Paracrine mechanisms of mesenchymal stem cell-based therapy: Current status and perspectives

Cell Transplantation

Volumn 23, Issue 9, 2014, Pages 1045-1059

  Liang, Xiaoting ^a   Ding, Yue ^a,b   Zhang, Yuelin ^a   Tse, Hung Fat ^a   Lian, Qizhou ^a  

^a UNIVERSITY OF HONG KONG   (Hong Kong)

^b XIAMEN UNIVERSITY   (China)

Author keywords

Mechanism; Mesenchymal stem cells (MSCs); Paracrine effects

Indexed keywords

ANTIOXIDANT; ANGIOGENIC FACTOR; IMMUNOLOGIC FACTOR;

ANGIOGENESIS; APOPTOSIS; CARDIOVASCULAR DISEASE; CELL DIFFERENTIATION; CELL HOMING; CELL MIGRATION; CELL TRANSFER; CLINICAL TRIAL (TOPIC); DEGENERATIVE DISEASE; DNA MODIFICATION; EXOSOME; HUMAN; IMMUNOMODULATION; MESENCHYMAL STEM CELL TRANSPLANTATION; NONHUMAN; PARACRINE SIGNALING; REGULATORY MECHANISM; REVIEW; TISSUE REPAIR; BIOLOGICAL THERAPY; CYTOLOGY; MESENCHYMAL STROMA CELL; METABOLISM; TISSUE ENGINEERING; TRENDS;

ANGIOGENESIS INDUCING AGENTS; ANTIOXIDANTS; CELL- AND TISSUE-BASED THERAPY; HUMANS; IMMUNOLOGIC FACTORS; MESENCHYMAL STEM CELL TRANSPLANTATION; MESENCHYMAL STROMAL CELLS; PARACRINE COMMUNICATION; TISSUE ENGINEERING;

EID: 84906964309     PISSN: 09636897     EISSN: 15553892     Source Type: Journal    
DOI: 10.3727/096368913X667709     Document Type: Review

References (137)

1. Abbott, J. D.; Huang, Y.; Liu, D.; Hickey, R.; Krause, D. S.; Giordano, F. J. Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation 110(21):3300-3305; 2004.
2. Adutler-Lieber, S.; Ben-Mordechai, T.; Naftali-Shani, N.; Asher, E.; Loberman, D.; Raanani, E.; Leor, J. Human macrophage regulation via interaction with cardiac adipose tissue-derived mesenchymal stromal cells. J. Cardiovasc. Pharmacol. Ther. 18(1):78-86; 2013.
3. Aksu, A. E.; Horibe, E.; Sacks, J.; Ikeguchi, R.; Breitinger, J.; Scozio, M.; Unadkat, J.; Feili-Hariri, M. Co-infusion of donor bone marrow with host mesenchymal stem cells treats GVHD and promotes vascularized skin allograft survival in rats. Clin. Immunol. 127(3):348-358; 2008.
4. Alfaro, M. P.; Vincent, A.; Saraswati, S.; Thorne, C. A.; Hong, C. C.; Lee, E.; Young, P. P. SFRP2 suppression of bone morphogenic protein (BMP) and Wnt signaling mediates mesenchymal stem cell (MSC) self-renewal promoting engraftment and myocardial repair. J. Biol. Chem. 285(46):35645-35653; 2010.
5. Alvarez-Dolado, M.; Pardal, R.; Garcia-Vardugo, J. M.; Fike, J. R.; Lee, H. O.; Pfeffer, K.; Lois, C.; Morrison, S. J.; Alvarez-Buylla, A. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425(6961):968-973; 2003.
6. Amado, L. C.; Saliaris, A. P.; Schuleri, K. H.; St John, M.; Xie, J. S.; Cattaneo, S.; Durand, D. J.; Fitton, T.; Kuang, J. Q.; Stewart, G.; Lehrke, S.; Baumgartner, W. W.; Martin, B. J.; Heldman, A. W.; Hare, J. M. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc. Natl. Acad. Sci. USA 102(32):11474-11479; 2005.
7. Amsalem, Y.; Mardor, Y.; Feinberg, M. S.; Landa, N.; Miller, L.; Daniels, D.; Ocherashvilli, A.; Holbova, R.; Yosef, O.; Barbash, I. M.; Leor, J. Iron-oxide labeling and outcome of transplanted mesenchymal stem cells in the infarcted myocardium. Circulation 116(11 Suppl):I38-I45; 2007.
8. Arthur, A.; Zannettino, A.; Gronthos, S. The therapeutic applications of multipotential mesenchymal/stromal stem cells in skeletal tissue repair. J. Cell. Physiol. 218(2):237-245; 2009.
9. Asanuma, H.; Meldrum, D. R.; Meldrum, K. K. Therapeutic applications of mesenchymal stem cells to repair kidney injury. J. Urol. 184(1):26-33; 2010.
10. Assis, A. C.; Carvalho, J. L.; Jacoby, B. A.; Ferreira, R. L.; Castanheira, P.; Diniz, S. O.; Cardoso, V. N.; Goes, A. M.; Ferreira, A. J. Time-dependent migration of systemically delivered bone marrow mesenchymal stem cells to the infarcted heart. Cell Transplant. 19(2):219-230; 2010.
11. Bartholomew, A.; Sturgeon, C.; Siatskas, M.; Ferrer, K.; McIntosh, K.; Patil, S.; Hardy, W.; Devine, S.; Ucker, D.; Deans, R.; Moseley, A.; Hoffman, R. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp. Hematol. 30(1):42-48; 2002.
