Cellular and Molecular Life Sciences

, Volume 72, Issue 24, pp 4759–4770 | Cite as

Role of mesenchymal stem cell-derived fibrinolytic factor in tissue regeneration and cancer progression

  • Beate Heissig
  • Douaa Dhahri
  • Salita Eiamboonsert
  • Yousef Salama
  • Hiroshi Shimazu
  • Shinya Munakata
  • Koichi Hattori


Tissue regeneration during wound healing or cancer growth and progression depends on the establishment of a cellular microenvironment. Mesenchymal stem cells (MSC) are part of this cellular microenvironment, where they functionally modulate cell homing, angiogenesis, and immune modulation. MSC recruitment involves detachment of these cells from their niche, and finally MSC migration into their preferred niches; the wounded area, the tumor bed, and the BM, just to name a few. During this recruitment phase, focal proteolysis disrupts the extracellular matrix (ECM) architecture, breaks cell–matrix interactions with receptors, and integrins, and causes the release of bioactive fragments from ECM molecules. MSC produce a broad array of proteases, promoting remodeling of the surrounding ECM through proteolytic mechanisms. The fibrinolytic system, with its main player plasmin, plays a crucial role in cell migration, growth factor bioavailability, and the regulation of other protease systems during inflammation, tissue regeneration, and cancer. Key components of the fibrinolytic cascade, including the urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1), are expressed in MSC. This review will introduce general functional properties of the fibrinolytic system, which go beyond its known function of fibrin clot dissolution (fibrinolysis). We will focus on the role of the fibrinolytic system for MSC biology, summarizing our current understanding of the role of the fibrinolytic system for MSC recruitment and the functional consequences for tissue regeneration and cancer. Aspects of MSC origin, maintenance, and the mechanisms by which these cells contribute to altered protease activity in the microenvironment under normal and pathological conditions will also be discussed.


Plasmin uPAR uPA Integrin Cancer Tissue-type plasminogen activator Wound healing MMP Cancer Microenvironment Niche Hematopoiesis Chemokine TGF-b Colorectal cancer Hypoxia 



Mesenchymal stem cells


Extracellular matrix


Bone marrow




Vascular endothelial growth factor-A (VEGF-A)


Matrix metalloproteinase


Urokinase-type plasminogen activator receptor


Plasminogen activator inhibitor-1


Urokinase-type plasminogen activator


Cluster of differentiation


Fibroblast growth factor-2


Transforming growth factor-β


Tissue-type plasminogen activator


Hematopoietic stem cell


Monocyte chemoattractant protein-1


Soluble uPAR


Plasminogen activator


Hypoxia inducible factor α


Hepatocyte growth factor


Colorectal cancer


Human epidermal growth factor receptor 2



We thank Stephanie C Napier for proofreading of the manuscript. This work was supported in part by grants from the Japan Society for the Promotion of Science and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (K.H.) Grant-in-Aid for Scientific Research on Priority Areas from the MEXT (K.H.), Mitsubishi Pharma Research Foundation (K.H), Naito Grant (B.H.), Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT (B.H.), Program for Improvement of the Research Environment for Young Researchers funded by the Special Coordination Funds for Promoting Science and Technology of the MEXT, Japan (B.H.).


