Mesenchymal Stem Cells for Lung Repair and Regeneration

  • Daniel J. WeissEmail author
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


Mesenchymal stem cells (MSCs) are cells of stromal origin that have now been isolated from a wide variety of adult tissues as well as from tissues involved in fetal growth and development, including umbilical cord blood, Wharton’s jelly, amniotic fluid, and placenta. Originally characterized as supporting bone marrow stromal cells, MSCs are now recognized to have a broad range of activities, including the ability to differentiate into a wide variety of adult cell types as well as to have potent immunomodulatory properties. As such, they are increasingly being investigated for use in lung diseases. Initial focus was on structural engraftment and repair of diseased or injured lung. More recent areas of research include use of MSCs for ex vivo three-dimensional lung tissue engineering and for use in immunomodulation of inflammatory and immune-mediated lung diseases. MSCs may also serve as cellular delivery vehicles for lung and other cancers. However, the MSC field is complicated by lack of consistent approaches in both cell isolation and culture as well as in nomenclature. Further, it is unclear whether MSCs obtained from different tissue sources have comparable properties. The long-term tumorigenic potential of MSC administration in humans also remains unclear. Nonetheless, a current clinical trial investigating the safety and potential efficacy of systemic administration of MSCs in patients with chronic obstructive pulmonary disease demonstrates the potential for therapeutic use of MSCs for a range of lung diseases.


Lung Mesenchymal stem cell Immunomodulation Lung bioengineering 


  1. 1.
    Friedenstein AJ, Gorskaja JF, and Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 1976; 4(5):267–274.PubMedGoogle Scholar
  2. 2.
    Caplan AI. Osteogenesis imperfecta, rehabilitation medicine, fundamental research and mesenchymal stem cells. Connect Tissue Res 1995; 31(4):S9–S14.PubMedCrossRefGoogle Scholar
  3. 3.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, and Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4):315–317.PubMedCrossRefGoogle Scholar
  4. 4.
    Sueblinvong V, Loi R, Eisenhauer PL, Bernstein IM, Suratt BT, Spees JL, and Weiss DJ. Derivation of lung epithelium from human cord blood-derived mesenchymal stem cells. Am J Respir Crit Care Med 177:701–711, 2008.PubMedCrossRefGoogle Scholar
  5. 5.
    Meng X, Ichim TE, Zhong J, Rogers A, Yin Z, Jackson J, Wang H, Ge W, Bogin V, Chan KW, Thebaud B, and Riordan NH. Endometrial regenerative cells: a novel stem cell population. J Transl Med 2007; 5:57.PubMedCrossRefGoogle Scholar
  6. 6.
    Miao Z, Jin J, Chen L, Zhu J, Huang W, Zhao J, Qian H, and Zhang X. Isolation of mesenchymal stem cells from human placenta: comparison with human bone marrow mesenchymal stem cells. Cell Biol Int 2006; 30(9):681–687.PubMedCrossRefGoogle Scholar
  7. 7.
    Traktuev DO, Merfeld-Clauss S, Li J, Kolonin M, Arap W, Pasqualini R, Johnstone BH, and March KLA. population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ Res 2008; 102(1):77–85.PubMedCrossRefGoogle Scholar
  8. 8.
    Lee OK, Kuo TK, Chen WM, Lee KD, Hsieh SL, and Chen TH. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 2004; 103(5):1669–1675.PubMedCrossRefGoogle Scholar
  9. 9.
    Lee MW, Choi J, Yang MS, Moon YJ, Park JS, Kim HC, and Kim YJ. Mesenchymal stem cells from cryopreserved human umbilical cord blood. Biochem Biophys Res Commun 2004; 320(1):273–278.PubMedCrossRefGoogle Scholar
  10. 10.
    Bieback K, Kern S, Kluter H, and Eichler H. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 2004; 22(4):625–634.PubMedCrossRefGoogle Scholar
  11. 11.
    Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, Fu YS, Lai MC, and Chen CC. Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells 2004; 22(7):1330–1337.PubMedCrossRefGoogle Scholar
  12. 12.
    Fukuchi Y, Nakajima H, Sugiyama D, Hirose I, Kitamura T, and Tsuji K. Human placenta-derived cells have mesenchymal stem/progenitor cell potential. Stem Cells 2004; 22(5):649–658.PubMedCrossRefGoogle Scholar
  13. 13.
    Li D, Wang GY, Dong BH, Zhang YC, Wang YX, and Sun BC. Biological characteristics of human placental mesenchymal stem cells and their proliferative response to various cytokines. Cells Tissues Organs 2007; 186(3):169–179.PubMedCrossRefGoogle Scholar
  14. 14.
    Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, Taureau C, Cousin B, Abbal M, Laharrague P, Penicaud L, Casteilla L, and Blancher A. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 2005; 129(1):118–129.PubMedCrossRefGoogle Scholar
  15. 15.
    Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez M, and Bueren JA. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells 2006; 24(11):2582–2591.PubMedCrossRefGoogle Scholar
  16. 16.
