The potential of mesenchymal stem cells in the management of radiation enteropathy

Cell Death and Disease

Volumn 6, Issue , 2015, Pages

  Chang, P Y ^a,b   Qu, Y Q ^a   Wang, J ^b   Dong, L H ^a  

^a THE FIRST HOSPITAL OF JILIN UNIVERSITY   (China)

^b CHANGCHUN INSTITUTE OF APPLIED CHEMISTRY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

BACTERIUM; CARCINOGENICITY; CELL DAMAGE; CELL INTERACTION; DYSBIOSIS; ENDOTHELIUM INJURY; EPITHELIZATION; FIBROGENESIS; HOMEOSTASIS; HUMAN; IMMUNOCOMPETENT CELL; INFLAMMATION; INTESTINAL STEM CELL INJURY; INTESTINE INJURY; ISCHEMIA; MALIGNANT NEOPLASTIC DISEASE; MAST CELL; MESENCHYMAL STEM CELL; MESENCHYMAL STEM CELL BASED GENE THERAPY; MESENCHYMAL STEM CELL TRANSPLANTATION; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PRIORITY JOURNAL; RADIATION ENTEROPATHY; REVIEW; STEM CELL GENE THERAPY; THERAPY EFFECT; TISSUE INJURY; TUMOR GROWTH; ABDOMINAL NEOPLASMS; ADVERSE EFFECTS; ANIMAL; CYTOLOGY; DUODENAL ULCER; GAMMA RADIATION; INTESTINAL PERFORATION; MESENCHYMAL STROMA CELL; MESENTERIC ISCHEMIA; MOUSE; MUCOSITIS; PATHOLOGY; PELVIC NEOPLASMS; PHYSIOLOGY; QUALITY OF LIFE; RADIATION INJURIES; REGENERATION; TREATMENT OUTCOME;

ABDOMINAL NEOPLASMS; ANIMALS; DUODENAL ULCER; GAMMA RAYS; HUMANS; INTESTINAL PERFORATION; MESENCHYMAL STEM CELL TRANSPLANTATION; MESENCHYMAL STROMAL CELLS; MESENTERIC ISCHEMIA; MICE; MUCOSITIS; PELVIC NEOPLASMS; QUALITY OF LIFE; RADIATION INJURIES; REGENERATION; TREATMENT OUTCOME;

EID: 84938880354     PISSN: None     EISSN: 20414889     Source Type: Journal    
DOI: 10.1038/cddis.2015.189     Document Type: Review

References (150)

1. Hauer-Jensen M, Denham JW, Andreyev HJ. Radiation enteropathy-pathogenesis, treatment and prevention. Nat Rev Gastroenterol Hepatol 2014; 11: 470-479.
2. Tucker SL, Thames HD, Michalski JM, Bosch WR, Mohan R, Winter K et al. Estimation of ?/? for late rectal toxicity based on RTOG 94-06. Int J Radiat Oncol Biol Phys 2011; 81: 600-605.
3. Brenner DJ. Fractionation and late rectal toxicity. Int J Radiat Oncol Biol Phys 2004; 60: 1013-1015.
4. Kennedy GD, Heise CP. Radiation colitis and proctitis. Clin Colon Rectal Surg 2007; 20: 64-72.
5. Andreyev HJ, Davidson SE, Gillespie C, Allum WH, Swarbrick E. Practice guidance on the management of acute gastrointestinal problems arising as a result of treatment for cancer. Gut 2012; 61: 179-192.
6. Chaple A, Francois S, Douay L, Benderitter M, Voswinkel J. New insights for pelvic radiation disease treatment: multipotent stromal cell is a promise mainstay treatment for the restoration of abdominopelvic severe chronic damages induced by radiotherapy. World J Stem Cells 2013; 5: 106-111.
7. Gilbert JD, Byard RW. Fatal ischemic enteritis with hemorrhage-A late complication of treated Wilms tumor. J Forensic Sci 2013; 58: 234-236.
8. Sarin A, Safar B. Management of radiation proctitis. Gastroenterol Clin North Am 2013; 42: 913-925.
9. Spinelli A, Correale C, Szabo H, Montorsi M. Intestinal fibrosis in Crohn's disease: medical treatment or surgery Curr Drug Targets 2010; 11: 242-248.