  1. 1.
    Lu P, Weaver VM, Werb Z (2012) The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 196:395–406PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Gutova M, Najbauer J, Frank RT, Kendall SE, Gevorgyan A et al (2008) Urokinase plasminogen activator and urokinase plasminogen activator receptor mediate human stem cell tropism to malignant solid tumors. Stem Cells 26:1406–1413PubMedCrossRefGoogle Scholar
  3. 3.
    Heissig B, Lund LR, Akiyama H, Ohki M, Morita Y et al (2007) The plasminogen fibrinolytic pathway is required for hematopoietic regeneration. Cell Stem Cell 1:658–670PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Heissig B, Ohki M, Ishihara M, Tashiro Y, Nishida C et al (2009) Contribution of the fibrinolytic pathway to hematopoietic regeneration. J Cell Physiol 221:521–525PubMedCrossRefGoogle Scholar
  5. 5.
    Tjwa M, Moura R, Moons L, Plaisance S, De Mol M et al (2009) Fibrinolysis-independent role of plasmin and its activators in the hematopoietic recovery after myeloablation. J Cell Mol Med 13:4587–4595PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Gong Y, Fan Y, Hoover-Plow J (2011) Plasminogen regulates stromal cell-derived factor-1/CXCR4-mediated hematopoietic stem cell mobilization by activation of matrix metalloproteinase-9. Arterioscler Thromb Vasc Biol 31:2035–2043PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP (1968) Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6:230–247PubMedCrossRefGoogle Scholar
  8. 8.
    Latsinik NV, Luria EA, Friedenstein AJ, Samoylina NL, Chertkov IL (1970) Colony-forming cells in organ cultures of embryonal liver. J Cell Physiol 75:163–165PubMedCrossRefGoogle Scholar
  9. 9.
    Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF et al (1974) Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol 2:83–92PubMedGoogle Scholar
  10. 10.
    da Silva Meirelles L, Chagastelles PC, Nardi NB (2006) Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 119:2204–2213CrossRefGoogle Scholar
  11. 11.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147PubMedCrossRefGoogle Scholar
  12. 12.
    Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI et al (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13:4279–4295PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Bieback K, Kern S, Kluter H, Eichler H (2004) Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 22:625–634PubMedCrossRefGoogle Scholar
  14. 14.
    Tsai MS, Lee JL, Chang YJ, Hwang SM (2004) Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol. Hum Reprod 19:1450–1456PubMedCrossRefGoogle Scholar
  15. 15.
    Kim JW, Kim SY, Park SY, Kim YM, Kim JM et al (2004) Mesenchymal progenitor cells in the human umbilical cord. Ann Hematol 83:733–738PubMedCrossRefGoogle Scholar
  16. 16.
    Friedenstein AJ (1980) Stromal mechanisms of bone marrow: cloning in vitro and retransplantation in vivo. Haematol Blood Transfus 25:19–29PubMedGoogle Scholar
  17. 17.
    Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I et al (2005) Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy 7:393–395PubMedCrossRefGoogle Scholar
  18. 18.
    Lv FJ, Tuan RS, Cheung KM, Leung VY (2014) Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells 32:1408–1419PubMedCrossRefGoogle Scholar
  19. 19.
    Houlihan DD, Mabuchi Y, Morikawa S, Niibe K, Araki D et al (2012) Isolation of mouse mesenchymal stem cells on the basis of expression of Sca-1 and PDGFR-α. Nat Protocols 7:2103–2111PubMedCrossRefGoogle Scholar
  20. 20.
    Park CW, Kim KS, Bae S, Son HK, Myung PK et al (2009) Cytokine secretion profiling of human mesenchymal stem cells by antibody array. Int J Stem Cells 2:59–68PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Prockop DJ (1997) Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276:71–74PubMedCrossRefGoogle Scholar
  22. 22.
    Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK et al (2012) Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol 3:297PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H et al (2009) Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev 18:683–692PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Aurich H, Sgodda M, Kaltwasser P, Vetter M, Weise A et al (2009) Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut 58:570–581PubMedCrossRefGoogle Scholar
  25. 25.
    Boulland JL, Leung DS, Thuen M, Vik-Mo E, Joel M et al (2012) Evaluation of intracellular labeling with micron-sized particles of iron oxide (MPIOs) as a general tool for in vitro and in vivo tracking of human stem and progenitor cells. Cell Transplant 21:1743–1759PubMedCrossRefGoogle Scholar
  26. 26.
    Schrepfer S, Deuse T, Reichenspurner H, Fischbein MP, Robbins RC et al (2007) Stem Cell Transplantation: the lung barrier. Transpl Proc 39:573–576CrossRefGoogle Scholar
  27. 27.
    Shi XL, Gu JY, Han B, Xu HY, Fang L et al (2010) Magnetically labeled mesenchymal stem cells after autologous transplantation into acutely injured liver. World J Gastroenterol 16:3674–3679PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Hu SL, Lu PG, Zhang LJ, Li F, Chen Z et al (2012) In vivo magnetic resonance imaging tracking of SPIO-labeled human umbilical cord mesenchymal stem cells. J Cell Biochem 113:1005–1012PubMedCrossRefGoogle Scholar
  29. 29.
    Collen D, Lijnen HR (1991) Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 78:3114–3124PubMedGoogle Scholar
  30. 30.
    Rijken DC, Lijnen HR (2009) New insights into the molecular mechanisms of the fibrinolytic system. J Thromb Haemost 7:4–13PubMedCrossRefGoogle Scholar
  31. 31.
    Heissig B, Ohki-Koizumi M, Tashiro Y, Gritli I, Sato-Kusubata K et al (2012) New functions of the fibrinolytic system in bone marrow cell-derived angiogenesis. Int J Hematol 95:131–137PubMedCrossRefGoogle Scholar
  32. 32.
    Fuchs H, Simon MM, Wallich R, Bechtel M, Kramer MD (1996) Borrelia burgdorferi induces secretion of pro-urokinase-type plasminogen activator by human monocytes. Infect Immun 64:4307–4312PubMedCentralPubMedGoogle Scholar
  33. 33.
    Deryugina EI, Quigley JP (2012) Cell surface remodeling by plasmin: a new function for an old enzyme. J Biomed Biotechnol 2012:564259PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Ploug M, Ronne E, Behrendt N, Jensen AL, Blasi F et al (1991) Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol. J Biol Chem 266:1926–1933PubMedGoogle Scholar
  35. 35.
    Santibanez JF (2013) Transforming growth factor-Beta and urokinase-type plasminogen activator: dangerous partners in tumorigenesis-implications in skin cancer. ISRN Dermatol 2013:597927PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Smith HW, Marshall CJ (2010) Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 11:23–36PubMedCrossRefGoogle Scholar
  37. 37.
    Cesarman-Maus G, Hajjar KA (2005) Molecular mechanisms of fibrinolysis. Br J Haematol 129:307–321PubMedCrossRefGoogle Scholar
  38. 38.
    Nielsen LS, Hansen JG, Skriver L, Wilson EL, Kaltoft K et al (1982) Purification of zymogen to plasminogen activator from human glioblastoma cells by affinity chromatography with monoclonal antibody. Biochemistry 21:6410–6415PubMedCrossRefGoogle Scholar
  39. 39.
    Ellis V, Behrendt N, Dano K (1991) Plasminogen activation by receptor-bound urokinase. A kinetic study with both cell-associated and isolated receptor. J Biol Chem 266:12752–12758PubMedGoogle Scholar
  40. 40.
    Solberg H, Ploug M, Hoyer-Hansen G, Nielsen BS, Lund LR (2001) The murine receptor for urokinase-type plasminogen activator is primarily expressed in tissues actively undergoing remodeling. J Histochem Cytochem 49:237–246PubMedCrossRefGoogle Scholar
  41. 41.