    Summer R, Fitzsimmons K, Dwyer D, Murphy J, and Fine A. Isolation of an adult mouse lung mesenchymal progenitor cell population. Am J Respir Cell Mol Biol 2007; 37(2):152–159.PubMedCrossRefGoogle Scholar
  17. 17.
    Hennrick KT, Keeton AG, Nanua S, Kijek TG, Goldsmith AM, Sajjan US, Bentley JK, Lama VN, Moore BB, Schumacher RE, Thannickal VJ, and Hershenson MB. Lung cells from neonates show a mesenchymal stem cell phenotype. Am J Respir Crit Care Med 2007; 175(11):1158–1164.PubMedCrossRefGoogle Scholar
  18. 18.
    Lama VN, Smith L, Badri L, Flint A, Andrei AC, Murray S, Wang Z, Liao H, Toews GB, Krebsbach PH, Peters-Golden M, Pinsky DJ, Martinez FJ, and Thannickal VJ. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest 2007; 117(4):989–996.PubMedCrossRefGoogle Scholar
  19. 19.
    Kern S, Eichler H, Stoeve J, Kluter H, and Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006; 24(5):1294–1301.PubMedCrossRefGoogle Scholar
  20. 20.
    Chang YJ, Shih DT, Tseng CP, Hsieh TB, Lee DC, and Hwang SM. Disparate mesenchyme-lineage tendencies in mesenchymal stem cells from human bone marrow and umbilical cord blood. Stem Cells 2006; 24(3):679–685.PubMedCrossRefGoogle Scholar
  21. 21.
    Tsai MS, Hwang SM, Chen KD, Lee YS, Hsu LW, Chang YJ, Wang CN, Peng HH, Chang YL, Chao AS, Chang SD, Lee KD, Wang TH, Wang HS, and Soong YK. Functional network analysis of the transcriptomes of mesenchymal stem cells derived from amniotic fluid, amniotic membrane, cord blood, and bone marrow. Stem Cells 2007; 25(10):2511–2523.PubMedCrossRefGoogle Scholar
  22. 22.
    Bernardo ME, Emons JA, Karperien M, Nauta AJ, Willemze R, Roelofs H, Romeo S, Marchini A, Rappold GA, Vukicevic S, Locatelli F, and Fibbe WE. Human mesenchymal stem cells derived from bone marrow display a better chondrogenic differentiation compared with other sources. Connect Tissue Res 2007; 48(3):132–140.PubMedCrossRefGoogle Scholar
  23. 23.
    Panepucci RA, Siufi JL, Silva WA Jr, Proto-Siquiera R, Neder L, Orellana M, Rocha V, Covas DT, and Zago MA. Comparison of gene expression of umbilical cord vein and bone marrow-derived mesenchymal stem cells. Stem Cells 2004; 22(7):1263–1278.PubMedCrossRefGoogle Scholar
  24. 24.
    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, and Hedrick MH. Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs 2003; 174(3):101–109.PubMedCrossRefGoogle Scholar
  25. 25.
    Keyser KA, Beagles KE, and Kiem HP. Comparison of mesenchymal stem cells from different tissues to suppress T-cell activation. Cell Transplant 2007; 16(5):555–562.PubMedGoogle Scholar
  26. 26.
    Kunisaki SM, Fuchs JR, Steigman SA, and Fauza DOA. Comparative analysis of cartilage engineered from different perinatal mesenchymal progenitor cells. Tissue Eng 2007; 13(11):2633–2644.PubMedCrossRefGoogle Scholar
  27. 27.
    Haynesworth SE, Baber MA, and Caplan AI. Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. J Cell Physiol 1996; 166(3):585–592.PubMedCrossRefGoogle Scholar
  28. 28.
    Grayson WL, Zhao F, Izadpanah R, Bunnell B, and Ma T. Effects of hypoxia on human mesenchymal stem cell expansion and plasticity in 3D constructs. J Cell Physiol 2006; 207(2):331–339.PubMedCrossRefGoogle Scholar
  29. 29.
    Stolzing A, and Scutt A. Effect of reduced culture temperature on antioxidant defences of mesenchymal stem cells. Free Radic Biol Med 2006; 41(2):326–338.PubMedCrossRefGoogle Scholar
  30. 30.
    Lisignoli G, Cristino S, Piacentini A, Cavallo C, Caplan AI, and Facchini A. Hyaluronan-based polymer scaffold modulates the expression of inflammatory and degradative factors in mesenchymal stem cells: involvement of CD44 and CD54. J Cell Physiol 2006; 207(2):364–373.PubMedCrossRefGoogle Scholar
  31. 31.
    Engler AJ, Sen S, Sweeney HL, and Discher DE. Matrix elasticity directs stem cell lineage specification. Cell 2006; 126(4):677–689.PubMedCrossRefGoogle Scholar
  32. 32.