12. Becker, A. J.; McCulloch, E. A.; Till, J. E. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 197:452-454; 1963.
13. Chang, C. P.; Chio, C. C.; Cheong, C. U.; Chao, C. M.; Cheng, B. C.; Lin, M. T. Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury. Clin. Sci. 124(3):165-176; 2013.
14. Chen, J.; Chemaly, E.; Liang, L.; Kho, C.; Lee, A.; Park, J.; Altman, P.; Schecter, A. D.; Hajjar, R. J.; Tarzami, S. T. Effects of CXCR4 gene transfer on cardiac function after ischemia-reperfusion injury. Am. J. Pathol. 176(4):1705-1715; 2010.
15. Chen, S. L.; Fang, W. W.; Ye, F.; Liu, Y. H.; Qian, J.; Shan, S. J.; Zhang, J. J.; Chunhua, R. Z.; Liao, L. M.; Lin, S.; Sun, J. P. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am. J. Pathol. 94(1):92-95; 2004.
16. Cselenyak, A.; Pankotai, E.; Horvath, E. M.; Kiss, L.; Lacza, Z. Mesenchymal stem cells rescue cardiomyoblasts from cell death in an in vitro ischemia model via direct cell-to-cell connections. BMC Cell Biol. 11:29; 2010.
17. Cui, X.; Chen, J.; Zacharek, A.; Li, Y.; Roberts, C.; Kapke, A.; Savant-Bhonsale, S.; Chopp, M. Nitric oxide donor upregulation of stromal cell-derived factor-1/ chemokine(CXC motif) receptor 4 enhances bone marrow stromal cell migration into ischemic brain after stroke. Stem Cells 25(11):2777-2785; 2007.
18. Dayan, V.; Yannarelli, G.; Billia, F.; Filomeno, P.; Wang, X. H.; Davies, J. E.; Keating, A. Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction. Basic Res. Cardiol. 106(6):1299-1310; 2011.
19. Deak, E.; Seifried, E.; Henschler, R. Homing pathways of mesenchymal stromal cells (MSCs) and their role in clinical applications. Int. Rev. Immunol. 29(5):514-529; 2010.
20. Devine, S. M.; Cobbs, C.; Jennings, M.; Bartholomew, A.; Hoffman, R. Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood 101(8):2999-3001; 2003.
21. Di Nicola, M.; Carlo-Stella, C.; Magni, M.; Milanesi, M.; Longoni, P. D.; Matteucci, P.; Grisanti, S.; Gianni, A. M. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99(10):3838-3843; 2002.
22. Djouad, F.; Fritz, V.; Apparailly, F.; Louis-Plence, P.; Bony, C.; Sany, J.; Jorgensen, C.; Noel, D. Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis. Arthritis Rheum. 52(5):1595-1603; 2005.
23. Dong, F.; Harvey, J.; Finan, A.; Weber, K.; Agarwal, U.; Penn, M. S. Myocardial CXCR4 expression is required for mesenchymal stem cell mediated repair following acute myocardial infarction. Circulation 126(3):314-324; 2012.
24. Eun, L. Y.; Song, B. W.; Cha, M. J.; Song, H.; Kim, I. K.; Choi, E.; Chang, W.; Lim, S.; Choi, E. J.; Ham, O.; Lee, S. Y.; Byun, K. H.; Jang, Y.; Hwang, K. C. Overexpression of phosphoinositide-3-kinase class II alpha enhances mesenchymal stem cell survival in infarcted myocardium. Biochem. Biophys. Res. Commun. 402(2):272-279; 2010.
25. Fan, L.; Lin, C.; Zhuo, S.; Chen, L.; Liu, N.; Luo, Y.; Fang, J.; Huang, Z.; Lin, Y.; Chen, J. Transplantation with survivin-engineered mesenchymal stem cells results in better prognosis in a rat model of myocardial infarction. Eur. J. Heart Fail. 11(11):1023-1030; 2009.
26. Fierro, F. A.; Kalomoiris, S.; Sondergaard, C. S.; Nolta, J. A. Effects on proliferation and differentiation of multipotent bone marrow stromal cells engineered to express growth factors for combined cell and gene therapy. Stem Cells 29(11):1727-1737; 2011.
27. Fisher, A. B. Reactive oxygen species and cell signaling with lung ischemia. Undersea Hyperb. Med. 31(1):97-103; 2004.
28. Folkman, J. Tumor angiogenesis: Therapeutic implications. N. Engl. J. Med. 285(21):1182-1186; 1971.
29. Forsythe, J. A.; Jiang, B. H.; Iyer, N. V.; Agani, F.; Leung, S. W.; Koos, R. D.; Semenza, G. L. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 16(9):4604-4613; 1996.
30. Fu, Q. L.; Chow, Y. Y.; Sun, S. J.; Zeng, Q. X.; Li, H. B.; Shi, J. B.; Sun, Y. Q.; Wen, W.; Tse, H. F.; Lian, Q.; Xu, G. Mesenchymal stem cells derived from human induced pluripotent stem cells modulate T-cell phenotypes in allergic rhinitis. Allergy 67(10):1215-1222; 2012.
31. Gatti, S.; Bruno, S.; Deregibus, M. C.; Sordi, A.; Cantaluppi, V.; Tetta, C.; Camussi, G. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol. Dial. Transplant. 26(5):1474-1483; 2011.