    Loskutoff DJ, van Mourik JA, Erickson LA, Lawrence D (1983) Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells. Proc Natl Acad Sci USA 80:2956–2960PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Kruithof EK, Baker MS, Bunn CL (1995) Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood 86:4007–4024PubMedGoogle Scholar
  43. 43.
    Heeb MJ, Espana F, Geiger M, Collen D, Stump DC et al (1987) Immunological identity of heparin-dependent plasma and urinary protein C inhibitor and plasminogen activator inhibitor-3. J Biol Chem 262:15813–15816PubMedGoogle Scholar
  44. 44.
    Schleef RR, Loskutoff DJ (1988) Fibrinolytic system of vascular endothelial cells. Role of plasminogen activator inhibitors. Haemostasis 18:328–341PubMedGoogle Scholar
  45. 45.
    Zorio E, Gilabert-Estelles J, Espana F, Ramon LA, Cosin R et al (2008) Fibrinolysis: the key to new pathogenetic mechanisms. Curr Med Chem 15:923–929PubMedCrossRefGoogle Scholar
  46. 46.
    Tashiro Y, Nishida C, Sato-Kusubata K, Ohki-Koizumi M, Ishihara M et al (2012) Inhibition of PAI-1 induces neutrophil-driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice. Blood 119:6382–6393PubMedCrossRefGoogle Scholar
  47. 47.
    Loskutoff DJ, Samad F (1998) The adipocyte and hemostatic balance in obesity: studies of PAI-1. Arterioscler Thromb Vasc Biol 18:1–6PubMedCrossRefGoogle Scholar
  48. 48.
    Werb Z (1997) ECM and cell surface proteolysis: regulating cellular ecology. Cell 91:439–442PubMedCrossRefGoogle Scholar
  49. 49.
    Carmeliet P, Moons L, Lijnen R, Baes M, Lemaitre V et al (1997) Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet 17:439–444PubMedCrossRefGoogle Scholar
  50. 50.
    Lijnen HR, Silence J, Lemmens G, Frederix L, Collen D (1998) Regulation of gelatinase activity in mice with targeted inactivation of components of the plasminogen/plasmin system. Thromb Haemost 79:1171–1176PubMedGoogle Scholar
  51. 51.
    Lijnen HR, Silence J, Van Hoef B, Collen D (1998) Stromelysin-1 (MMP-3)-independent gelatinase expression and activation in mice. Blood 91:2045–2053PubMedGoogle Scholar
  52. 52.
    Lijnen HR, Van Hoef B, Collen D (2001) Inactivation of the serpin alpha(2)-antiplasmin by stromelysin-1. Biochim Biophys Acta 1547:206–213PubMedCrossRefGoogle Scholar
  53. 53.
    Watt FM, Huck WTS (2013) Role of the extracellular matrix in regulating stem cell fate. Nat Rev Mol Cell Biol 14:467–473PubMedCrossRefGoogle Scholar
  54. 54.
    Ehninger A, Trumpp A (2011) The bone marrow stem cell niche grows up: mesenchymal stem cells and macrophages move in. J Exp Med 208:421–428PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD et al (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466:829–834PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ et al (2006) Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124:407–421PubMedCrossRefGoogle Scholar
  57. 57.
    Mendez-Ferrer S, Lucas D, Battista M, Frenette PS (2008) Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452:442–447PubMedCrossRefGoogle Scholar
  58. 58.
    Gale RP (1985) Antineoplastic chemotherapy myelosuppression: mechanisms and new approaches. Exp Hematol 13(Suppl 16):3–7PubMedGoogle Scholar
  59. 59.
    Heissig B, Rafii S, Akiyama H, Ohki Y, Sato Y et al (2005) Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization. J Exp Med 202:739–750PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Ibrahim AA, Yahata T, Onizuka M, Dan T, Strihou De, Van Ypersele De Strihou C et al (2014) Inhibition of plasminogen activator inhibitor type-1 activity enhances rapid and sustainable hematopoietic regeneration. Stem Cells 32:946–958PubMedCrossRefGoogle Scholar
  61. 61.
    Kjoller L, Kanse SM, Kirkegaard T, Rodenburg KW, Ronne E et al (1997) Plasminogen activator inhibitor-1 represses integrin- and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation. Exp Cell Res 232:420–429PubMedCrossRefGoogle Scholar
  62. 62.