    Gregory CA, Ylostalo J, and Prockop DJ. Adult bone marrow stem/progenitor cells (MSCs) are preconditioned by microenvironmental “niches” in culture: a two-stage hypothesis for regulation of MSC fate. Sci STKE 2005; 2005(294):pe37.CrossRefGoogle Scholar
  33. 33.
    Lee RH, Hsu SC, Munoz J, Jung JS, Lee NR, Pochampally R, and Prockop DJA. subset of human rapidly self-renewing marrow stromal cells preferentially engraft in mice. Blood 2006; 107(5):2153–2161.PubMedCrossRefGoogle Scholar
  34. 34.
    Crigler L, Robey RC, Asawachaicharn A, Gaupp D, and Phinney DG. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol 2006; 198(1):54–64.PubMedCrossRefGoogle Scholar
  35. 35.
    Phinney DG. Biochemical heterogeneity of mesenchymal stem cell populations: clues to their therapeutic efficacy. Cell Cycle 2007; 6(23):2884–2889.PubMedCrossRefGoogle Scholar
  36. 36.
    Eaves CJ, Cashman JD, Sutherland HJ, Otsuka T, Humphries RK, Hogge DE et al. Molecular analysis of primitive hematopoietic cell proliferation control mechanisms. Ann N Y Acad Sci 1991; 628:298–306.PubMedCrossRefGoogle Scholar
  37. 37.
    Sabatini F, Petecchia L, Tavian M, Jodon de Villeroche V, Rossi GA, and Brouty-Boye D. Human bronchial fibroblasts exhibit a mesenchymal stem cell phenotype and multilineage differentiating potentialities. Lab Invest 2005; 85(8):962–971.PubMedCrossRefGoogle Scholar
  38. 38.
    Haniffa MA, Wang XN, Holtick U, Rae M, Isaacs JD, Dickinson AM, Hilkens CM, and Collin MP. Adult human fibroblasts are potent immunoregulatory cells and functionally equivalent to mesenchymal stem cells. J Immunol 2007; 179:1595–1604.PubMedGoogle Scholar
  39. 39.
    Phinney DG, Kopen G, Isaacson RL, and Prockop DJ. Plastic adherent stromal cells from the bone marrow of commonly used strains of inbred mice: variations in yield, growth, and differentiation. J Cell Biochem 1999; 72:570–585.PubMedCrossRefGoogle Scholar
  40. 40.
    Sekiya I, Larson BL, Smith JR, Pochampally R, Cui JG, and Prockop DJ. Expansion of human adult stem cells from bone marrow stroma: conditions that maximize the yields of early progenitors and evaluate their quality. Stem Cells 2002; 20:530–541.PubMedCrossRefGoogle Scholar
  41. 41.
    Aguilar S, Nye E, Chan J, Loebinger M, Spencer-Dene B, Fisk N, Stamp G, Bonnet D, and Janes SM. Murine but not human mesenchymal stem cells generate osteosarcoma-like lesions in the lung. Stem Cells 2007; 25(6):1586–1594.PubMedCrossRefGoogle Scholar
  42. 42.
    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, and Blazar BR. Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 2007; 25(2):371–379.PubMedCrossRefGoogle Scholar
  43. 43.
    Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, Montagna D, Maccario R, Villa R, Daidone MG, Zuffardi O, and Locatelli F. 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 2007; 67(19):9142–9149.PubMedCrossRefGoogle Scholar
  44. 44.
    Hattori K, Heissig B, Tashiro K, Honjo T, Tateno M, Shieh JH, Hackett NR, Quitoriano MS, Crystal RG, Rafii S, and Moore. MA. Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood 2001; 97(11):3354–3360.PubMedCrossRefGoogle Scholar
  45. 45.
    Kobayashi H, Tahara M, Worgall S, Rafii S, and Crystal RG. Mobilization of hematopoietic stem cells and progenitor cells to lung by intratracheal administration of an adenovirus encoding stromal cell-derived factor-1. Mol Ther 2003; 7:S112.CrossRefGoogle Scholar
  46. 46.
    Pitchford SC, Furze RC, Jones CP, Wengner AM, and Rankin SM. Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell 2009; 4(1):62–72.PubMedCrossRefGoogle Scholar
  47. 47.
    Lee B-C, Hsu H-C, Tseng W-Y I, Chen C-Y, Lin H-J, Ho Y-L, Su M-J, and Chen M-F. Cell therapy generates a favorable chemokine gradient for stem recruitment into the infarcted heart in rabbits. Eur J Heart Fail 2009; 11:238–245.PubMedCrossRefGoogle Scholar
  48. 48.
    Rochefort GY, Delorme B, Lopez A, Herault O, Bonnet P, Charbord P, Eder V, and Domenech J. Multipotential mesenchymal stem cells are mobilized into peripheral blood by hypoxia. Stem Cells 2006; 24(10):2202–2208.PubMedCrossRefGoogle Scholar
  49. 49.
    Rosova I, Dao M, Capoccia B, Link D, and Nolta JA. Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 2008; 26(8):2173–2182.PubMedCrossRefGoogle Scholar
  50. 50.