32. Ge, W.; Jiang, J.; Baroja, M. L.; Arp, J.; Zassoko, R.; Liu, W.; Bartholomew, A.; Garcia, B.; Wang, H. Infusion of mesenchymal stem cells and rapamycin synergize to attenuate alloimmune responses and promote cardiac allograft tolerance. Am. J. Transplant. 9(8):1760-1772; 2009.
33. Gerber, H. P.; Dixit, V.; Ferrara, N. Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J. Biol. Chem. 273(21):13313-13316; 1998.
34. Gnecchi, M.; He, H.; Liang, O. D.; Melo, L. G.; Morello, F.; Mu, H.; Noiseux, N.; Zhang, L.; Pratt, R. E.; Ingwall, J. S.; Dzau V. J. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat. Med. 11(4):367-368; 2005.
35. Gnecchi, M.; He, H.; Noiseux, N.; Liang, O. D.; Zhang, L.; Morello, F.; Mu, H.; Melo, L. G.; Pratt, R. E.; Ingwall, J. S.; Dzau, V. J. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 20(6):661-669; 2006.
36. Green, D. R.; Reed, J. C. Mitochondria and apoptosis. Science 281(5381):1309-1312; 1998.
37. Hatzistergos, K. E.; Quevedo, H.; Oskouei, B. N.; Hu, Q.; Feigenbaum, G. S.; Margitich, I. S.; Mazhari, R.; Boyle, A. J.; Zambrano, J. P.; Rodriguez, J. E.; Dulce, R.; Pattany, P. M.; Valdes, D.; Revilla, C.; Heldman, A. W.; McNiece, I.; Hare, J. M. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ. Res. 107(7):913-922; 2010.
38. He, W.; Zhang, L.; Ni, A.; Zhang, Z.; Mirotsou, M.; Mao, L.; Pratt, R. E.; Dzau, V. J. Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction. Proc. Natl. Acad. Sci. USA 107(49):21110-21115; 2010.
39. Hegyi, B.; Kudlik, G.; Monostori, E.; Uher, F. Activated T-cells and pro-inflammatory cytokines differentially regulate prostaglandin E2 secretion by mesenchymal stem cells. Biochem. Biophys. Res. Commun. 419(2):215-220; 2012.
40. Henry, T. D.; Annex, B. H.; McKendall, G. R.; Azrin, M. A.; Lopez, J. J.; Giordano, F. J.; Shah, P. K.; Willerson, J. T.; Benza, R. L.; Berman, D. S.; Gibson, C. M.; Bajamonde, A.; Rundle, A. C.; Fine, J.; McCluskey, E. R.; Viva Investigators. The VIVA trial: Vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation 107(10):1359-1365; 2003.
41. Huang, N. F.; Lam, A.; Fang, Q.; Sievers, R. E.; Li, S.; Lee, R. J. Bone marrow-derived mesenchymal stem cells in fibrin augment angiogenesis in the chronically infarcted myocardium. Regen. Med. 4(4):527-538; 2009.
42. Ilic, D.; Almeida, E. A.; Schlaepfer, D. D.; Dazin, P.; Aizawa, S.; Damsky, C. H. Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis. J. Cell Biol. 143(2):547-560; 1998.
43. Islam, M. N.; Das, S. R.; Emin, M. T.; Wei, M.; Sun, L.; Westphalen, K.; Rowlands, D. J.; Quadri, S. K.; Bhattacharya, S.; Bhattacharya, J. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat. Med. 18(5):759-765; 2012.
44. Jiang, B. H.; Rue, E.; Wang, G. L.; Roe, R.; Semenza, G. L. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J. Biol. Chem. 271(30):17771-17778; 1996.
45. Jiang, W.; Ma, A.; Wang, T.; Han, K.; Liu, Y.; Zhang, Y.; Dong, A.; Du, Y.; Huang, X.; Wang, J.; Lei, X.; Zheng, X. Homing and differentiation of mesenchymal stem cells delivered intravenously to ischemic myocardium in vivo: A time-series study. Pflugers Arch. 453(1):43-52; 2006.
46. Jiang, X. X.; Zhang, Y.; Liu, B.; Zhang, S. X.; Wu, Y.; Yu, X. D.; Mao, N. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105(10):4120-4126; 2005.
47. Kahles, T.; Luedike, P.; Endres, M.; Galla, H. J.; Steinmetz, H.; Busse, R.; Neumann-Haefelin, T.; Brandes, R. P. NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke 38(11):3000-3006; 2007.
48. Kajstura, J.; Rota, M.; Whang, B.; Cascapera, S.; Hosoda, T.; Bearzi, C.; Nurzynska, D.; Kasahara, H.; Zias, E.; Bonafe, M.; Nadal-Ginard, B.; Torella, D.; Nascimbene, A.; Quaini, F.; Urbanek, K.; Leri, A.; Anversa, P. Bone marrow cells differentiate in cardiac cell lineages after infarction independently of cell fusion. Circ. Res. 96(1):127-137; 2005.
49. Kamata, T. Roles of Nox1 and other Nox isoforms in cancer development. Cancer Sci. 100(8):1382-1388; 2009.
50. Kamihata, H.; Matsubara, H.; Nishiue, T.; Fujiyama, S.; Tsutsumi, Y.; Ozono, R.; Masaki, H.; Mori, Y.; Iba, O.; Tateishi, E.; Kosaki, A.; Shintani, S.; Murohara, T.; Imaizumi, T.; Iwasaka, T. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 104(9):1046-1052; 2001.