    Waltz DA, Natkin LR, Fujita RM, Wei Y, Chapman HA (1997) Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin. J Clin Invest 100:58–67PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Czekay R-P, Wilkins-Port CE, Higgins SP, Freytag J, Overstreet JM et al (2011) PAI-1: an Integrator of Cell Signaling and Migration. Int J Cell Biol 2011:9CrossRefGoogle Scholar
  64. 64.
    Stefansson S, Lawrence DA (1996) The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature 383:441–443PubMedCrossRefGoogle Scholar
  65. 65.
    Okumura Y, Kamikubo Y, Curriden SA, Wang J, Kiwada T et al (2002) Kinetic analysis of the interaction between vitronectin and the urokinase receptor. J Biol Chem 277:9395–9404PubMedCrossRefGoogle Scholar
  66. 66.
    Czekay RP, Aertgeerts K, Curriden SA, Loskutoff DJ (2003) Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol 160:781–791PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Estreicher A, Muhlhauser J, Carpentier JL, Orci L, Vassalli JD (1990) The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes. J Cell Biol 111:783–792PubMedCrossRefGoogle Scholar
  68. 68.
    Pluskota E, Soloviev DA, Plow EF (2003) Convergence of the adhesive and fibrinolytic systems: recognition of urokinase by integrin alpha Mbeta 2 as well as by the urokinase receptor regulates cell adhesion and migration. Blood 101:1582–1590PubMedCrossRefGoogle Scholar
  69. 69.
    Ploplis VA, French EL, Carmeliet P, Collen D, Plow EF (1998) Plasminogen deficiency differentially affects recruitment of inflammatory cell populations in mice. Blood 91:2005–2009PubMedGoogle Scholar
  70. 70.
    Gong Y, Hart E, Shchurin A, Hoover-Plow J (2008) Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice. J Clin Invest 118:3012–3024PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Hoyer-Hansen G, Ronne E, Solberg H, Behrendt N, Ploug M et al (1992) Urokinase plasminogen activator cleaves its cell surface receptor releasing the ligand-binding domain. J Biol Chem 267:18224–18229PubMedGoogle Scholar
  72. 72.
    Andolfo A, English WR, Resnati M, Murphy G, Blasi F et al (2002) Metalloproteases cleave the urokinase-type plasminogen activator receptor in the D1-D2 linker region and expose epitopes not present in the intact soluble receptor. Thromb Haemost 88:298–306PubMedGoogle Scholar
  73. 73.
    Resnati M, Pallavicini I, Wang JM, Oppenheim J, Serhan CN et al (2002) The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R. Proc Natl Acad Sci USA 99:1359–1364PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    de Paulis A, Montuori N, Prevete N, Fiorentino I, Rossi FW et al (2004) Urokinase induces basophil chemotaxis through a urokinase receptor epitope that is an endogenous ligand for formyl peptide receptor-like 1 and -like 2. J Immunol 173:5739–5748PubMedCrossRefGoogle Scholar
  75. 75.
    Tjwa M, Sidenius N, Moura R, Jansen S, Theunissen K et al (2009) Membrane-anchored uPAR regulates the proliferation, marrow pool size, engraftment, and mobilization of mouse hematopoietic stem/progenitor cells. J Clin Invest 119:1008–1018PubMedCentralPubMedGoogle Scholar
  76. 76.
    Selleri C, Montuori N, Ricci P, Visconte V, Carriero MV et al (2005) Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization. Blood 105:2198–2205PubMedCrossRefGoogle Scholar
  77. 77.
    Fietz T, Hattori K, Thiel E, Heissig B (2006) Increased soluble urokinase plasminogen activator receptor (suPAR) serum levels after granulocyte colony-stimulating factor treatment do not predict successful progenitor cell mobilization in vivo. Blood 107:3408–3409PubMedCrossRefGoogle Scholar
  78. 78.
    Lazarus HM, Haynesworth SE, Gerson SL, Caplan AI (1997) Human bone marrow-derived mesenchymal (stromal) progenitor cells (MPCs) cannot be recovered from peripheral blood progenitor cell collections. J Hematother 6:447–455PubMedGoogle Scholar
  79. 79.
    Hoogduijn MJ, Verstegen MM, Engela AU, Korevaar SS, Roemeling-van Rhijn M et al (2014) No evidence for circulating mesenchymal stem cells in patients with organ injury. Stem Cells Dev 23:2328–2335PubMedCrossRefGoogle Scholar
