human MSCs and effective utilization of such cells is expected to improve the repair effect of MSCs. This review summarizes recent advances in the clarification of MSC properties and discusses future perspectives.


Mesenchymal stem cells Adult stem cells Transdifferenitation Cytokines Repair 



This work was supported by the Japan New Energy and Industrial Technology Development Organization (NEDO) and Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO).


  1. Adas G, Arikan S, Karatepe O et al (2011) Mesenchymal stem cells improve the healing of ischemic colonic anastomoses (experimental study). Langenbecks Arch Surg 396:115–126PubMedCrossRefGoogle Scholar
  2. Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM et al (2003) Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425:968–973PubMedCrossRefGoogle Scholar
  3. Bianco P, Gehron Robey P (2000) Marrow stromal stem cells. J Clin Invest 105:1663–1668PubMedCrossRefGoogle Scholar
  4. Caplan AI (1991) Mesenchymal stem cells. J Orthop Res 9:641–650PubMedCrossRefGoogle Scholar
  5. Charbord P (2010) Bone marrow mesenchymal stem cells: historical overview and concepts. Hum Gene Ther 21:1045–1056PubMedCrossRefGoogle Scholar
  6. Chen J, Li Y, Katakowski M et al (2003) Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 73:778–786PubMedCrossRefGoogle Scholar
  7. Chino T, Tamai K, Yamazaki T et al (2008) Bone marrow cell transfer into fetal circulation can ameliorate genetic skin diseases by providing fibroblasts to the skin and inducing immune tolerance. Am J Pathol 173:803–814PubMedCrossRefGoogle Scholar
  8. Chopp M, Zhang XH, Li Y et al (2000) Spinal cord injury in rat: treatment with bone marrow stromal cell transplantation. Neuroreport 11:3001–3005PubMedCrossRefGoogle Scholar
  9. Crigler L, Robey RC, Asawachaicharn A et al (2006) Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol 198:54–64PubMedCrossRefGoogle Scholar
  10. de la Garza-Rodea AS, van der Velde I, Boersma H et al (2011) Long-term contribution of human bone marrow mesenchymal stromal cells to skeletal muscle regeneration in mice. Cell Transplant 20:217–231CrossRefGoogle Scholar
  11. Dezawa M, Ishikawa H, Itokazu Y et al (2005) Bone marrow stromal cells generate muscle cells and repair muscle degeneration. Science 309:314–317PubMedCrossRefGoogle Scholar
  12. Dezawa M, Kanno H, Hoshino M et al (2004) Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest 113:1701–1710PubMedGoogle Scholar
  13. Dezawa M, Takahashi I, Esaki M et al (2001) Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone-marrow stromal cells. Eur J Neurosci 14:1771–1776PubMedCrossRefGoogle Scholar
  14. D’Ippolito G, Diabira S, Howard GA et al (2004) Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. J Cell Sci 117(Pt 14):2971–2981PubMedCrossRefGoogle Scholar
  15. Fan CG, Zhang QJ, Zhou JR (2011) Therapeutic potentials of mesenchymal stem cells derived from human umbilical cord. Stem Cell Rev 7:195–207PubMedCrossRefGoogle Scholar
  16. Ferrari D, Gulinelli S, Salvestrini V et al (2011) Purinergic stimulation of human mesenchymal stem cells potentiates their chemotactic response to CXCL12 and increases the homing capacity and production of proinflammatory cytokines. Exp Hematol 39:360–374.e1−5Google Scholar
  17. Ferrari G, Cusella-De Angelis G, Coletta M et al (1998) Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279:1528–1530PubMedCrossRefGoogle Scholar
  18. Friedenstein AJ, Chailakhjan RK, Lalykina KS (1970) The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3:393–403PubMedGoogle Scholar