    Okuyama H, Krishnamachary B, Zhou YF, Nagasawa H, Bosch-Marce M, and Semenza GL. Expression of vascular endothelial growth factor receptor 1 in bone marrow-derived mesenchymal cells is dependent on hypoxia-inducible factor 1. J Biol Chem 2006; 281(22):15554–15563.PubMedCrossRefGoogle Scholar
  51. 51.
    Mansilla E, Marin GH, Drago H, Sturla F, Salas E, Gardiner C, Bossi S, Lamonega R, Guzman A, Nunez A, Gil MA, Piccinelli G, Ibar R, and Soratti C. Bloodstream cells phenotypically identical to human mesenchymal bone marrow stem cells circulate in large amounts under the influence of acute large skin damage: new evidence for their use in regenerative medicine. Transplant Proc 2006; 38(3):967–969.PubMedCrossRefGoogle Scholar
  52. 52.
    Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 2008; 3:301–313.PubMedCrossRefGoogle Scholar
  53. 53.
    Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 2007; 131:324–336.PubMedCrossRefGoogle Scholar
  54. 54.
    da Silva Meirelles L, Caplan AI, and Nardi NB. In search of the in vivo identity of mesenchymal stem cells. Stem Cells 2008; 26:2287–2299.PubMedCrossRefGoogle Scholar
  55. 55.
    Jarvinen L, Badri L, Wettlaufer S, Ohtsuka T, Standiford TJ, Toews GB, Pinsky DJ, Peters-Golden M, and Lama VN Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol 2008; 181(6):4389–4396.PubMedGoogle Scholar
  56. 56.
    Weiss DJ, Kolls JK, Ortiz LA, Panoskaltis-Mortari A, and Prockop DJ. Stem cells and cell therapy approaches for lung diseases. Conference report. Proc Am Thorac Soc 2008; 5:637–667.PubMedCrossRefGoogle Scholar
  57. 57.
    Wang G, Bunnell BA, Painter RG, Tom S, Lanson NA, Spees JL, Bertucci D, Peister A, Weiss DJ, Valentine VG, Prockop DJ, and Kolls JK Adult stem cells from bone marrow stroma differentiate into airway epithelial cells: potential therapy for cystic fibrosis. Proc Natl Acad Sci USA 2005; 102(1):186–191.PubMedCrossRefGoogle Scholar
  58. 58.
    Carraro G, Perin L, Sedrakyan S, Giuliani S, Tiozzo C, Lee J, Turcatel G, De Langhe SP, Driscoll B, Bellusci S et al. Human amniotic fluid stem cells can integrate and differentiate into epithelial lung lineages. Stem Cells 2008; 26:2902–2911.PubMedCrossRefGoogle Scholar
  59. 59.
    Mondrinos MJ, Koutzaki S, Lelkes PI, and Finck CM. A tissue-engineered model of fetal distal lung tissue. Am J Physiol Lung Cell Mol Physiol 2007; 293(3):L639–L650.PubMedCrossRefGoogle Scholar
  60. 60.
    Mondrinos MJ, Koutzaki S, Jiwanmall E, Li M, Dechadarevian JP, Lelkes PI, and Finck CM. Engineering three-dimensional pulmonary tissue constructs. Tissue Eng 2006; 12(4):717–728.PubMedCrossRefGoogle Scholar
  61. 61.
    Lin YM, Boccaccini AR, Polak JM, Bishop AE, and Maquet V. Biocompatibility of poly-DL-lactic acid (PDLLA) for lung tissue engineering. J Biomater Appl 2006; 21(2):109–118.PubMedCrossRefGoogle Scholar
  62. 62.
    Choe MM, Sporn PH, and Swartz MA. Extracellular matrix remodeling by dynamic strain in a three-dimensional tissue-engineered human airway wall model. Am J Respir Cell Mol Biol 2006; 35(3):306–313.PubMedCrossRefGoogle Scholar
  63. 63.
    Andrade CF, Wong AP, Waddell TK, Keshavjee S, and Liu M. Cell-based tissue engineering for lung regeneration. Am J Physiol Lung Cell Mol Physiol 2007; 292(2):L510–L518.PubMedCrossRefGoogle Scholar
  64. 64.
    Cortiella J, Nichols JE, Kojima K, Bonassar LJ, Dargon P, Roy AK, Vacant MP, Niles JA, and Vacanti CA. Tissue-engineered lung: an in vivo and in vitro comparison of polyglycolic acid and pluronic F-127 hydrogel/somatic lung progenitor cell constructs to support tissue growth. Tissue Eng 2006; 12(5):1213–1225.PubMedCrossRefGoogle Scholar
  65. 65.
    Liu M, Xu J, Souza P, Tanswell B, Tanswell AK, and Post M. The effect of mechanical strain on fetal rat lung cell proliferation: comparison of two- and three-dimensional culture systems. In Vitro Cell Dev Biol Anim 1995; 31(11):858–866.PubMedCrossRefGoogle Scholar
  66. 66.