  80. 80.
    Vallabhaneni KC, Tkachuk S, Kiyan Y, Shushakova N, Haller H et al (2011) Urokinase receptor mediates mobilization, migration, and differentiation of mesenchymal stem cells. Cardiovasc Res 90:113–121PubMedCrossRefGoogle Scholar
  81. 81.
    Syrovets T, Lunov O, Simmet T (2012) Plasmin as a proinflammatory cell activator. J Leukoc Biol 92:509–519PubMedCrossRefGoogle Scholar
  82. 82.
    Gaestel M, Kotlyarov A, Kracht M (2009) Targeting innate immunity protein kinase signalling in inflammation. Nat Rev Drug Discov 8:480–499PubMedCrossRefGoogle Scholar
  83. 83.
    Aguirre-Ghiso JA, Liu D, Mignatti A, Kovalski K, Ossowski L (2001) Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol Biol Cell 12:863–879PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Nykjaer A, Conese M, Christensen EI, Olson D, Cremona O et al (1997) Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. EMBO J 16:2610–2620PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Sturge J, Wienke D, East L, Jones GE, Isacke CM (2003) GPI-anchored uPAR requires Endo180 for rapid directional sensing during chemotaxis. J Cell Biol 162:789–794PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Brizzi MF, Tarone G, Defilippi P (2012) Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche. Curr Opin Cell Biol 24:645–651PubMedCrossRefGoogle Scholar
  87. 87.
    Hynes RO (2009) The Extracellular Matrix: not Just Pretty Fibrils. Science 326:1216–1219PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Munakata S, Tashiro Y, Nishida C, Sato A, Komiyama H et al (2015) Inhibition of plasmin protects against colitis in mice by suppressing matrix metalloproteinase 9-mediated cytokine release from myeloid cells. Gastroenterology 148(565–578):e564Google Scholar
  89. 89.
    Rifkin DB, Mazzieri R, Munger JS, Noguera I, Sung J (1999) Proteolytic control of growth factor availability. APMIS 107:80–85PubMedCrossRefGoogle Scholar
  90. 90.
    Fredriksson L, Li H, Fieber C, Li X, Eriksson U (2004) Tissue plasminogen activator is a potent activator of PDGF-CC. EMBO J 23:3793–3802PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Dean RA, Cox JH, Bellac CL, Doucet A, Starr AE et al (2008) Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR + CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx. Blood 112:3455–3464PubMedCrossRefGoogle Scholar
  92. 92.
    Syrovets T, Simmet T (2004) Novel aspects and new roles for the serine protease plasmin. Cell Mol Life Sci 61:873–885PubMedCrossRefGoogle Scholar
  93. 93.
    Sato A, Nishida C, Sato-Kusubata K, Ishihara M, Tashiro Y et al (2015) Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking. Leukemia 29:145–156PubMedCrossRefGoogle Scholar
  94. 94.
    Yao Y, Tsirka SE (2010) The C terminus of mouse monocyte chemoattractant protein 1 (MCP1) mediates MCP1 dimerization while blocking its chemotactic potency. J Biol Chem 285:31509–31516PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Ishihara M, Nishida C, Tashiro Y, Gritli I, Rosenkvist J et al (2012) Plasmin inhibitor reduces T-cell lymphoid tumor growth by suppressing matrix metalloproteinase-9-dependent CD11b(+)/F4/80(+) myeloid cell recruitment. Leukemia 26:332–339PubMedCrossRefGoogle Scholar
  96. 96.
    Mei J, Liu Y, Dai N, Hoffmann C, Hudock KM et al (2012) Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice. J Clin Investig 122:974–986PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Song J, Wu C, Zhang X, Sorokin LM (2013) In vivo processing of CXCL5 (LIX) by matrix metalloproteinase (MMP)-2 and MMP-9 promotes early neutrophil recruitment in IL-1beta-induced peritonitis. J Immunol 190:401–410PubMedCrossRefGoogle Scholar
  98. 98.