51. Kanki, S.; Segers, V. F.; Wu, W.; Kakkar, R.; Gannon, J.; Sys, S. U.; Sandrasagra, A.; Lee, R. T. Stromal cell-derived factor-1 retention and cardioprotection for ischemic myocardium. Circ. Heart Fail. 4(4):509-518; 2011.
52. Kawada, H.; Fujita, J.; Kinjo, K.; Matsuzaki, Y.; Tsuma, M.; Miyatake, H.; Muguruma, Y.; Tsuboi, K.; Itabashi, Y.; Ikeda, Y.; Ogawa, S.; Okano, H.; Hotta, T.; Ando, K.; Fukuda, K. Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood 104(12):3581-3587; 2004.
53. Kim, S. W.; Han, H.; Chae, G. T.; Lee, S. H.; Bo, S.; Yoon, J. H.; Lee, Y. S.; Lee, K. S.; Park, H. K.; Kang, K. S. Successful stem cell therapy using umbilical cord blood-derived multipotent stem cells for Buerger’s disease and ischemic limb disease animal model. Stem Cells 24(6):1620-1626; 2006.
54. Kinnaird, T.; Stabile, E.; Burnett, M. S.; Epstein, S. E. Bone-marrow-derived cells for enhancing collateral development: Mechanisms, animal data, and initial clinical experiences. Circ. Res. 95(4):354-363; 2004.
55. Kinnaird, T.; Stabile, E.; Burnett, M. S.; Shou, M.; Lee, C. W.; Barr, S.; Fuchs, S.; Epstein, S. E. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 109(12): 1543-1549; 2004.
56. Kitaori, T.; Ito, H.; Schwarz, E. M.; Tsutsumi, R.; Yoshitomi, H.; Oishi, S.; Nakano, M.; Fujii, N.; Nagasawa, T.; Nakamura, T. 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(3):813-823; 2009.
57. Kong, D.; Melo, L. G.; Gnecchi, M.; Zhang, L.; Mostoslavsky, G.; Liew, C. C.; Pratt, R. E.; Dzau, V. J. Cytokine-induced mobilization of circulating endothelial progenitor cells enhances repair of injured arteries. Circulation 110(14):2039-2046; 2004.
58. Kucic, T.; Copland, I. B.; Cuerquis, J.; Coutu, D. L.; Chalifour, L. E.; Gagnon, R. F.; Galipeau, J. Mesenchymal stromal cells genetically engineered to overexpress IGF-I enhance cell-based gene therapy of renal failure-induced anemia. Am. J. Physiol. Renal Physiol. 295(2):F488-F496; 2008.
59. Laflamme, M. A.; Zbinden, S.; Epstein, S. E.; Murry, C. E. Cell-based therapy for myocardial ischemia and infarction: Pathophysiological mechanisms. Annu. Rev. Pathol. 2:307-339; 2007.
60. Lai, R. C.; Arslan, F.; Lee, M. M.; Sze, N. S.; Choo, A.; Chen, T. S.; Salto-Tellez, M.; Timmers, L.; Lee, C. N.; El Oakley, R. M.; Pasterkamp, G.; de Kleijn, D. P.; Lim, S. K. Exosome secreted by MSC reduces myocardial ischemia/ reperfusion injury. Stem Cell Res. 4(3):214-222; 2010.
61. Lai, R. C.; Tan, S. S.; Teh, B. J.; Sze, S. K.; Arslan, F.; de Kleijn, D. P.; Choo, A.; Lim, S. K. Proteolytic potential of the MSC exosome proteome: Implications for an exo-some-mediated delivery of therapeutic proteasome. Int. J. Proteomics. 2012:971907; 2012.
62. Lee, B. C.; Hsu, H. C.; Tseng, W. Y.; Chen, C. Y.; Lin, H. J.; Ho, Y. L.; Su, M. J.; Chen, M. F. Cell therapy generates a favourable chemokine gradient for stem cell recruitment into the infarcted heart in rabbits. Eur. J. Heart Fail. 11(3):238-245; 2009.
63. Leroux, L.; Descamps, B.; Tojais, N. F.; Seguy, B.; Oses, P.; Moreau, C.; Daret, D.; Ivanovic, Z.; Boiron, J. M.; Lamaziere, J. M.; Dufourcq, P.; Couffinhal, T.; Duplaa, C. Hypoxia preconditioned mesenchymal stem cells improve vascular and skeletal muscle fiber regeneration after ischemia through a Wnt4-dependent pathway. Mol. Ther. 18(8):1545-1552; 2010.
64. Li, J.; Li, D.; Liu, X.; Tang, S.; Wei, F. Human umbilical cord mesenchymal stem cells reduce systemic inflammation and attenuate LPS-induced acute lung injury in rats. J. Inflamm. 9(1):33; 2012.
65. Li, W.; Ma, N.; Ong, L. L.; Nesselmann, C.; Klopsch, C.; Ladilov, Y.; Furlani, D.; Piechaczek, C.; Moebius, J. M.; Lutzow, K.; Lendlein, A.; Stamm, C.; Li, R. K.; Steinhoff, G. Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells 25(8):2118-2127; 2007.