10. Gothard L, Cornes P, Brooker S, Earl J, Glees J, Hall E et al. Phase II study of vitamin E and pentoxifylline in patients with late side effects of pelvic radiotherapy. Radiother Oncol 2005; 75: 334-341.
11. Hamama S, Delanian S, Monceau V, Vozenin MC. Therapeutic management of intestinal firbosis induced by radiation therapy: from molecular profiling to new intervention strategies et vice et versa. Fibrogenesis Tissue Repair 2012; 5: S13.
12. Bourgier C, Haydont V, Milliat F, Francois A, Holler V, Lasser P et al. Inhibition of Rho kinase modulates radiation induced fibrogenic phenotype in intestinal smooth muscle cells through alteration of the cytoskeleton and connective tissue growth factor expression. Gut 2005; 54: 336-343.
13. Haydont V, Bourgier C, Pocard M, Lusinchi A, Aigueperse J, Mathé D et al. Pravastatin Inhibits the Rho/CCN2/extracellular matrix cascade in human fibrosis explants and improves radiation-induced intestinal firbosis in rats. Clin Cancer Res 2007; 13: 5331-5340.
14. Wang J, Boerma M, Fu Q, Kulkarni A, Fink LM, Hauer-Jensen M. Simvastatin ameliorates radiation enteropathy development after localized, fractionated irradiation by a protein C-independent mechanism. Int J Radiat Oncol Biol Phys 2007; 68: 1483-1490.
15. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418: 41-49.
16. Park BS, Kim WS, Choi JS, Kim HK, Won JH, Ohkubo F et al. Hair growth stimulated by conditioned medium of adipose-derived stem cells is enhanced by hypoxia: evidence of increased growth factor secretion. Biomed Res 2010; 31: 27-34.
17. Yagi H, Soto-Gutierrez A, Parekkadan B, Kitagawa Y, Tompkins RG, Kobayashi N et al. Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transplant 2010; 19: 667-679.
18. Singh S, Saraiva L, Elkinton PT, Friedland JS. Regulation of matrix metalloproteinase-1,-3 and-9 in Mycobaterium tuberculosis-dependent respiratory networks by the rapamycinsensitive PI3K/p70(S6K) cascade. FASEB J 2014; 28: 85-93.
19. Newell LF, Deans RJ, Maziarz RT. Adult adherent stromal cells in the management of graftversus-host disease. Expert Opin Biol Ther 2014; 14: 231-246.
20. Wang D, Li J, Zhang Y, Zhang M, Chen J, Li X et al. Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study. Arthritis Res Ther 2014; 16: R79.
21. Koh YG, Choi YJ. Intrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee 2012; 19: 902-907.
22. Herreros MD, Garcia-Arranz M, Guadalajara H, De-La-Quintana P, Garcia-Olmo DFATT Collaborative Group, Autologous expanded adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistulas: a phase III randomized clinical trial (FATT 1: fistula Advanced Therapy Trial 1) and long-term evaluation. Dis Colon Rectum 2012; 55: 762-772.
23. Voswinkel J, Francois S, Simon JM, Benderitter M, Gorin NC, Mohty M et al. Use of mesenchymal stem cells (MSCs) in chronic inflammatory fistulizing and fibrotic diseases: a comprehensive review. Clin Rev Allergy Immunol 2013; 45: 180-192.
24. Langberg CW, Sauer T, Reitan JB, Hauer-Jensen M. Relationship between intestinal fibrosis and histopathologic and morphometric changes in consequential and late radiation enteropathy. Acta Oncol 1996; 35: 81-87.
25. Latella G, Di Gregorio J, Flati V, Rieder F, Lawrence IC. Mechanisms of initiation and progression of intestinal fibrosis in IBD. Scand J Gastroenterol 2015; 50: 53-65.
26. Umar S. Intestinal stem cells. Curr Gastroenterol Rep 2010; 12: 340-348.
27. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 2009; 459: 262-265.
28. van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 2009; 71: 241-260.