    Sueblinvong V, Larson ER, Spees JL, and Weiss DJ. Three-dimensional culture systems can induced lung epithelial cells markers expression by mesenchymal stem cells in vitro. Proc Am Thorac Soc 2008; 177:A720.Google Scholar
  67. 67.
    Sueblinvong V, Eisenhauer PL, Larson ER, Iatridis JC, and Weiss DJ. Three-dimensional culture systems and mechanical stretch can induce lung epithelial cell marker expression by mesenchymal stem cells in vitro. Pediatr Pulmonol 2008; Suppl 31:291.Google Scholar
  68. 68.
    Kunisaki SM, Armant M, Kao GS, Stevenson K, Kim H, and Fauza DO. Tissue engineering from human mesenchymal amniocytes: a prelude to clinical trials. J Pediatr Surg 2007; 42(6):974–979; discussion 979–80.PubMedCrossRefGoogle Scholar
  69. 69.
    Kunisaki SM, Jennings RW, and Fauza DO. Fetal cartilage engineering from amniotic mesenchymal progenitor cells. Stem Cells Dev 2006; 15(2):245–253.PubMedCrossRefGoogle Scholar
  70. 70.
    Kunisaki SM, Freedman DA, and Fauza DO. Fetal tracheal reconstruction with cartilaginous grafts engineered from mesenchymal amniocytes. J Pediatr Surg 2006; 41(4):675–682; discussion 675–82.PubMedCrossRefGoogle Scholar
  71. 71.
    Kunisaki SM, Fuchs JR, Kaviani A, Oh JT, LaVan DA, Vacanti JP, Wilson JM, and Fauza DO. Diaphragmatic repair through fetal tissue engineering: a comparison between mesenchymal amniocyte- and myoblast-based constructs. J Pediatr Surg 2006; 41(1):34–39; discussion 34–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Fuchs JR, Hannouche D, Terada S, Zand S, Vacanti JP, and Fauza DO. Cartilage engineering from ovine umbilical cord blood mesenchymal progenitor cells. Stem Cells 2005; 23(7):958–964.PubMedCrossRefGoogle Scholar
  73. 73.
    Fuchs JR, Kaviani A, Oh JT, LaVan D, Udagawa T, Jennings RW, Wilson JM, and Fauza DO. Diaphragmatic reconstruction with autologous tendon engineered from mesenchymal amniocytes. J Pediatr Surg 2004; 39(6):834–838; discussion 834–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Kaviani A, Guleserian K, Perry TE, Jennings RW, Ziegler MM, and Fauza DO. Fetal tissue engineering from amniotic fluid. J Am Coll Surg 2003; 196(4):592–597.PubMedCrossRefGoogle Scholar
  75. 75.
    Kojima K, Ignotz RA, Kushibiki T, Tinsley KW, Tabata Y, and Vacanti CA. Tissue-engineered trachea from sheep marrow stromal cells with transforming growth factor beta2 released from biodegradable microspheres in a nude rat recipient. J Thorac Cardiovasc Surg 2004; 128(1):147–153.PubMedCrossRefGoogle Scholar
  76. 76.
    Shigemura N, Okumura M, Mizuno S, Imanishi Y, Matsuyama A, Shiono H, Nakamura T, and Sawa Y. Lung tissue engineering technique with adipose stromal cells improves surgical outcome for pulmonary emphysema. Am J Respir Crit Care Med 2006; 174(11):1199–1205.PubMedCrossRefGoogle Scholar
  77. 77.
    Stagg J. Immune regulation by mesenchymal stem cells: two sides to the coin. Tissue Antigens 2007; 69:1–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Keating A. Mesenchymal stromal cells. Curr Opin Hematol 2006; 13:419–425.PubMedCrossRefGoogle Scholar
  79. 79.
    Rasmusson I. Immune modulation by mesenchymal stem cells. Exp Cell Res 2006; 312:2169–2179.PubMedCrossRefGoogle Scholar
  80. 80.
    Nauta AJ, and Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007; 110:3499–3506.PubMedCrossRefGoogle Scholar
  81. 81.
  82. 82.
  83. 83.
    Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, and Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99:3838–3843.PubMedCrossRefGoogle Scholar
  84. 84.
    Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, Deans R et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002; 30:42–48.PubMedCrossRefGoogle Scholar
  85. 85.
    Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, and Dazzi F. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003; 101:3722–3729.PubMedCrossRefGoogle Scholar
  86. 86.
    Klyushnenkova E, Mosca JD, Zernetkina V, Majumdar MK, Beggs KJ, Simonetti DW, Deans RJ, and McIntosh KR. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci 2005; 12:47–57.PubMedCrossRefGoogle Scholar
  87. 87.
    Aggarwal S, and Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105:1815–1822.PubMedCrossRefGoogle Scholar
  88. 88.
    Le Blanc K, Rasmusson I, Gotherstrom C, Seidel C, Sundberg B, Sundin M, Rosendahl K, Tammik C, and Ringden O. Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scand J Immunol 2004; 60:307–315.PubMedCrossRefGoogle Scholar
  89. 89.