66. Li, W.; Ren, G.; Huang, Y.; Su, J.; Han, Y.; Li, J.; Chen, X.; Cao, K.; Chen, Q.; Shou, P.; Zhang, L.; Yuan, Z. R.; Roberts, A. I.; Shi, S.; Le, A. D.; Shi, Y. Mesenchymal stem cells: A double-edged sword in regulating immune responses. Cell Death Differ. 19(9):1505-1513; 2012.
67. Lian, Q. Z.; Zhang, Y. L.; Zhang, J. Q.; Zhang, H. K.; Wu, X. G.; Zhang, Y.; Lam, F. F. Y.; Kang, S.; Xia, J. C.; Lai, W. H.; Au, K. W.; Chow, Y. Y.; Siu, C. W.; Lee, C. N.; Tse, H. F. Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice. Circulation 121(9):1113-1123; 2010.
68. Lin, F.; Moran, A.; Igarashi, P. Intrarenal cells, not bone marrow-derived cells, are the major source for regeneration in postischemic kidney. J. Clin. Invest. 115(7):1756-1764; 2005.
69. Liu, D.; Huang, L.; Wang, Y.; Wang, W.; Wehrens, X. H.; Belousova, T.; Abdelrahim, M.; DiMattia, G.; Sheikh-Hamad, D. Human stanniocalcin-1 suppresses angiotensin II-induced superoxide generation in cardiomyocytes through UCP3-mediated anti-oxidant pathway. PLoS One 7(5): e36994; 2012.
70. Liu, H.; Lu, K.; MacAry, P. A.; Wong, K. L.; Heng, A.; Cao, T.; Kemeny, D. M. Soluble molecules are key in maintaining the immunomodulatory activity of murine mesenchymal stromal cells. J. Cell. Sci. 125(Part 1):200-208; 2012.
71. Liu, H.; McTaggart, S. J.; Johnson, D. W.; Gobe, G. C. Original article anti-oxidant pathways are stimulated by mesenchymal stromal cells in renal repair after ischemic injury. Cytotherapy 14(2):162-172; 2012.
72. Liu, Z. Y.; Ganju, R. K.; Wang, J. F.; Schweitzer, K.; Weksler, B.; Avraham, S.; Groopman, J. E. Characterization of signal transduction pathways in human bone marrow endothelial cells. Blood 90(6):2253-2259; 1997.
73. Lobo, M.; Zachary, I. Nuclear localization and apoptotic regulation of an amino-terminal domain focal adhesion kinase fragment in endothelial cells. Biochem. Biophys. Res. Commun. 276(3):1068-1074; 2000.
74. Lull, M. E.; Block, M. L. Microglial activation and chronic neurodegeneration. Neurotherapeutics 7(4):354-365; 2010.
75. Luo, Y.; Wang, Y.; Poynter, J. A.; Manukyan, M. C.; Herrmann, J. L.; Abarbanell, A. M.; Weil, B. R.; Meldrum, D. R. Pretreating mesenchymal stem cells with interleukin-1beta and transforming growth factor-beta synergistically increases vascular endothelial growth factor production and improves mesenchymal stem cell-mediated myocardial protection after acute ischemia. Surgery 151(3):353-363; 2012.
76. Markel, T. A.; Wang, Y.; Herrmann, J. L.; Crisostomo, P. R.; Wang, M.; Novotny, N. M.; Herring, C. M.; Tan, J.; Lahm, T.; Meldrum, D. R. 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(6):H2308-H2314; 2008.
77. Meisel, R.; Zibert, A.; Laryea, M.; Gobel, U.; Daubener, W.; Dilloo, D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 103(12): 4619-4621; 2004.
78. Minguell, J. J.; Erices, A. Mesenchymal stem cells and the treatment of cardiac disease. Exp. Biol. Med. 231(1): 39-49; 2006.
79. Mirotsou, M.; Jayawardena, T. M.; Schmeckpeper, J.; Gnecchi, M.; Dzau, V. J. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J. Mol. Cell. Cardiol. 50(2):280-289; 2011.
80. Mirotsou, M.; Zhang, Z.; Deb, A.; Zhang, L.; Gnecchi, M.; Noiseux, N.; Mu, H.; Pachori, A.; Dzau, V. Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc. Natl. Acad. Sci. USA 104(5):1643-1648; 2007.
81. Muller-Ehmsen, J.; Krausgrill, B.; Burst, V.; Schenk, K.; Neisen, U. C.; Fries, J. W.; Fleischmann, B. K.; Hescheler, J.; Schwinger, R. H. Effective engraftment but poor midterm persistence of mononuclear and mesenchymal bone marrow cells in acute and chronic rat myocardial infarction. J. Mol. Cell. Cardiol. 41(5):876-884; 2006.
82. Murry, C. E.; Soonpaa, M. H.; Reinecke, H.; Nakajima, H.; Nakajima, H. O.; Rubart, M.; Pasumarthi, K. B.; Virag, J. I.; Bartelmez, S. H.; Poppa, V.; Bradford, G.; Dowell, J. D.; Williams, D. A.; Field, L. J. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428(6983):664-668; 2004.
83. Nagaya, N.; Fujii, T.; Iwase, T.; Ohgushi, H.; Itoh, T.; Uematsu, M.; Yamagishi, M.; Mori, H.; Kangawa, K.; Kitamura, S. Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis. Am. J. Physiol. Heart Circ. Physiol. 287(6):H2670-H2676; 2004.
84. Nasef, A.; Mathieu, N.; Chapel, A.; Frick, J.; Francois, S.; Mazurier, C.; Boutarfa, A.; Bouchet, S.; Gorin, N. C.; Thierry, D.; Fouillard, L. Immunosuppressive effects of mesenchymal stem cells: Involvement of HLA-G. Transplantation 84(2):231-237; 2007.