29. Ishizuka S, Martin K, Booth C, Potten CS, de Murcia G, Bürkle A. Poly(ADP-ribose) polymerase-1 is a survival factor for radiation-exposed intestinal epithelial stem cells in vivo. Nucleic Acids Res 2003; 31: 6198-6205.
30. Zhu Y, Huang YF, Kek C, Bulavin DV. Apoptosis differently affects lineage tracing of Lgr5 and Bmi1 intestinal stem cell populations. Cell Stem Cell 2013; 12: 298-303.
31. Frankenberg-Schwager M, Gebauer A, Koppe C, Wolf H, Pralle E, Frankenberg D. Single-strand annealing, conservative homologous recombination, nonhomologous DNA end joining, and the cell cycle-dependent repair of DNA double-strand breaks induced by sparsely or densely ionizing radiation. Radiat Res 2009; 171: 265-273.
32. Schepers AG, Vries R, van den Born M, van de Wetering M, Clevers H. Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes. EMBO J 2011; 30: 1104-1109.
33. Metcalfe C, Kljavin NM, Ybarra R, de Sauvage FJ. Lgr5+ stem cells are indispensible for radiation-induced intestinal regeneration. Cell Stem Cell 2014; 14: 149-159.
34. Sangiorgi E, Capecchi MR. Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 2008; 40: 915-920.
35. Montgomery RK, Carlone DL, Richmond CA, Farilla L, Kranendonk ME, Henderson DE et al. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc Natl Acad Sci USA 2011; 108: 179-184.
36. Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG, van den Born M et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 2011; 469: 415-418.
37. Gilbert S, Nivarhi H, Mayhew CN, Lo YH, Noah TK, Vallance J et al. Activated STAT5 confers resistance to intestinal injury by increasing intestinal stem cell proliferation and regeneration. Stem Cell Reports 2015; 4: 209-225.
38. Ungvari Z, Podlusky A, Sosnowska D, Tucsek Z, Toth P, Deak F et al. Ionizing radiation promotes the acquisition of a senescence-Associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: role of increased DNA damage and decreased DNA repair capacity in microvascular radiosensitiivity. J Gerontol A Biol Sci Med Sci 2013; 68: 1443-1457.
39. Abderrahmani R, Francois A, Buard V, Tarlet G, Blirando K, Hneino M et al. PAI-1-dependent endothelial cell death determines severity of radiation-induced intestinal injury. PLoS One 2012; 7: e35740.
40. Paris F, Fuks Z, Kang A, Capodieci P, Juan G, Ehleiter D et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 2001; 293: 293-297.
41. Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med 2011; 208: 1339-1350.
42. Giblin JP, Hewlett LJ, Hannah MJ. Basal secretion of von Willebrand factor from human endothelial cells. Blood 2008; 112: 957-964.
43. Kopaniak MM, Issekutz AC, Movat HZ. Kinetics of acute inflammation induced by E coli in rabbits. Quantitation of blood flow, enchanced vascular permeability, hemorrhage, and leukocyte accumulation. Am J Pathol 1980; 98: 485-498.
44. Nikjoo H, O'Neill P, Terrissol M, Goodhead DT. Modelling of radiation-induced DNA damage: the early physical and chemical event. Int J Radiat Biol 1994; 66: 453-457.
45. Hill S, Van Remmen H. Mitochondrial stress signaling in longevity: A new role for mitochondrial function in aging. Redox Biol 2014; 2: 936-944.
46. Martindale JL, Holbrook NJ. Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 2002; 192: 1-15.
47. Almeida AS, Figueiredo-Pereira C, Vieira HL. Carbon monoxide and mitochondriamodulation of cell metabolism, redox response and cell death. Front Physiol 2015; 6: 33.
48. Mittal M, Siddigui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammatory and tissue injury. Antioxid Redox Signal 2014; 20: 1126-1167.
49. Johnson LB, Riaz AA, Adawi D, Wittgren L, Bäck S, Thornberg C et al. Radiation enteropathy and leucocyte-endothelial cell reactions in a refined small bowel model. BMC Surg 2004; 4: 10.
50. Rao RM, Yang L, Garcia-Cardena G, Luscinskas FW. Endothelial-dependent mechanisms of leukocyte recruitment to the vascular wall. Circ Res 2007; 101: 234-247.
51. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013; 13: 159-175.
52. Reumaux D, de Boer M, Meijer AB, Duthilleul P, Roos D. Expression of myeloperoxidase (MPO) by neutrophils is necessary for their activation by anti-neutrophil cytoplasm autoantibodies (ANCA) against MPO. J Leukoc Biol 2003; 73: 841-849.
53. Wonderlich J, Shearer G, Livingstone A, Brooks A. Induction and measurement of cytotoxic T lymphocyte activity. Curr Protoc Immunol 2006; Chapter 3: Unit 3.11.
54. Kugelberg E. Pattern recognition receptors: curbing gut inflammation. Nat Rev Immunol 2014; 14: 583.
55. Wang J, Hauer-Jensen M. Neuroimmune interactions: potential target for mitigating or treating intestinal radiation injury. Br J Radiol 2007; 1: S41-S48.
56. McLaughlin MM, Dacquisto MP, Jacobus DP, Horowitz RE. Effects of the germfree state on responses of mice to whole-body irradiation. Radiat Res 1964; 23: 333-349.
57. Ferreira MR, Muls A, Dearnaley DP, Andreyev HJ. Microbiota and radiation-induced bowel toxicity: lesions from inflammatory bowel disease for the oncologist. Lancet Oncol 2014; 15: e139-e147.
58. Packey CD, Ciorba MA. Microbial influences on the small intestinal response to radiation injury. Curr Opin Gastroenterol 2010; 26: 88-94.
59. Manichanh C, Varela E, Martinez C, Antolin M, Liopis M, Doré J et al. The gut microbiota predispose to the pathophysiology of acute postradiotherapy diarrhea. Am J Gastroenterol 2008; 103: 1754-1761.
60. Crawford PA, Gordon JI. Microbial regulation of intestinal radiosensitivity. Proc Natl Acad Sci USA 2005; 102: 13254-13259.
61. Perez-Chanona E, Mühlbauer M, Jobin C. The microbiota protects against ischemia/reperfusion-induced intestinal injury through nucleotide-binding oligomerization domaincontaining protein 2 (NOD2) signaling. Am J Pathol 2014; 184: 2965-2975.
62. Ciorba MA, Stenson WF. Probiotic therapy in radiation-induced intestinal injury and repair. Ann NY Acad Sci 2009; 1165: 190-194.
63. Lawrance IC, Rogler G, Bamias G, Breynaert C, Florholmen J, Pellino G et al. Cellular and molecular mediators of intestinal fibrosis. J Crohns Colitis 2014; e-pub ahead of print 8 October 2014; doi: 10.1016/j.crohns.2014.09.008.
64. Haydont V, Vozenin-Brotons MC. Maintenance of radiation-induced intestinal fibrosis: cellular and molecular features. World J Gastroenterol 2007; 13: 2675-2683.
65. Yarnold J, Brotons MC. Pathogenetic mechanisms in radiation fibrosis. Radiother Oncol 2010; 97: 149-161.
66. Sémont A, Francois S, Mouiseddine M, Francois A, Saché A, Frick J et al. Mesenchymal stem cells increase self-renewal of small intestinal epithelium and accelerate structural recovery after radiation injury. Adv Exp Med Biol 2006; 585: 19-30.
67. Sémont A, Mouiseddine M, Francois A, Demarguay C, Mathieu N, Chapel A et al. Mesenchymal stem cells improve small intestinal integrity though regulation of endogenous epithelial cell homeostasis. Cell Death Differ 2010; 17: 952-961.
68. Kudo K, Liu Y, Takahashi K, Tarusawa K, Osanai M, Hu DL et al. Transplantation of mesenchymal stem cells to prevent radiation-induced intestinal injury in mice. J Radiat Res 2010; 51: 73-79.
69. Kudo K, Abe Y, Hu DL, Kijima H, Nakane A. Colonization and differentiation of transplanted embryonic stem cells in the irradiated intestine of mice. Tohoku J Exp Med 2007; 212: 143-150.
70. Saha S, Bhanja P, Kabarriti R, Liu L, Alfieri AA, Guha C. Bone marrow stromal cell transplantation mitigates radiation-induced gastrointestinal syndrome in mice. PLoS One 2011; 6: e24072.