    Rasmusson I, Ringden O, Sundberg B, and Le Blanc K. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res 2005; 305:33–41.PubMedCrossRefGoogle Scholar
  90. 90.
    Rasmusson I, Ringden O, Sundberg B, and Le Blanc K. Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 2003; 76:1208–1213.PubMedCrossRefGoogle Scholar
  91. 91.
    Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, Galun E, and Rachmilewitz J. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 2005; 105:2214–2219.PubMedCrossRefGoogle Scholar
  92. 92.
    Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, and Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004; 103:4619–4621.PubMedCrossRefGoogle Scholar
  93. 93.
    Deng W, Han Q, Liao L, You S, Deng H, and Zhao RC. Effects of allogeneic bone marrow-derived mesenchymal stem cells on T and B lymphocytes from bxsb mice. DNA Cell Biol 2005; 24:458–463.PubMedCrossRefGoogle Scholar
  94. 94.
    Caplan AI, and Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem 2006; 98:1076–1084.PubMedCrossRefGoogle Scholar
  95. 95.
    Sheng H, Wang Y, Jin Y, Zhang Q, Zhang Y, Wang L, Shen B, Yin S, Liu W, Cui L et al. A critical role of IFNgamma in priming msc-mediated suppression of T cell proliferation through up-regulation of b7-h1. Cell Res 2008; 18:846–857.PubMedCrossRefGoogle Scholar
  96. 96.
    English K, Barry FP, Field-Corbett CP, and Mahon BP. IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett 2007; 110:91–100.PubMedCrossRefGoogle Scholar
  97. 97.
    Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, and Shi Y. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2008; 2:141–150.PubMedCrossRefGoogle Scholar
  98. 98.
    Chang CJ, Yen ML, Chen YC, Chien CC, Huang HI, Bai CH, and Yen BL. Placenta-derived multipotent cells exhibit immunosuppressive properties that are enhanced in the presence of interferon-gamma. Stem Cells 2006; 24:2466–2477.PubMedCrossRefGoogle Scholar
  99. 99.
    Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 2006; 24:386–398.PubMedCrossRefGoogle Scholar
  100. 100.
    Delarosa O, Lombardo E, Beraza A, Mancheno P, Ramirez C, Menta R, Rico L, Camarillo E, Garcia L, Abad JL et al. Requirement of IFN-gammamediated indoleamine 2,3 dioxygenase expression in the modulation of lymphocyte proliferation by human adipose-derived stem cells. Tissue Eng Part A October 2009; 2795–2806.Google Scholar
  101. 101.
    Schinkothe T, Bloch W, and Schmidt A. In vitro secreting profile of human mesenchymal stem cells. Stem Cells Dev 2008; 17:199–206.PubMedCrossRefGoogle Scholar
  102. 102.
    Phinney DG, Hill K, Michelson C, DuTreil M, Hughes C, Humphries S, Wilkinson R, Baddoo M, and Bayly E. Biological activities encoded by the murine mesenchymal stem cell transcriptome provide a basis for their developmental potential and broad therapeutic efficacy. Stem Cells 2006; 24(1):186–198.PubMedCrossRefGoogle Scholar
  103. 103.
    Pevsner-Fischer M, Morad V, Cohen-Sfady M, Rousso-Noori L, Zanin-Zhorov A, Cohen S, Cohen IR, and Zipori D. Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood 2007; 109(4):1422–1432.PubMedCrossRefGoogle Scholar
  104. 104.
    Huang W, La Russa V, Alzoubi A, and Schwarzenberger P. Interleukin-17A: a T-cell-derived growth factor for murine and human mesenchymal stem cells. Stem Cells 2006; 24(6):1512–1518.PubMedCrossRefGoogle Scholar
  105. 105.
    Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, and Phinney DG. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA 2003; 100(14):8407–8411.PubMedCrossRefGoogle Scholar
  106. 106.
    Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, and Phinney DG. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA 2007; 104(26):11002–11007.PubMedCrossRefGoogle Scholar
  107. 107.
    Mei SH, McCarter SD, Deng Y, Parker CH, Liles WC, and Stewart DJ. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med 2007; 4(9):e269.PubMedCrossRefGoogle Scholar
  108. 108.
    Xu J, Qu J, Cao L, Sai Y, Chen C, He L, and Yu L. Mesenchymal stem cell-based angiopoietin-1 gene therapy for acute lung injury induced by lipopolysaccharide in mice. J Pathol 2008; 214(4):472–481.PubMedCrossRefGoogle Scholar
  109. 109.
    Baber SR, Deng W, Master RG, Bunnell BA, Taylor BK, Murthy SN, Hyman AL, and Kadowitz PJ. Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol 2007; 292(2):H1120–H1128.PubMedCrossRefGoogle Scholar
  110. 110.
