[en] Background
Inflammatory bowel diseases (IBD) are chronic relapsing diseases in which
pro-inflammatory immune cells and cytokines induce intestinal tissue damage
and disability. Mesenchymal stromal cells (MSCs) exert powerful immunomodulatory effects and stimulate tissue repair.
Aim
To review the current data on mesenchymal stromal cell therapy in IBD.
Method
We searched PubMed and ‘ClinicalTrials.gov’ databases using the terms ‘mesenchymal stromal cells’, ‘mesenchymal stem cell transplantation’, ‘inflammatory bowel diseases’, ‘Crohn disease’ and ‘colitis, ulcerative’. Additional publications were identified from individual article reference lists.
Results
MSCs include inhibition of Th1/Th17 lymphocytes and recruitment of regulatory T lymphocytes, induction of antigen-presenting cells into a regulatorylike profile, and stimulation of epithelial cell differentiation and proliferation. More than 200 patients with refractory fistulas have been treated with local injections of MSCs, resulting in complete response in more than half, and in
overall response in approximately two thirds of patients. In refractory luminal Crohn’s disease, 49 cases of systemic MSC infusions have been reported, while trials with autologous MSCs resulted in mitigated responses, studies using allogeneic MSCs were promising, with around 60% of patients experiencing a response and around 40% achieving clinical remission.
Conclusions
Mesenchymal stromal cells might represent a promising therapy for IBD, especially for Crohn’s disease. There remain many unsolved questions concerning the optimal origin and source of mesenchymal stromal cells, dosage and modalities of administration. Moreover, mesenchymal stromal cells still need to prove their effectiveness compared with conventional treatments in
randomised controlled trials.
Disciplines :
Hematology
Author, co-author :
GREGOIRE, Céline ; Centre Hospitalier Universitaire de Liège - CHU > Frais communs médecine - Pool assistants
LECHANTEUR, Chantal ; Centre Hospitalier Universitaire de Liège - CHU > Thérapie cellulaire
BRIQUET, Alexandra ; Centre Hospitalier Universitaire de Liège - CHU > Service d'hématologie clinique
BAUDOUX, Etienne ; Centre Hospitalier Universitaire de Liège - CHU > Thérapie cellulaire
BARON, Frédéric ; Centre Hospitalier Universitaire de Liège - CHU > Service d'hématologie clinique
LOUIS, Edouard ; Centre Hospitalier Universitaire de Liège - CHU > Service de gastroentérologie, hépatologie, onco. digestive
BEGUIN, Yves ; Centre Hospitalier Universitaire de Liège - CHU > Service d'hématologie clinique
Language :
English
Title :
Review article: mesenchymal stromal cell therapy for inflammatory bowel diseases
Chassaing B, Darfeuille-Michaud A. The commensal microbiota and enteropathogens in the pathogenesis of inflammatory bowel diseases. Gastroenterology 2011; 140: 1720–8.
MacDonald TT, Monteleone I, Fantini MC, Monteleone G. Regulation of homeostasis and inflammation in the intestine. Gastroenterology 2011; 140: 1768–75.
Young HE, Mancini ML, Wright RP, et al. Mesenchymal stem cells reside within the connective tissues of many organs. Dev Dyn 1995; 202: 137–44.
Lv F-J, Tuan RS, Cheung KMC, Leung VYL. Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells 2014; 32: 1408–19.
Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315–7.
Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003; 31: 890–6.
Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003; 75: 389–97.
Ren G, Su J, Zhang L, et al. Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 2009; 27: 1954–62.
Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringdén O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003; 57: 11–20.
Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002; 30: 42–8.
Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99: 3838–43.
Krampera M, Glennie S, Dyson J, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003; 101: 3722–9.
Malcherek G, Jin N, Hückelhoven AG, et al. Mesenchymal stromal cells inhibit proliferation of virus-specific CD8(+) T cells. Leukemia 2014; 28: 2388–94.
Liu X-J, Zhang J-F, Sun B, et al. Reciprocal effect of mesenchymal stem cell on experimental autoimmune encephalomyelitis is mediated by transforming growth factor-beta and interleukin-6. Clin Exp Immunol 2009; 158: 37–44.
Ina K, Itoh J, Fukushima K, et al. Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. J Immunol 1999; 163: 1081–90.
Itoh J, de La Motte C, Strong SA, Levine AD, Fiocchi C. Decreased Bax expression by mucosal T cells favours resistance to apoptosis in Crohn's disease. Gut 2001; 49: 35–41.
Dias CB, Milanski M, Portovedo M, et al. Defective apoptosis in intestinal and mesenteric adipose tissue of Crohn's disease patients. PLoS ONE 2014; 9: e98547.