71. Francois M, Birman E, Forner KA, Gaboury L, Gallipeau J. Adoptive transfer of mesenchymal stromal cells accelerates intestinal epithelium recovery of irradiated mice in an interleukin-6-dependent manner. Cytotherapy 2012; 14: 1164-1170.
72. Gao Z, Zhang Q, Han Y, Cheng X, Lu Y, Fan L et al. Mesenchymal stromal cell-conditioned medium prevents radiation-induced small intestine injury in mice. Cytotherapy 2012; 14: 267-273.
73. Chang P, Qu Y, Liu Y, Cui S, Zhu D, Wang H et al. Multi-therapeutic effects of human adipose-derived mesenchymal stem cells on radiation-induced intestinal injury. Cell Death Dis 2013; 4: e685.
74. Linard C, Busson E, Holler V, Strup-Perrot C, Lacave-Lapalun JV, Lhomme B et al. Repeated autologous bone marrow-derived mesenchymal stem cell injections improve radiation-induced proctitis in pigs. Stem Cells Transl Med 2013; 2: 916-927.
75. Bessout R, Sémont A, Demarguay C, Charcosset A, Benderitter M, Mathieu N. Mesenchymal stem cell therapy induces glucocorticoid synthesis in colonic mucosa and suppresses radiation-Activated T cells: new insights into MSC immunomodulation. Mucosal Immunol 2014; 7: 656-669.
76. Zong ZW, Cheng TM, Su YP, Ran XZ, Shen Y, Li N et al. Recruitment of transplanted dermal multipotent stem cells to sites of injury in rats with combined radiation and wound injury by interaction of SDF-1 and CXCR4. Radiat Res 2008; 170: 444-450.
77. Ji JF, He BP, Dheen ST, Tay SS. Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal never injury. Stem Cells 2004; 22: 415-427.
78. Francois S, Bensidhoum M, Moureseddine M, Mazurier C, Allenet B, Sémont A et al. Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage. Stem Cells 2006; 24: 1020-1029.
79. Zhang J, Gong JF, Zhang W, Zhu WM, Li JS. Effects of transplated bone marrow mesenchymal stem cells on the irradiated intestine of mice. J Biomed Sci 2008; 15: 585-594.
80. Yang C, Chen HX, Zhou Y, Liu MX, Wang JX, Ren SP et al. Manganese superoxide dismutase gene therapy protects against irradiation-induced intestinal injury. Curr Gene Ther 2013; 13: 305-314.
81. Hu J, Yang Z, Wang J, Tang Y, Liu H, Zhang B et al. Infusion of Trx-1-overexpressing huc MSC prolongs the survival of acutely irradiated NOD/SCID mice by decreasing excessive inflammatory injury. PLoS One 2013; 8: e78227.
82. Zangi L, Margalit R, Reich-Zeliger S, Bachar-Lustig E, Beilhack A, Negrin R et al. Direct imaging of immune rejection and memory induction by allogeneic mesenchymal stromal cells. Stem Cells 2009; 27: 2865-2874.
83. Hu C, Yong X, Li C, Lü M, Liu D, Chen L et al. CXCL12/CXCR4 axis promotes mesenchymal stem cell mobilization to burn wounds and contributes to wound repair. J Surg Res 2013; 183: 427-434.
84. Ren G, Zhao X, Zhang L, Zhang J, L'Huillier A, Ling W et al. Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J Immunol 2010; 184: 2321-2328.
85. Ringe J, Strassburg S, Neumann K, Endres M, Notter M, Burmester GR et al. Towards in situ tissue repair: human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2. J Cell Biochem 2007; 101: 135-146.
86. Paguet-Fifield S, Schlüter H, Li A, Aitken T, Gangatirkar P, Blashki D et al. A role for pericytes as microenvironmental regulators of human skin tissue regeneration. J Clin Invest 2009; 119: 2795-2806.
87. Linero I, Chaparro O. Paracrine effect of mesenchymal stem cells from human adipose tissue in bone regeneration. PLoS One 2014; 9: e107001.
88. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105: 1815-1822.