    Xu J, Woods CR, Mora AL, Joodi R, Brigham KL, Iyer S, and Rojas M. Prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice. Am J Physiol Lung Cell Mol Physiol 2007; 293(1):L131–L141.PubMedCrossRefGoogle Scholar
  111. 111.
    Gupta N, Su X, Popov B, Lee JW, Serikov V, and Matthay MA. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 2007; 179(3):1855–1863.PubMedGoogle Scholar
  112. 112.
    McCarter SD, Mei SH, Lai PF, Zhang QW, Parker CH, Suen RS, Hood RD, Zhao YD, Deng Y, Han RN, Dumont DJ, and Stewart DJ. Cell-based angiopoietin-1 gene therapy for acute lung injury. Am J Respir Crit Care Med 2007; 175(10):1014–1026.PubMedCrossRefGoogle Scholar
  113. 113.
    Lee JW, Gupta N, Fang X, Frank JA, and Matthay MA. Human mesenchymal stem cells reduce endotoxin induced acute lung injury in the ex vivo perfused human lung. Am J Respir Cell Mol Biol 2008; 177:A598.Google Scholar
  114. 114.
    Shigemura N, Okumura M, Mizuno S, Imanishi Y, Nakamura T, and Sawa Y Autologous transplantation of adipose tissue-derived stromal cells ameliorates pulmonary emphysema. Am J Transplant 2006; 6(11):2592–2600.PubMedCrossRefGoogle Scholar
  115. 115.
  116. 116.
  117. 117.
    Pereboeva L, Komarova S, Mikheeva G, Krasnykh V, and Curiel DT. Approaches to utilize mesenchymal progenitor cells as cellular vehicles. Stem Cells 2003; 21(4):389–404.PubMedCrossRefGoogle Scholar
  118. 118.
    Komarova S, Kawakami Y, Stoff-Khalili MA, Curiel DT, and Pereboeva L. Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses. Mol Cancer Ther 2006; 5(3):755–766.PubMedCrossRefGoogle Scholar
  119. 119.
    Kurozumi K, Nakamura K, Tamiya T, Kawano Y, Ishii K, Kobune M, Hirai S, Uchida H, Sasaki K, Ito Y, Kato K, Honmou O, Houkin K, Date I, and Hamada H. Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model. Mol Ther 2005; 11(1):96–104.PubMedCrossRefGoogle Scholar
  120. 120.
    Zachos T, Diggs A, Weisbrode S, Bartlett J, and Bertone A. Mesenchymal stem cell-mediated gene delivery of bone morphogenetic protein-2 in an articular fracture model. Mol Ther 2007; 15(8):1543–1550.PubMedCrossRefGoogle Scholar
  121. 121.
    Yu Y, Yao AH, Chen N, Pu LY, Fan Y, Lv L, Sun BC, Li GQ, and Wang XH. Mesenchymal stem cells over-expressing hepatocyte growth factor improve small-for-size liver grafts regeneration. Mol Ther 2007; 15(7):1382–1389.PubMedCrossRefGoogle Scholar
  122. 122.
    Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN, Champlin RE, and Andreeff M. Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004; 96(21):1593–1603.PubMedCrossRefGoogle Scholar
  123. 123.
    Hall B, Dembinski J, Sasser AK, Studeny M, Andreeff M, and Marini F. Mesenchymal stem cells in cancer: tumor-associated fibroblasts and cell-based delivery vehicles. Int J Hematol 2007; 86(1):8–16.PubMedCrossRefGoogle Scholar
  124. 124.
    Stoff-Khalili MA, Rivera AA, Mathis JM, Banerjee NS, Moon AS, Hess A, Rocconi RP, Numnum TM, Everts M, Chow LT, Douglas JT, Siegal GP, Zhu ZB, Bender HG, Dall P, Stoff A, Pereboeva L, and Curiel DT. Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma. Breast Cancer Res Treat 2007; 105(2):157–167.PubMedCrossRefGoogle Scholar
  125. 125.
    Miletic H, Fischer Y, Litwak S, Giroglou T, Waerzeggers Y, Winkeler A, Li H, Himmelreich U, Lange C, Stenzel W, Deckert M, Neumann H, Jacobs AH, and von Laer D. Bystander killing of malignant glioma by bone marrow-derived tumor-infiltrating progenitor cells expressing a suicide gene. Mol Ther 2007; 15(7):1373–1381.PubMedCrossRefGoogle Scholar
  126. 126.
    Xin H, Kanehira M, Mizuguchi H, Hayakawa T, Kikuchi T, Nukiwa T, and Saijo Y. Targeted delivery of CX3CL1 to multiple lung tumors by mesenchymal stem cells. Stem Cells 2007; 25(7):1618–1626.PubMedCrossRefGoogle Scholar
  127. 127.
    Rachakatla RS, Marini F, Weiss ML, Tamura M, and Troyer D. Development of human umbilical cord matrix stem cell-based gene therapy for experimental lung tumors. Cancer Gene Ther 2007; 14(10):828–835.PubMedCrossRefGoogle Scholar
  128. 128.