85. Ohkouchi, S.; Block, G. J.; Katsha, A. M.; Kanehira, M.; Ebina, M.; Kikuchi, T.; Saijo, Y.; Nukiwa, T.; Prockop, D. J. Mesenchymal stromal cells protect cancer cells from ROS-induced apoptosis and enhance the Warburg effect by secreting STC1. Mol. Ther. 20(2):417-423; 2012.
86. Okazaki, T.; Magaki, T.; Takeda, M.; Kajiwara, Y.; Hanaya, R.; Sugiyama, K.; Arita, K.; Nishimura, M.; Kato, Y.; Kurisu, K. Intravenous administration of bone marrow stromal cells increases survivin and Bcl-2 protein expression and improves sensorimotor function following ischemia in rats. Neurosci. Lett. 430(2):109-114; 2008.
87. Oltvai, Z. N.; Milliman, C. L.; Korsmeyer, S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74(4):609-619; 1993.
88. O’Reilly, M. S.; Holmgren, L.; Shing, Y.; Chen, C.; Rosenthal, R. A.; Moses, M.; Lane, W. S.; Cao, Y.; Sage, E. H.; Folkman, J. Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79(2):315-328; 1994.
89. Orlic, D.; Kajstura, J.; Chimenti, S.; Bodine, D. M.; Leri, A.; Anversa, P. Bone marrow stem cells regenerate infarcted myocardium. Pediatr. Transplant. 7(Suppl 3):86-88; 2003.
90. Orlic, D.; Kajstura, J.; Chimenti, S.; Jakoniuk, I.; Anderson, S. M.; Li, B.; Pickel, J.; McKay, R.; Nadal-Ginard, B.; Bodine, D. M.; Leri, A.; Anversa, P. Bone marrow cells regenerate infarcted myocardium. Nature 410(6829):701-705; 2001.
91. Orr, W. C.; Sohal, R. S. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263(5150):1128-1130; 1994.
92. Otsuru, S.; Tamai, K.; Yamazaki, T.; Yoshikawa, H.; Kaneda, Y. Circulating bone marrow-derived osteoblast progenitor cells are recruited to the bone-forming site by the CXCR4/stromal cell-derived factor-1 pathway. Stem Cells 26(1):223-234; 2008.
93. Pan, G. Z.; Yang, Y.; Zhang, J.; Liu, W.; Wang, G. Y.; Zhang, Y. C.; Yang, Q.; Zhai, F. X.; Tai, Y.; Liu, J. R.; Zhang, Q.; Chen, G. H. Bone marrow mesenchymal stem cells ameliorate hepatic ischemia/reperfusion injuries via inactivation of the MEK/ERK signaling pathway in rats. J. Surg. Res. 178(2):935-948; 2012.
94. Pasha, Z.; Wang, Y.; Sheikh, R.; Zhang, D.; Zhao, T.; Ashraf, M. Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. Cardiovasc. Res. 77(1):134-142; 2008.
95. Penna, C.; Raimondo, S.; Ronchi, G.; Rastaldo, R.; Mancardi, D.; Cappello, S.; Losano, G.; Geuna, S.; Pagliaro, P. Early homing of adult mesenchymal stem cells in normal and infarcted isolated beating hearts. J. Cell. Mol. Med. 12(2):507-521; 2008.
96. Pittenger, M. F.; Martin, B. J. Mesenchymal stem cells and their potential as cardiac therapeutics. Circ. Res. 95(1):9-20; 2004.
97. Plotnikov, E. Y.; Khryapenkova, T. G.; Vasileva, A. K.; Marey, M. V.; Galkina, S. I.; Isaev, N. K.; Sheval, E. V.; Polyakov, V. Y.; Sukhikh, G. T.; Zorov, D. B. Cell-to-cell cross-talk between mesenchymal stem cells and cardiomyocytes in co-culture. J. Cell. Mol. Med. 12(5A):1622-1631; 2008.
98. Polchert, D.; Sobinsky, J.; Douglas, G.; Kidd, M.; Moadsiri, A.; Reina, E.; Genrich, K.; Mehrotra, S.; Setty, S.; Smith, B.; Bartholomew, A. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur. J. Immunol. 38(6):1745-1755; 2008.
99. Pons, J.; Huang, Y.; Arakawa-Hoyt, J.; Washko, D.; Takagawa, J.; Ye, J.; Grossman, W.; Su, H. VEGF improves survival of mesenchymal stem cells in infarcted hearts. Biochem. Biophys. Res. Commun. 376(2):419-422; 2008.
100. Pugh, C. W.; O’Rourke, J. F.; Nagao, M.; Gleadle, J. M.; Ratcliffe, P. J. Activation of hypoxia-inducible factor-1; definition of regulatory domains within the alpha subunit. J. Biol. Chem. 272(17):11205-11214; 1997.
101. Ratajczak, J.; Wysoczynski, M.; Hayek, F.; Janowska- Wieczorek, A.; Ratajczak, M. Z. Membrane-derived microvesicles: Important and underappreciated mediators of cell-to-cell communication. Leukemia 20(9):1487-1495; 2006.
102. Ren, G.; Zhang, L.; Zhao, X.; Xu, G.; Zhang, Y.; Roberts, A. I.; Zhao, R. C.; Shi, Y. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2(2):​ 141-150; 2008.