89. Maggini J, Mirkin G, Bognanni I, Holmberg J, Piazzón IM, Nepomnaschy I et al. Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS One 2010; 5: e9252.
90. Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 2009; 15: 42-49.
91. Pils MC, Pisano F, Fasnacht N, Heinrich JM, Groebe L, Schippers A et al. Monocytes/macrophages and/or neutrophils are the target of IL-10 in the LPS endotoxemia model. Eur J Immunol 2010; 40: 443-448.
92. Spaggiari GM, Abdelrazik H, Becchetti F, Moretta L. MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood 2009; 113: 6576-6583.
93. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 2008; 111: 1327-1333.
94. Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Borg C et al. 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 2008; 26: 212-222.
95. Hsu WT, Lin CH, Chiang BL, Jui HY, Wu KK, Lee CM. Prostaglandin E2 potentiates mesenchymal stem cell-induced IL-10+IFN-?+CD4+ regulatory T cells to control transplant arteriosclerosis. J Immunol 2013; 190: 2372-2380.
96. Gonzalez-Rey E, Anderson P, González MA, Rico L, Büscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009; 58: 929-939.
97. Parekkadan B, Upadhyay R, Dunham J, Iwamoto Y, Mizoguchi E, Mizoguchi A et al. Bone marrow stromal cell transplants prevent experimental enterocolitis and require host CD11b+ splenocytes. Gastroenterology 2011; 140: 966-975.
98. Brown JM, Nemeth K, Kushnir-Sukhov NM, Metcalfe DD, Mezey E. Bone marrow stromal cells inhibit mast cell function via a COX2-dependent mechanism. Clin Exp Allergy 2011; 41: 526-534.
99. Kim HS, Yun JW, Shin TH, Lee SH, Lee BC, Yu KR. Human umbilical cord blood mesenchymal stem cell-derived PGE2 and TGF-?1 Alleviate atopic dermatitis by reducing mast cell degranulation. Stem Cells 2015; 33: 1254-1266.
100. Lombard E, van der Poll T, DelaRosa O, Dalemans W. Mesenchymal stem cells as a therapeutic tool to treat sepsis. World J Stem Cells 2015; 7: 368-379.
101. Meisel R, Brockers S, Heseler K, Degistirici O, Bülle H, Woite C et al. Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. Leukemia 2011; 25: 648-654.
102. Krasnodembskaya A, Samarani G, Song Y, Zhou H, Su X, Lee JW et al. Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes. Am J Physiol Lung Cell Mol Physiol 2012; 302: L1003-L1013.
103. Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee JW et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells 2010; 28: 2229-2238.
104. Chang W, Song BW, Moon JY, Cha MJ, Ham O, Lee SY et al. Anti-death strategies against oxidative stress in grafted mesenchymal stem cells. Histol Histopathol 2013; 28: 1529-1536.
105. Lange C, Brunswig-Spickenheier B, Cappallo-Obermann H, Eggert K, Gehling UM, Rudolph C et al. Radiation rescue: mesenchymal stromal cells protect from lethal irradiation. PLoS One 2011; 6: e14486.
106. Brittan M, Chance V, Elia G, Poulsom R, Alison MR, MacDonald TT et al. A regenerative role for bone marrow following experimental colitis: contribution to neovasculogenesis and myofibroblasts. Gastroenterology 2005; 128: 1984-1995.
107. Okamoto R, Yajima T, Yamazaki M, Kanai T, Mukai M, Okamoto S et al. Damaged epithelial regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med 2002; 8: 1011-1017.
108. Guan A, Gong H, Ye Y, Jia J, Zhang G, Li B et al. Regulation of p53 by jagged 1 contributes to angiotensin II-induced impairment of myocardial angiogenesis. PLoS One 2013; 8: e76529.
109. Demidov ON, Timofeev O, Lwin HN, Kek C, Appella E, Bulavin DV. Wip1 phosphatase regulates p53-dependent apoptosis of stem cells and tumorigenesis in the mouse intestine. Cell Stem Cell 2007; 1: 180-190.
110. John S. Mesenchymal stem cells in cancer. Stem Cell Rev 2008; 4: 119-124.
111. Kuhn NZ, Tuan RS. Regulation of stemness and stem cell niche of mesenchymal stem cells: implications in tumorigenesis and metastasis. J Cell Physiol 2010; 222: 268-277.