Monteleone I, Monteleone G, Fina D, et al. A functional role of flip in conferring resistance of Crohn's disease lamina propria lymphocytes to FAS-mediated apoptosis. Gastroenterology 2006; 130: 389–97.
Akiyama K, Chen C, Wang D, et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 2012; 10: 544–55.
Glennie S, Soeiro I, Dyson PJ, Lam EW-F, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005; 105: 2821–7.
Benvenuto F, Ferrari S, Gerdoni E, et al. Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem Cells 2007; 25: 1753–60.
Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 2011; 140: 1756–67.
Siakavellas SI, Bamias G. Role of the IL-23/IL-17 axis in Crohn's disease. Discov Med 2012; 14: 253–62.
Bandzar S, Gupta S, Platt MO. Crohn's disease: a review of treatment options and current research. Cell Immunol. 2013; 286: 45–52.
Chao K, Zhang S, Yao J, et al. Imbalances of CD4(+) T-cell subgroups in Crohn's disease and their relationship with disease activity and prognosis. J Gastroenterol Hepatol 2014; 29: 1808–14.
Geem D, Harusato A, Flannigan K, Denning TL. Harnessing regulatory T cells for the treatment of inflammatory bowel disease. Inflamm Bowel Dis 2015; 21: 1409–18.
Di Ianni M, Del Papa B, De Ioanni M, et al. Mesenchymal cells recruit and regulate T regulatory cells. Exp Hematol 2008; 36: 309–18.
Prevosto C, Zancolli M, Canevali P, Zocchi MR, Poggi A. Generation of CD4+ or CD8+ regulatory T cells upon mesenchymal stem cell-lymphocyte interaction. Haematologica 2007; 92: 881–8.
Gao F, Chiu SM, Motan DAL, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis 2016; 7: e2062.
Selmani Z, Naji A, Zidi I, 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: 212–22.
Batten P, Sarathchandra P, Antoniw JW, et al. Human mesenchymal stem cells induce T cell anergy and downregulate T cell allo-responses via the TH2 pathway: relevance to tissue engineering human heart valves. Tissue Eng 2006; 12: 2263–73.
Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005; 106: 1755–61.
González MA, Gonzalez-Rey E, Rico L, Büscher D, Delgado M. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis Rheum 2009; 60: 1006–19.
Madec AM, Mallone R, Afonso G, et al. Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells. Diabetologia 2009; 52: 1391–9.
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: 929–39.
González MA, Gonzalez-Rey E, Rico L, Büscher D, Delgado M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology 2009; 136: 978–89.
He X-W, He X-S, Lian L, Wu X-J, Lan P. Systemic infusion of bone marrow-derived mesenchymal stem cells for treatment of experimental colitis in mice. Dig Dis Sci 2012; 57: 3136–44.
Parekkadan B, Upadhyay R, Dunham J, et al. Bone marrow stromal cell transplants prevent experimental enterocolitis and require host CD11b+ splenocytes. Gastroenterology 2011; 140: 966–75.
Mann ER, Li X. Intestinal antigen-presenting cells in mucosal immune homeostasis: Crosstalk between dendritic cells, macrophages and B-cells. World J Gastroenterol 2014; 20: 9653–64.
Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol 2006; 177: 2080–7.
Ramasamy R, Fazekasova H, Lam EW-F, Soeiro I, Lombardi G, Dazzi F. Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation 2007; 83: 71–6.
Li Y-P, Paczesny S, Lauret E, et al. Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway. J Immunol 2008; 180: 1598–608.
Zhang B, Liu R, Shi D, et al. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2 dependent regulatory dendritic cell population. Blood 2009; 113: 46–57.
Chiesa S, Morbelli S, Morando S, et al. Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proc Natl Acad Sci USA 2011; 108: 17384–9.
Maggini J, Mirkin G, Bognanni I, et al. Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS ONE 2010; 5: e9252.
Németh K, Leelahavanichkul A, Yuen PST, 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: 42–9.
Anderson P, Souza-Moreira L, Morell M, et al. Adipose-derived mesenchymal stromal cells induce immunomodulatory macrophages which protect from experimental colitis and sepsis. Gut 2013; 62: 1131–41.
Augello A, Tasso R, Negrini SM, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol 2005; 35: 1482–90.
Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood 2006; 107: 367–72.
Rosado MM, Bernardo ME, Scarsella M, et al. Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells. Stem Cells Dev 2015; 24: 93–103.
Peng Y, Chen X, Liu Q, et al. Mesenchymal stromal cells infusions improve refractory chronic graft versus host disease through an increase of CD5+ regulatory B cells producing interleukin 10. Leukemia 2015; 29: 636–46.