103. Ripa, R. S.; Jorgensen, E.; Wang, Y.; Thune, J. J.; Nilsson, J. C.; Sondergaard, L.; Johnsen, H. E.; Kober, L.; Grande, P.; Kastrup, J. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: Result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial. Circulation 113(16):1983-1992; 2006.
104. Rosova, I.; Dao, M.; Capoccia, B.; Link, D.; Nolta, J. A. Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 26(8):2173-2182; 2008.
105. Sattler, C.; Steinsdoerfer, M.; Offers, M.; Fischer, E.; Schierl, R.; Heseler, K.; Daubener, W.; Seissler, J. Inhibition of T-cell proliferation by murine multipotent mesenchymal stromal cells is mediated by CD39 expression and adenosine generation. Cell Transplant. 20(8):1221-1230; 2011.
106. Schuleri, K. H.; Boyle, A. J.; Hare, J. M. Mesenchymal stem cells for cardiac regenerative therapy. Handb. Exp. Pharmacol. 180:195-218; 2007.
107. Selmani, Z.; Naji, A.; Zidi, I.; Favier, B.; Gaiffe, E.; Obert, L.; Borg, C.; Saas, P.; Tiberghien, P.; Rouas-Freiss, N.; Carosella, E. D.; Deschaseaux, F. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells 26(1):212-222; 2008.
108. Shabbir, A.; Zisa, D.; Suzuki, G.; Lee, T. Heart failure therapy mediated by the trophic activities of bone marrow mesenchymal stem cells: A noninvasive therapeutic regimen. Am. J. Physiol. Heart Circ. Physiol. 296(6):H1888-H1897; 2009.
109. Sheng, H.; Wang, Y.; Jin, Y.; Zhang, Q.; Zhang, Y.; Wang, L.; Shen, B.; Yin, S.; Liu, W.; Cui, L.; Li, N. A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res. 18(8):846-857; 2008.
110. Shintani, S.; Murohara, T.; Ikeda, H.; Ueno, T.; Sasaki, K.; Duan, J.; Imaizumi, T. Augmentation of postnatal neo-vascularization with autologous bone marrow transplantation. Circulation 103(6):897-903; 2001.
111. Sohal, R. S.; Ku, H. H.; Agarwal, S.; Forster, M. J.; Lal, H. Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse. Mech. Ageing Dev. 74(1-2): 121-133; 1994.
112. Song, Y. S.; Lee, H. J.; Doo, S. H.; Lee, S. J.; Lim, I.; Chang, K. T.; Kim, S. U. Mesenchymal stem cells over-expressing hepatocyte growth factor (HGF) inhibit collagen deposit and improve bladder function in rat model of bladder outlet obstruction. Cell Transplant. 21(8):1641-1650; 2012.
113. Sudres, M.; Norol, F.; Trenado, A.; Gregoire, S.; Charlotte, F.; Levacher, B.; Lataillade, J. J.; Bourin, P.; Holy, X.; Vernant, J. P.; Klatzmann, D.; Cohen, J. L. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J. Immunol. 176(12):7761-7767; 2006.
114. Sun, Y. Q.; Deng, M. X.; He, J.; Zeng, Q. X.; Wen, W.; Wong, D. S.; Tse, H. F.; Xu, G.; Lian, Q.; Shi, J.; Fu, Q. L. Human pluripotent stem cell-derived mesenchymal stem cells prevent allergic airway inflammation in mice. Stem Cells 30(12):2692-2699; 2012.
115. Tang, J.; Wang, J.; Yang, J.; Kong, X.; Zheng, F.; Guo, L.; Zhang, L.; Huang, Y. Mesenchymal stem cells over-expressing SDF-1 promote angiogenesis and improve heart function in experimental myocardial infarction in rats. Eur. J. Cardiothorac. Surg. 36(4):644-650; 2009.
116. Tang, J. M.; Wang, J. N.; Zhang, L.; Zheng, F.; Yang, J. Y.; Kong, X.; Guo, L. Y.; Chen, L.; Huang, Y. Z.; Wan, Y.; Chen, S. Y. VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovasc. Res. 91(3):402-411; 2011.
117. Tang, Y. L.; Zhao, Q.; Qin, X.; Shen, L.; Cheng, L.; Ge, J.; Phillips, M. I. Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. Ann. Thorac. Surg. 80(1):229-236; 2005.
118. Tasso, R.; Ilengo, C.; Quarto, R.; Cancedda, R.; Caspi, R. R.; Pennesi, G. Mesenchymal stem cells induce functionally active T-regulatory lymphocytes in a paracrine fashion and ameliorate experimental autoimmune uveitis. Invest. Ophthalmol. Vis. Sci. 53(2):786-793; 2012.
119. Timmers, L.; Lim, S. K.; Arslan, F.; Armstrong, J. S.; Hoefer, I. E.; Doevendans, P. A.; Piek, J. J.; El Oakley, R. M.; Choo, A.; Lee, C. N.; Pasterkamp, G.; de Kleijn, D. P. Reduction of myocardial infarct size by human mes-enchymal stem cell conditioned medium. Stem Cell Res. 1(2):129-137; 2007.
120. Tse, H. F.; Kwong, Y. L.; Chan, J. K. F.; Lo, G.; Ho, C. L.; Lau, C. P. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 361(9351):47-49; 2003.