  19. Friedenstein AJ, Petrakova KV, Kurolesova AI et al (1968) Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6:230–247PubMedCrossRefGoogle Scholar
  20. Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438PubMedCrossRefGoogle Scholar
  21. Gilchrist ES, Plevris JN (2010) Bone marrow-derived stem cells in liver repair: 10 years down the line. Liver Transpl 16:118–129PubMedCrossRefGoogle Scholar
  22. Gnecchi M, He H, Noiseux N et al (2006) Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 20:661–669PubMedCrossRefGoogle Scholar
  23. Gordon MY, Levicar N, Pai M et al (2006) Characterization and clinical application of human CD34+ stem/progenitor cell populations mobilized into the blood by granulocyte colony-stimulating factor. Stem Cells 24:1822–1830PubMedCrossRefGoogle Scholar
  24. Grove DA, Xu J, Joodi R et al (2011) Attenuation of early airway obstruction by mesenchymal stem cells in a murine model of heterotopic tracheal transplantation. J Heart Lung Transplant 30:341–350PubMedCrossRefGoogle Scholar
  25. Harris RG, Herzog EL, Bruscia EM et al (2004) Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 305:90–93PubMedCrossRefGoogle Scholar
  26. He X, Ma J, Jabbari E (2010) Migration of marrow stromal cells in response to sustained release of stromal-derived factor-1alpha from poly(lactide ethylene oxide fumarate) hydrogels. Int J Pharm 390:107–116PubMedCrossRefGoogle Scholar
  27. Hong HS, Lee J, Lee E et al (2009) A new role of substance P as an injury-inducible messenger for mobilization of CD29(+) stromal-like cells. Nat Med 15:425–435PubMedCrossRefGoogle Scholar
  28. Horwitz EM, Le Blanc K, Dominici M et al (2005) Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy 7:393–395PubMedCrossRefGoogle Scholar
  29. Horwitz EM, Prockop DJ, Fitzpatrick LA et al (1999) Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5:309–313PubMedCrossRefGoogle Scholar
  30. Jiang Y, Jahagirdar BN, Reinhardt RL et al (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49PubMedCrossRefGoogle Scholar
  31. 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
  32. Korbling M, Estrov Z (2003) Adult stem cells for tissue repair—a new therapeutic concept? N Engl J Med 349:570–582PubMedCrossRefGoogle Scholar
  33. Kucia M, Reca R, Campbell FR et al (2006) A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct–4 + stem cells identified in adult bone marrow. Leukemia 20:857–869PubMedCrossRefGoogle Scholar
  34. Kuroda Y, Kitada M, Wakao S et al (2010) Unique multipotent cells in adult human mesenchymal cell populations. Proc Natl Acad Sci USA 107:8639–8643PubMedCrossRefGoogle Scholar
  35. Kuznetsov SA, Mankani MH, Gronthos S et al (2001) Circulating skeletal stem cells. J Cell Biol 153:1133–1140PubMedCrossRefGoogle Scholar
  36. Kuznetsov SA, Mankani MH, Leet AI et al (2007) Circulating connective tissue precursors: extreme rarity in humans and chondrogenic potential in guinea pigs. Stem Cells 25:1830–1839PubMedCrossRefGoogle Scholar
  37. Lapidot T, Petit I (2002) Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp Hematol 30:973–981PubMedCrossRefGoogle Scholar
  38. Li Y, Chopp M, Chen J et al (2000) Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. J Cereb Blood Flow Metab 20:1311–1319PubMedCrossRefGoogle Scholar
  39. Liu H, Xue W, Ge G et al (2010) Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1alpha in MSCs. Biochem Biophys Res Commun 401:509–515PubMedCrossRefGoogle Scholar
  40. Makino S, Fukuda K, Miyoshi S et al (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103:697–705PubMedCrossRefGoogle Scholar