    Okaji Y, Tashiro Y, Gritli I, Nishida C, Sato A et al (2012) Plasminogen deficiency attenuates postnatal erythropoiesis in male C57BL/6 mice through decreased activity of the LH-testosterone axis. Exp Hematol 40:143–154PubMedCrossRefGoogle Scholar
  99. 99.
    Lund LR, Green KA, Stoop AA, Ploug M, Almholt K et al (2006) Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice. EMBO J 25:2686–2697PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Romer J, Bugge TH, Pyke C, Lund LR, Flick MJ et al (1996) Plasminogen and wound healing. Nat Med 2:725PubMedCrossRefGoogle Scholar
  101. 101.
    Ma LJ, Mao SL, Taylor KL, Kanjanabuch T, Guan Y et al (2004) Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes 53:336–346PubMedCrossRefGoogle Scholar
  102. 102.
    Tamura Y, Kawao N, Okada K, Yano M, Okumoto K et al (2013) Plasminogen activator inhibitor-1 is involved in streptozotocin-induced bone loss in female mice. Diabetes 62:3170–3179PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Fadini GP, Albiero M, Vigili de Kreutzenberg S, Boscaro E, Cappellari R et al (2013) Diabetes impairs stem cell and proangiogenic cell mobilization in humans. Diabetes Care 36:943–949PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Schaffer M, Witte M, Becker HD (2002) Models to study ischemia in chronic wounds. Int J Low Extrem Wounds 1:104–111PubMedCrossRefGoogle Scholar
  105. 105.
    Clark RA, Lanigan JM, DellaPelle P, Manseau E, Dvorak HF et al (1982) Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization. J Invest Dermatol 79:264–269PubMedCrossRefGoogle Scholar
  106. 106.
    Bensaid W, Triffitt JT, Blanchat C, Oudina K, Sedel L et al (2003) A biodegradable fibrin scaffold for mesenchymal stem cell transplantation. Biomaterials 24:2497–2502PubMedCrossRefGoogle Scholar
  107. 107.
    Basiouny HS, Salama NM, Maadawi ZM, Farag EA (2013) Effect of bone marrow derived mesenchymal stem cells on healing of induced full-thickness skin wounds in albino rat. Int J Stem Cells 6:12–25PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Chiellini C, Cochet O, Negroni L, Samson M, Poggi M et al (2008) Characterization of human mesenchymal stem cell secretome at early steps of adipocyte and osteoblast differentiation. BMC Mol Biol 9:26PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Copland IB, Lord-Dufour S, Cuerquis J, Coutu DL, Annabi B et al (2009) Improved autograft survival of mesenchymal stromal cells by plasminogen activator inhibitor 1 inhibition. Stem Cells 27:467–477PubMedCrossRefGoogle Scholar
  110. 110.
    Tsai MS, Hwang SM, Chen KD, Lee YS, Hsu LW et al (2007) Functional network analysis of the transcriptomes of mesenchymal stem cells derived from amniotic fluid, amniotic membrane, cord blood, and bone marrow. Stem Cells 25:2511–2523PubMedCrossRefGoogle Scholar
  111. 111.
    Lin MT, Kuo IH, Chang CC, Chu CY, Chen HY et al (2008) Involvement of hypoxia-inducing factor-1alpha-dependent plasminogen activator inhibitor-1 up-regulation in Cyr61/CCN1-induced gastric cancer cell invasion. J Biol Chem 283:15807–15815PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    Tamama K, Kawasaki H, Kerpedjieva SS, Guan J, Ganju RK et al (2011) Differential roles of hypoxia inducible factor subunits in multipotential stromal cells under hypoxic condition. J Cell Biochem 112:804–817PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Neuss S, Becher E, Woltje M, Tietze L, Jahnen-Dechent W (2004) Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem Cells 22:405–414PubMedCrossRefGoogle Scholar
  114. 114.
    Muller-Ehmsen J, Krausgrill B, Burst V, Schenk K, Neisen UC et al (2006) Effective engraftment but poor mid-term persistence of mononuclear and mesenchymal bone marrow cells in acute and chronic rat myocardial infarction. J Mol Cell Cardiol 41:876–884PubMedCrossRefGoogle Scholar
  115. 115.
    Lane SW, Williams DA, Watt FM (2014) Modulating the stem cell niche for tissue regeneration. Nat Biotech 32:795–803CrossRefGoogle Scholar
  116. 116.