121. Urbanek, K.; Rota, M.; Cascapera, S.; Bearzi, C.; Nascimbene, A.; De Angelis, A.; Hosoda, T.; Chimenti, S.; Baker, M.; Limana, F.; Nurzynska, D.; Torella, D.; Rotatori, F.; Rastaldo, R.; Musso, E.; Quaini, F.; Leri, A.; Kajstura, J.; Anversa, P. Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival. Circ. Res. 97(7):663-673; 2005.
122. Valgimigli, M.; Rigolin, G. M.; Cittanti, C.; Malagutti, P.; Curello, S.; Percoco, G.; Bugli, A. M.; Della Porta, M.; Bragotti, L. Z.; Ansani, L.; Mauro, E.; Lanfranchi, A.; Giganti, M.; Feggi, L.; Castoldi, G.; Ferrari, R. Use of granulocyte-colony stimulating factor during acute myo-cardial infarction to enhance bone marrow stem cell mobilization in humans: Clinical and angiographic safety profile. Eur. Heart J. 26(18):1838-1845; 2005.
123. Wang, G. L.; Jiang, B. H.; Rue, E. A.; Semenza, G. L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA 92(12):5510-5514; 1995.
124. Wang, J. A.; Chen, T. L.; Jiang, J.; Shi, H.; Gui, C.; Luo, R. H.; Xie, X. J.; Xiang, M. X.; Zhang, X. Hypoxic preconditioning attenuates hypoxia/reoxygenation-induced apoptosis in mesenchymal stem cells. Acta Pharmacol. Sin. 29(1):74-82; 2008.
125. Wang, S. P.; Wang, Z. H.; Peng, D. Y.; Li, S. M.; Wang, H.; Wang, X. H. Therapeutic effect of mesenchymal stem cells in rats with intracerebral hemorrhage: Reduced apoptosis and enhanced neuroprotection. Mol. Med. Rep. 6(4):848-854; 2012.
126. Ward, P. A. The sepsis seesaw: Seeking a heart salve. Nat. Med. 15(5):497-498; 2009.
127. Whone, A. L.; Kemp, K.; Sun, M.; Wilkins, A.; Scolding, N. J. Human bone marrow mesenchymal stem cells protect catecholaminergic and serotonergic neuronal perikarya and transporter function from oxidative stress by the secretion of glial-derived neurotrophic factor. Brain Res. 1431:86-96; 2012.
128. Wiehe, J. M.; Kaya, Z.; Homann, J. M.; Wohrle, J.; Vogt, K.; Nguyen, T.; Rottbauer, W.; Torzewski, J.; Fekete, N.; Rojewski, M.; Schrezenmeier, H.; Moepps, B.; Zimmermann, O. GMP-adapted overexpression of CXCR4 in human mesenchymal stem cells for cardiac repair. Int. J. Cardiol. 167(5):2073-2081; 2013.
129. Xiang, J.; Tang, J.; Song, C.; Yang, Z.; Hirst, D. G.; Zheng, Q. J.; Li, G. Mesenchymal stem cells as a gene therapy carrier for treatment of fibrosarcoma. Cytotherapy 11(5):516-526; 2009.
130. Yagi, H.; Soto-Gutierrez, A.; Parekkadan, B.; Kitagawa, Y.; Tompkins, R. G.; Kobayashi, N.; Yarmush, M. L. Mesenchymal stem cells: Mechanisms of immunomodulation and homing. Cell Transplant. 19(6):667-679; 2010.
131. Yamagiwa, S.; Gray, J. D.; Hashimoto, S.; Horwitz, D. A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J. Immunol. 166(12):7282-7289; 2001.
132. Yang, S. H.; Park, M. J.; Yoon, I. H.; Kim, S. Y.; Hong, S. H.; Shin, J. Y.; Nam, H. Y.; Kim, Y. H.; Kim, B.; Park, C. G. Soluble mediators from mesenchymal stem cells suppress T cell proliferation by inducing IL-10. Exp. Mol. Med. 41(5):315-324; 2009.
133. Yousef, M.; Schannwell, C. M.; Kostering, M.; Zeus, T.; Brehm, M.; Strauer, B. E. The BALANCE Study: Clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction. J. Am. Coll. Cardiol. 53(24): 2262-2269; 2009.
134. Yu, J.; Li, M.; Qu, Z.; Yan, D.; Li, D.; Ruan, Q. 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(5):496-505; 2010.
135. Zarjou, A.; Kim, J.; Traylor, A. M.; Sanders, P. W.; Balla, J.; Agarwal, A.; Curtis, L. M. Paracrine effects of mesenchymal stem cells in cisplatin-induced renal injury require heme oxygenase-1. Am. J. Physiol. Renal Physiol. 300(1): F254-F262; 2011.
136. Zhang, S.; Jia, Z.; Ge, J.; Gong, L.; Ma, Y.; Li, T.; Guo, J.; Chen, P.; Hu, Q.; Zhang, P.; Liu, Y.; Li, Z.; Ma, K.; Li, L.; Zhou, C. Purified human bone marrow multipotent mesenchymal stem cells regenerate infarcted myocardium in experimental rats. Cell Transplant. 14(10):787-798; 2005.
137. Zhang, Z.; Li, H.; Ma, Z.; Feng, J.; Gao, P.; Dong, H.; Zhang, Z. Efficient cardiomyogenic differentiation of bone marrow mesenchymal stromal cells by combination of Wnt11 and bone morphogenetic protein 2. Exp. Biol. Med. 237(7):768-776; 2012.