    Kanehira M, Xin H, Hoshino K, Maemondo M, Mizuguchi H, Hayakawa T, Matsumoto K, Nakamura T, Nukiwa T, and Saijo Y. Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells. Cancer Gene Ther 2007; 14(11):894–903.PubMedCrossRefGoogle Scholar
  129. 129.
    Hakkarainen T, Sarkioja M, Lehenkari P, Miettinen S, Ylikomi T, Suuronen R, Desmond RA, Kanerva A, and Hemminki A. Human mesenchymal stem cells lack tumor tropism but enhance the antitumor activity of oncolytic adenoviruses in orthotopic lung and breast tumors. Hum Gene Ther 2007; 18(7):627–641.PubMedCrossRefGoogle Scholar
  130. 130.
    Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, and Weinberg RA. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449(7162):557–563.PubMedCrossRefGoogle Scholar
  131. 131.
    Avital I, Moreira AL, Klimstra DS, Leversha M, Papadopoulos EB, Brennan M, and Downey RJ. Donor-derived human bone marrow cells contribute to solid organ cancers developing after bone marrow transplantation. Stem Cells 2007; 25(11):2903–2909.PubMedCrossRefGoogle Scholar
  132. 132.
    Djouad F, Bony C, Apparailly F, Louis-Plence P, Jorgensen C, and Noel D. Earlier onset of syngeneic tumors in the presence of mesenchymal stem cells. Transplantation 2006; 82(8):1060–1066.PubMedCrossRefGoogle Scholar
  133. 133.
    Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, Cai X, Fox JG, Goldenring JR, and Wang TC. Gastric cancer originating from bone marrow-derived cells. Science 2004; 306(5701):1568–1571.PubMedCrossRefGoogle Scholar
  134. 134.
    Cogle CR, Theise ND, Fu D, Ucar D, Lee S, Guthrie SM, Lonergan J, Rybka W, Krause DS, and Scott EW. Bone marrow contributes to epithelial cancers in mice and humans as developmental mimicry. Stem Cells 2007; 25(8):1881–1887.PubMedCrossRefGoogle Scholar
  135. 135.
    Rubio D, Garcia S, Paz MF, De la Cueva T, Lopez-Fernandez LA, Lloyd AC, Garcia-Castro J, and Bernad A. Molecular characterization of spontaneous mesenchymal stem cell transformation. PLoS One 2008; 3(1):e1398.PubMedCrossRefGoogle Scholar
  136. 136.
    Rubio D, Garcia-Castro J, Martin MC, de la Fuente R, Cigudosa JC, Lloyd AC, and Bernad A. Spontaneous human adult stem cell transformation. Cancer Res 2005; 65(8):3035–3039.PubMedGoogle Scholar
  137. 137.
    Horwitz EM, Prockop DJ, Gordon PL, Koo WW, Fitzpatrick LA, Neel MD, McCarville ME, Orchard PJ, Pyeritz RE, and Brenner MK. Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 2001; 97(5):1227–1231.PubMedCrossRefGoogle Scholar
  138. 138.
    Spees JL, Gregory CA, Singh H, Tucker HA, Peister A, Lynch PJ, Hsu SC, Smith J, and Prockop DJ. Internalized antigens must be removed to prepare hypoimmunogenic mesenchymal stem cells for cell and gene therapy. Mol Ther 2004; 9(5):747–756.PubMedCrossRefGoogle Scholar
  139. 139.
    Gregory CA, Reyes E, Whitney MJ, and Spees JL. Enhanced engraftment of mesenchymal stem cells in a cutaneous wound model by culture in allogenic species-specific serum and administration in fibrin constructs. Stem Cells 2006; 24(10):2232–2243.PubMedCrossRefGoogle Scholar
  140. 140.
    Muller I, Kordowich S, Holzwarth C, Spano C, Isensee G, Staiber A, Viebahn S, Gieseke F, Langer H, Gawaz MP, Horwitz EM, Conte P, Handgretinger R, and Dominici M. Animal serum-free culture conditions for isolation and expansion of multipotent mesenchymal stromal cells from human BM. Cytotherapy 2006; 8(5):437–444.PubMedCrossRefGoogle Scholar
  141. 141.
    Bernardo ME, Avanzini MA, Perotti C, Cometa AM, Moretta A, Lenta E, Del Fante C, Novara F, de Silvestri A, Amendola G, Zuffardi O, Maccario R, and Locatelli F. Optimization of in vitro expansion of human multipotent mesenchymal stromal cells for cell-therapy approaches: further insights in the search for a fetal calf serum substitute. J Cell Physiol 2007; 211(1):121–130.PubMedCrossRefGoogle Scholar
  142. 142.
    Schrepfer S, Deuse T, Reichenspurner H, Fischbein MP, Robbins RC, and Pelletier MP. Stem cell transplantation: the lung barrier. Transplant Proc 2007; 39(2):573–576.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Division of Pulmonary and Critical Care, Vermont Lung CenterUniversity of Vermont College of MedicineBurlingtonUSA

Personalised recommendations