Traggiai E, Volpi S, Schena F, et al. Bone marrow-derived mesenchymal stem cells induce both polyclonal expansion and differentiation of B cells isolated from healthy donors and systemic lupus erythematosus patients. Stem Cells 2008; 26: 562–9.
Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 2006; 24: 74–85.
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: 1327–33.
Rasmusson I, Ringdén O, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 2003; 76: 1208–13.
Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 2012; 12: 383–96.
Meisel R, Zibert A, Laryea M, Göbel U, Däubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004; 103: 4619–21.
Sato K, Ozaki K, Oh I, et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 2007; 109: 228–34.
Nasef A, Mathieu N, Chapel A, et al. Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation 2007; 84: 231–7.
Kim HS, Shin TH, Lee BC, et al. Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. Gastroenterology 2013; 145: 1392–403.
Parekkadan B, Fletcher AL, Li M, et al. Aire controls mesenchymal stem cell-mediated suppression in chronic colitis. Mol Ther 2012; 20: 178–86.
Lombardo E, Delarosa O. Modulation of adult mesenchymal stem cells activity by toll-like receptors: implications on therapeutic potential. Mediators Inflamm 2010; 2010: 865601.
Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PLoS ONE 2010; 5: e10088.
Pevsner-Fischer M, Morad V, Cohen-Sfady M, et al. Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood 2007; 109: 1422–32.
Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2008; 2: 141–50.
Duijvestein M, Wildenberg ME, Welling MM, et al. Pretreatment with interferon-γ enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis. Stem Cells 2011; 29: 1549–58.
Chen Y, Song Y, Miao H, et al. Gene delivery with IFN-γ-expression plasmids enhances the therapeutic effects of MSCs on DSS-induced mouse colitis. Inflamm Res 2015; 64: 671–81.
Fan H, Zhao G, Liu L, et al. Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis. Cell Mol Immunol 2012; 9: 473–81.
Devine SM, 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 2003; 101: 2999–3001.
Bruck F, Belle L, Lechanteur C, et al. Impact of bone marrow-derived mesenchymal stromal cells on experimental xenogeneic gr-aft-versus-host disease. Cytotherapy 2013; 15: 267–79.
Tanaka F, Tominaga K, Ochi M, et al. Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats. Life Sci 2008; 83: 771–9.
Chen QQ, Yan L, Wang CZ, et al. Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses. World J Gastroenterol 2013; 19: 4702–17.
Castelo-Branco MTL, Soares IDP, Lopes DV, et al. Intraperitoneal but not intravenous cryopreserved mesenchymal stromal cells home to the inflamed colon and ameliorate experimental colitis. PLoS ONE 2012; 7: e33360.
Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther 2008; 15: 730–8.
Yagi H, Soto-Gutierrez A, Parekkadan B, et al. Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transplant. 2010. p. 667–79.
Ko IK, Kim B-G, Awadallah A, et al. Targeting improves MSC treatment of inflammatory bowel disease. Mol Ther 2010; 18: 1365–72.
Wakitani S, Saito T, Caplan AI. Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve 1995; 18: 1417–26.
Rose RA, Keating A, Backx PH. Do mesenchymal stromal cells transdifferentiate into functional cardiomyocytes?. Circ Res 2008;103: e120.
Cashman TJ, Gouon-Evans V, Costa KD. Mesenchymal stem cells for cardiac therapy: practical challenges and potential mechanisms. Stem Cell Rev 2013; 9: 254–65.
Kunter U, Rong S, Djuric Z, et al. Transplanted mesenchymal stem cells accelerate glomerular healing in experimental glomerulonephritis. J Am Soc Nephrol 2006; 17: 2202–12.
Herrera MB, Bussolati B, Bruno S, Fonsato V, Romanazzi GM, Camussi G. Mesenchymal stem cells contribute to the renal repair of acute tubular epithelial injury. Int J Mol Med 2004; 14: 1035–41.
Meier RPH, Müller YD, Morel P, Gonelle-Gispert C, Bühler LH. Transplantation of mesenchymal stem cells for the treatment of liver diseases, is there enough evidence?. Stem Cell Res 2013; 11: 1348–64.
Inamdar AC, Inamdar AA. Mesenchymal stem cell therapy in lung disorders: pathogenesis of lung diseases and mechanism of action of mesenchymal stem cell. Exp Lung Res 2013; 39: 315–27.
Xu F, Hu Y, Zhou J, Wang X. Mesenchymal stem cells in acute lung injury: are they ready for translational medicine? J Cell Mol Med 2013; 17: 927–35.
Paul G, Anisimov SV. The secretome of mesenchymal stem cells: potential implications for neuroregeneration. Biochimie, 2013; 95: 2246–56.