  41. Markel TA, Wang Y, Herrmann JL et al (2008) VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function. Am J Physiol Heart Circ Physiol 295:H2308–H2314PubMedCrossRefGoogle Scholar
  42. Meng E, Guo Z, Wang H et al (2008) High mobility group box 1 protein inhibits the proliferation of human mesenchymal stem cells and promotes their migration and differentiation along osteoblastic pathway. Stem Cells Dev 17:805–813PubMedCrossRefGoogle Scholar
  43. Mezey E, Chandross KJ, Harta G et al (2000) Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290:1779–1782PubMedCrossRefGoogle Scholar
  44. Misao Y, Takemura G, Arai M et al (2006) Bone marrow-derived myocyte-like cells and regulation of repair-related cytokines after bone marrow cell transplantation. Cardiovasc Res 69:476–490PubMedCrossRefGoogle Scholar
  45. Molyneaux KA, Zinszner H, Kunwar PS et al (2003) The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival. Development 130:4279–4286PubMedCrossRefGoogle Scholar
  46. Niedzwiedzki T, Dabrowski Z, Miszta H et al (1993) Bone healing after bone marrow stromal cell transplantation to the bone defect. Biomaterials 14:115–121PubMedCrossRefGoogle Scholar
  47. Orlic D, Kajstura J, Chimenti S et al (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410:701–705PubMedCrossRefGoogle Scholar
  48. Oswald J, Boxberger S, Jorgensen B et al (2004) Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 22:377–384PubMedCrossRefGoogle Scholar
  49. Owen ME, Cave J, Joyner CJ (1987) Clonal analysis in vitro of osteogenic differentiation of marrow CFU-F. J Cell Sci 87(Pt 5):731–738PubMedGoogle Scholar
  50. Oyagi S, Hirose M, Kojima M et al (2006) Therapeutic effect of transplanting HGF-treated bone marrow mesenchymal cells into CCl4-injured rats. J Hepatol 44:742–748PubMedCrossRefGoogle Scholar
  51. Park HC, Shim YS, Ha Y et al (2005) Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte-macrophage colony stimulating factor. Tissue Eng 11:913–922PubMedCrossRefGoogle Scholar
  52. Parr AM, Tator CH, Keating A (2007) Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant 40:609–619PubMedCrossRefGoogle Scholar
  53. Petersen BE, Bowen WC, Patrene KD et al (1999) Bone marrow as a potential source of hepatic oval cells. Science 284:1168–1170PubMedCrossRefGoogle Scholar
  54. Philp D, Nguyen M, Scheremeta B et al (2004) Thymosin beta4 increases hair growth by activation of hair follicle stem cells. FASEB J 18:385–387PubMedGoogle Scholar
  55. Phinney DG (2007) Biochemical heterogeneity of mesenchymal stem cell populations: clues to their therapeutic efficacy. Cell Cycle 6:2884–2889PubMedCrossRefGoogle Scholar
  56. Phinney DG, Prockop DJ (2007) Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair–current views. Stem Cells 25:2896–2902PubMedCrossRefGoogle Scholar
  57. Pittenger MF, Mackay AM, Beck SC et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147PubMedCrossRefGoogle Scholar
  58. Prindull G, Zipori D (2004) Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood 103:2892–2899PubMedCrossRefGoogle Scholar
  59. Prockop DJ (1997) Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276:71–74PubMedCrossRefGoogle Scholar
  60. Qiu J, Nishimura M, Wang Y et al (2008) Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 28:927–938PubMedCrossRefGoogle Scholar
  61. Rogers LC, Bevilacqua NJ, Armstrong DG (2008) The use of marrow-derived stem cells to accelerate healing in chronic wounds. Int Wound J 5:20–25PubMedCrossRefGoogle Scholar