112. Han Z, Jing Y, Zhang S, Liu Y, Shi Y, Wei L. The role of immunesuppression of mesenchymal stem cells in tissue repair and tumor growth. Cell Biosci 2012; 2: 8.
113. Røsland GV, Svendsen A, Torsvik A, Sobala E, Mc Cormack E, Immervoll H et al. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res 2009; 69: 5331-5339.
114. Burns JS, Abdallah BM, Guldberg P, Rygaard J, Schrøder HD, Kassem M. Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomeraseimmortalized human mesenchymal stem cells. Cancer Res 2005; 65: 3126-3135.
115. Rubio D, Garcia-Castro J, Martín MC, de la Fuente R, Cigudosa JC, Lloyd AC et al. Spontaneous human adult stem cell transformation. Cancer Res 2005; 65: 3035-3039.
116. Li H, Fan X, Kovi RC, Jo Y, Moguin B, Konz R et al. Spontaneous expression of embryonic factors and p53 point mutations in aged mesenchymal stem cells: a model of age-related tumorigenesis in mice. Cancer Res 2007; 67: 10889-10898.
117. Rodriguez R, Rubio R, Masip M, Catalina P, Nieto A, de la Cueva T et al. Loss of p53 induces tumorigenesis in p21-deficient mesenchymal stem cells. Neoplasia 2009; 11: 397-407.
118. Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A et al. 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: 9142-9149.
119. Choumerianou DM, Dimitriou H, Perdikogianni C, Martimianaki G, Riminucci M, Kalmanti M. Study of oncogenic transformation in ex vivo expanded mesenchymal cells, from paediatric bone marrow. Cell Prolif 2008; 41: 909-922.
120. Zimmerlin L, Park TS, Zambidis ET, Donnenberg VS, Donnenberg AD. Mesenchymal stem cell secretome and regenerative therapy after cancer. Biochimie 2013; 95: 2235-2245.
121. Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF, Rovira II et al. Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. J Exp Med 2006; 203: 1235-1247.
122. Li X, Ling W, Pennisi A, Wang Y, Khan S, Heidaran M et al. Human placenta-derived adherent cells prevent bone loss, stimulate bone formation, and suppress growth of multiple myeloma in bone. Stem Cells 2011; 29: 263-273.
123. Ahn JO, Coh YR, Lee HW, Shin IS, Kang SK, Youn HY. Human adipose tissue-derived mesenchymal stem cells inhibit melanoma growth in vitro and in vivo. Anticancer Res 2015; 35: 159-168.
124. Nasuno M, Arimura Y, Nagaishi K, Isshiki H, Onodera K, Nakagaki S et al. Mesenchymal stem cells cancel azoxymethane-induced tumor initiation. Stem Cells 2014; 32: 913-925.
125. Katsuno T, Ochi M, Tominaga K, Tanaka F, Sogawa M, Tanigawa T et al. Mesenchymal stem cells administrated in the early phase of tumorigenesis inhibit colorectal tumor development in rats. J Clin Biochem Nutr 2013; 53: 170-175.
126. Lu YR, Yuan Y, Wang XJ, Wei LL, Chen YN, Cong C et al. The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo. Cancer Biol Ther 2008; 7: 245-251.
127. Qiao L, Xu Z, Zhao T, Zhao Z, Shi M, Zhao RC et al. Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model. Cell Res 2008; 18: 500-507.
128. Abd-Allah SH, Shalaby SM, El-Shai AS, Elkader EA, Hussein S, Emam E et al. Effect of bone marrow-derived mesenchymal stromal cells on hepatoma. Cytotherapy 2014; 16: 1197-1206.
129. Ahn JO, Chae JS, Coh YR, Jung WS, Lee HW, Shin IS et al. Human adipose tissue-derived mesenchymal stem cells inhibit T-cell lymphoma growth in vitro and in vivo. Anticancer Res 2014; 34: 4839-4847.
130. Chien LY, Hsiao JK, Hsu SC, Yao M, Lu CW, Liu HM et al. In vivo magnetic resonance imaging of cell tropism, trafficking mechanism, and therapeutic impact of human mesenchymal stem cells in a murine glioma model. Biomaterials 2011; 32: 3275-3284.