    Mooney DJ, Vandenburgh H (2008) Cell delivery mechanisms for tissue repair. Cell Stem Cell 2:205–213PubMedCrossRefGoogle Scholar
  117. 117.
    Daley GQ, Scadden DT (2008) Prospects for stem cell-based therapy. Cell 132:544–548PubMedCrossRefGoogle Scholar
  118. 118.
    Herren T, Swaisgood C, Plow EF (2003) Regulation of plasminogen receptors. Front Biosci 1:d1–d8CrossRefGoogle Scholar
  119. 119.
    Shen Y, Guo Y, Mikus P, Sulniute R, Wilczynska M et al (2012) Plasminogen is a key proinflammatory regulator that accelerates the healing of acute and diabetic wounds. Blood 119:5879–5887PubMedCrossRefGoogle Scholar
  120. 120.
    Neuss S, Schneider RK, Tietze L, Knuchel R, Jahnen-Dechent W (2010) Secretion of fibrinolytic enzymes facilitates human mesenchymal stem cell invasion into fibrin clots. Cells Tissues Organs 191:36–46PubMedCrossRefGoogle Scholar
  121. 121.
    Deng G, Curriden SA, Wang S, Rosenberg S, Loskutoff DJ (1996) Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release? J Cell Biol 134:1563–1571PubMedCrossRefGoogle Scholar
  122. 122.
    Bajou K, Masson V, Gerard RD, Schmitt PM, Albert V et al (2001) The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. J Cell Biol 152:777–784PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Myohanen H, Vaheri A (2004) Regulation and interactions in the activation of cell-associated plasminogen. Cell Mol Life Sci 61:2840–2858PubMedCrossRefGoogle Scholar
  124. 124.
    Menon LG, Picinich S, Koneru R, Gao H, Lin SY et al (2007) Differential gene expression associated with migration of mesenchymal stem cells to conditioned medium from tumor cells or bone marrow cells. Stem Cells 25:520–528PubMedCrossRefGoogle Scholar
  125. 125.
    Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659PubMedCrossRefGoogle Scholar
  126. 126.
    Hogan NM, Joyce MR, Murphy JM, Barry FP, O’Brien T et al (2013) Impact of Mesenchymal Stem Cell secreted PAI-1 on colon cancer cell migration and proliferation. Biochem Biophys Res Commun 435:574–579PubMedCrossRefGoogle Scholar
  127. 127.
    Shinagawa K, Kitadai Y, Tanaka M, Sumida T, Kodama M et al (2010) Mesenchymal stem cells enhance growth and metastasis of colon cancer. Int J Cancer 127:2323–2333PubMedCrossRefGoogle Scholar
  128. 128.
    Pulukuri SMK, Gorantla B, Dasari VR, Gondi CS, Rao JS (2010) Epigenetic Upregulation of Urokinase Plasminogen Activator Promotes the Tropism of Mesenchymal Stem Cells for Tumor Cells. Mol Cancer Res 8:1074–1083PubMedCentralPubMedCrossRefGoogle Scholar
  129. 129.
    De Boeck A, Pauwels P, Hensen K, Rummens JL, Westbroek W et al (2013) Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling. Gut 62:550–560PubMedCrossRefGoogle Scholar
  130. 130.
    Chandran VI, Eppenberger-Castori S, Venkatesh T, Vine KL, Ranson M (2015) HER2 and uPAR cooperativity contribute to metastatic phenotype of HER2-positive breast cancer. Oncoscience 2:207–224PubMedCentralCrossRefGoogle Scholar
  131. 131.
    Sier CF, Verspaget HW, Griffioen G, Verheijen JH, Quax PH et al (1991) Imbalance of plasminogen activators and their inhibitors in human colorectal neoplasia. Implications of urokinase in colorectal carcinogenesis. Gastroenterology 101:1522–1528PubMedGoogle Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Beate Heissig
    • 1
    • 4
  • Douaa Dhahri
    • 1
  • Salita Eiamboonsert
    • 1
  • Yousef Salama
    • 1
  • Hiroshi Shimazu
    • 2
  • Shinya Munakata
    • 2
  • Koichi Hattori
    • 2
    • 3
  1. 1.Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical ScienceUniversity of TokyoTokyoJapan
  2. 2.Division of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical ScienceUniversity of TokyoTokyoJapan
  3. 3.Center for Genome and Regenerative MedicineJuntendo University School of MedicineTokyoJapan
  4. 4.Atopy (Allergy) CenterJuntendo University School of MedicineTokyoJapan

Personalised recommendations