  62. Schachinger V, Assmus B, Erbs S et al (2009) Intracoronary infusion of bone marrow-derived mononuclear cells abrogates adverse left ventricular remodelling post-acute myocardial infarction: insights from the reinfusion of enriched progenitor cells and infarct remodelling in acute myocardial infarction (REPAIR-AMI) trial. Eur J Heart Fail 11:973–979PubMedCrossRefGoogle Scholar
  63. Snykers S, De Kock J, Rogiers V et al (2009) In vitro differentiation of embryonic and adult stem cells into hepatocytes: state of the art. Stem Cells 27:577–605PubMedCrossRefGoogle Scholar
  64. Spees JL, Olson SD, Ylostalo J et al (2003) Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci USA 100:2397–2402PubMedCrossRefGoogle Scholar
  65. Takashima Y, Era T, Nakao K et al (2007) Neuroepithelial cells supply an initial transient wave of MSC differentiation. Cell 129:1377–1388PubMedCrossRefGoogle Scholar
  66. Terada N, Hamazaki T, Oka M et al (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416:542–545PubMedCrossRefGoogle Scholar
  67. Terai S, Sakaida I, Yamamoto N et al (2003) An in vivo model for monitoring trans-differentiation of bone marrow cells into functional hepatocytes. J Biochem 134:551–558PubMedCrossRefGoogle Scholar
  68. Terai S, Yamamoto N, Omori K et al (2002) A new cell therapy using bone marrow cells to repair damaged liver. J Gastroenterol 37(suppl 14):162–163PubMedGoogle Scholar
  69. Thomas ED (2000) Landmarks in the development of hematopoietic cell transplantation. World J Surg 24:815–818PubMedCrossRefGoogle Scholar
  70. Till JE, McCulloch CE (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–222PubMedCrossRefGoogle Scholar
  71. Tolar J, Le Blanc K, Keating A et al (2010) Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells 28:1446–1455PubMedCrossRefGoogle Scholar
  72. Vallabhaneni KC, Tkachuk S, Kiyan Y et al (2011) Urokinase receptor mediates mobilization, migration, and differentiation of mesenchymal stem cells. Cardiovasc Res 90:113–121PubMedCrossRefGoogle Scholar
  73. Weissman IL, Shizuru JA (2008) The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases. Blood 112:3543–3553PubMedCrossRefGoogle Scholar
  74. Wislet-Gendebien S, Hans G, Leprince P et al (2005) Plasticity of cultured mesenchymal stem cells: switch from nestin-positive to excitable neuron-like phenotype. Stem Cells 23:392–402PubMedCrossRefGoogle Scholar
  75. Wojakowski W, Kucia M, Zuba-Surma E et al (2011) Very small embryonic-like stem cells in cardiovascular repair. Pharmacol Ther 129:21–28PubMedCrossRefGoogle Scholar
  76. Wright KT, El Masri W, Osman A et al (2011) Bone marrow for the treatment of spinal cord injury: mechanisms and clinical application. Stem Cells 29:169–178PubMedCrossRefGoogle Scholar
  77. Xu YX, Chen L, Hou WK et al (2009) Mesenchymal stem cells treated with rat pancreatic extract secrete cytokines that improve the glycometabolism of diabetic rats. Transplant Proc 41:1878–1884PubMedCrossRefGoogle Scholar
  78. Yoshihara T, Ohta M, Itokazu Y et al (2007) Neuroprotective effect of bone marrow-derived mononuclear cells promoting functional recovery from spinal cord injury. J Neurotrauma 24:1026–1036PubMedCrossRefGoogle Scholar
  79. Yu J, Li M, Qu Z et al (2010) SDF-1/CXCR4-mediated migration of transplanted bone marrow stromal cells toward areas of heart myocardial infarction through activation of PI3K/Akt. J Cardiovasc Pharmacol 55:496–505PubMedGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2011

Authors and Affiliations

  • Yasumasa Kuroda
    • 1
  • Masaaki Kitada
    • 1
  • Shohei Wakao
    • 1
  • Mari Dezawa
    • 1
  1. 1.Department of Stem Cell Biology and HistologyTohoku University Graduate School of MedicineSendaiJapan

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