131. Vegh I, Grau M, Gracia M, Grande J, de la Torre P, Flores AI. Decidua mesenchymal stem cells migrated toward mammary tumors in vitro and in vivo affecting tumor growth and tumor development. Cancer Gene Ther 2013; 20: 8-16.
132. Abdel aziz MT, EI Asmar MF, Atta HM, Mahfouz S, Fouad HH, Roshdy NK et al. Efficacy of mesenchymal stem cells in suppression of hepatocarcinorigenesis in rats: possible role of Wnt signaling. J Exp Clin Cancer Res 2011; 30: 49.
133. Ma Y, Hao X, Zhang S, Zhang J. The in vitro and in vivo effects of human umbilical cord mesenchymal stem cells on the growth of breast cancer cells. Breast Cancer Res Treat 2012; 133: 473-485.
134. Zhu Y, Sun Z, Han Q, Liao L, Wang J, Bian C et al. Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 2009; 23: 925-933.
135. Lee RH, Kim B, Choi I, Kim H, Choi HS, Suh K et al. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem 2004; 14: 311-324.
136. Fodde R, Brabletz T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol 2007; 19: 150-158.
137. Han I, Yun M, Kim EO, Kim B, Jung MH, Kim SH. Umbilical cord tissue-derived mesenchymal stem cells induce aoptosis in PC-3 prostate cancer cells through activation of JNK and downregulation of PI3K/Akt signaling. Stem Cell Res Ther 2014; 5: 54.
138. Xiang J, Tang J, Song C, Yang Z, Hirst DG, Zheng QJ et al. Mesenchymal stem cells as a gene therapy carrier for treatment of fibrosarcoma. Cytotherapy 2009; 11: 516-526.
139. Nakamura K, Ito Y, Kawano Y, Kurozumi K, Kobune M, Tsuda H et al. Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther 2004; 11: 1155-1164.
140. Gao P, Ding Q, Wu Z, Jiang H, Fang Z. Therapeutic potential of human mesenchymal stem cells producing IL-12 in a mouse xenograft model of renal cell carcinoma. Cancer Lett 2010; 290: 157-166.
141. Chapel A, Francois S, Douay L, Benderitter M, Voswinkel J. Fifteen years of preclinical and clinical experiences about biotherapy treatment of lesions induced by accidental irradiation and radiotherapy. World J Stem Cells 2013; 5: 68-72.
142. Bernardo ME, Fibbe WE. Safety and efficacy of mesenchymal stromal cell therapy in autoimmune disorders. Ann NY Acad Sci 2012; 1266: 107-117.
143. Robey PG, Kuznetsov SA, Ren J, Klein HG, Sabatino M, Stroncek DF. Generation of clinical grade human bone marrow stromal cells for use in bone regeneration. Bone 2015; 70: 87-92.
144. Lai RC, Yeo RW, Lim SK. Mesenchymal stem cell exosomes. Semin Cell Dev Biol 2015; 40: 82-88.
145. Sokolova V, Ludwig AK, Hornung S, Rotan O, Horn PA, Epple M et al. Characterisation of exosomes derived from human cells by nanoparticle tracking analysis and scanning electron microscopy. Colloids Surf B Biointerfaces 2011; 87: 146-150.
146. Berardis S, Dwisthi Sattwika P, Najimi M, Sokal EM. Use of mesenchymal stem cells to treat liver fibrosis: Current situation and future prospects. World J Gastroenterol 2015; 21: 742-758.
147. Ohmori K, Masuda K, DeBoer DJ, Sakaguchi M, Tsujimoto H. Immunoblot analysis for IgEreactive components of fetal calf serum in dogs that developed allergic reactions after nonrabies vaccination. Vet Immunol Immunopathol 2007; 115: 166-171.
148. Abbott A. Leaked files slam stem-cell therapy. Nature 2014; 505: 139-140.
149. Salem HK, Thiemermann C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 2010; 28: 585-596.
150. Lodi D, Iannitti T, Palmieri B. Stem cells in clinical practice: applications and warnings. J Exp Clin Cancer Res 2011; 30: 9.