Prockop DJ. “Stemness” does not explain the repair of many tissues by mesenchymal stem/multipotent stromal cells (MSCs). Clin Pharmacol Ther 2007; 82: 241–3.
Kachgal S, Putnam AJ. Mesenchymal stem cells from adipose and bone marrow promote angiogenesis via distinct cytokine and protease expression mechanisms. Angiogenesis 2011; 14: 47–59.
Caplan AI. Why are MSCs therapeutic? New data: new insight. J Pathol 2009; 217: 318–24.
Hayashi Y, Tsuji S, Tsujii M, et al. Topical implantation of mesenchymal stem cells has beneficial effects on healing of experimental colitis in rats. J Pharmacol Exp Ther 2008; 326: 523–31.
Yabana T, Arimura Y, Tanaka H, et al. Enhancing epithelial engraftment of rat mesenchymal stem cells restores epithelial barrier integrity. J Pathol 2009; 218: 350–9.
García-Olmo D, García-Arranz M, Herreros D, Pascual I, Peiro C, Rodríguez-Montes JA. A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum 2005; 48: 1416–23.
Garcia-Olmo D, Herreros D, Pascual I, et al. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase ii clinical trial. Dis Colon Rectum 2009; 52: 79–86.
Guadalajara H, Herreros D, De-La-Quintana P, Trebol J, Garcia-Arranz M, Garcia-Olmo D. Long-term follow-up of patients undergoing adipose-derived adult stem cell administration to treat complex perianal fistulas. Int J Colorectal Dis 2012; 27: 595–600.
Cho YB, Lee WY, Park KJ, Kim M, Yoo HW, Yu CS. Autologous adipose tissue-derived stem cells for the treatment of Crohn's fistula: a phase I clinical study. Cell Transplant 2013; 22: 279–85.
Lee WY, Park KJ, Cho YB, et al. Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn's fistula. Stem Cells 2013; 31: 2575–81.
Ciccocioppo R, Bernardo ME, Sgarella A, et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease. Gut 2011; 60: 788–98.
De La Portilla F, Alba F, García-Olmo D, Herrerías JM, González FX, Galindo A. Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn's disease: results from a multicenter phase I/IIa clinical trial. Int J Colorectal Dis 2013; 28: 313–23.
Panès J, Garcia-Olmo D, Van Assche G, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Lancet 2016; 388: 1281–90.
Molendijk I, Bonsing BA, Roelofs H, et al. Allogeneic bone marrow-derived mesenchymal stromal cells promote healing of refractory perianal fistulas in patients with Crohn's disease. Gastroenterology. 2015; 149:918–27; e6.
Duijvestein M, Vos ACW, Roelofs H, et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study. Gut 2010; 59: 1662–9.
Dhere T, Copland I, Garcia M, et al. The safety of autologous and metabolically fit bone marrow mesenchymal stromal cells in medically refractory Crohn's disease – a phase 1 trial with three doses. Aliment Pharmacol Ther 2016; 44: 471–81.
Onken J, Gallup D, Hanson J, Pandak M, Custer L. Successful Outpatient Treatment of Refractory Crohn's Disease Using Adult Mesenchymal Stem Cells. American College of Gastroenterology Conference. Las Vegas, NV; 2006.
Liang J, Zhang H, Wang D, et al. Allogeneic mesenchymal stem cell transplantation in seven patients with refractory inflammatory bowel disease. Gut 2012; 61: 468–9.
Forbes GM, Sturm MJ, Leong RW, et al. A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn's disease refractory to biologic therapy. Clin Gastroenterol Hepatol 2014; 12: 64–71.
Bochev I, Elmadjian G, Kyurkchiev D, et al. Mesenchymal stem cells from human bone marrow or adipose tissue differently modulate mitogen-stimulated B-cell immunoglobulin production in vitro. Cell Biol Int 2008; 32: 384–93.
Ivanova-Todorova E, Bochev I, Mourdjeva M, et al. Adipose tissue-derived mesenchymal stem cells are more potent suppressors of dendritic cells differentiation compared to bone marrow-derived mesenchymal stem cells. Immunol Lett 2009; 126: 37–42.
Li X, Bai J, Ji X, Li R, Xuan Y, Wang Y. Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation and differentiation. Int J Mol Med 2014; 34: 695–704.
Puissant B, Barreau C, Bourin P, et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 2005; 129: 118–29.
Ribeiro A, Laranjeira P, Mendes S, et al. Mesenchymal stem cells from umbilical cord matrix, adipose tissue and bone marrow exhibit different capability to suppress peripheral blood B, natural killer and T cells. Stem Cell Res Ther 2013; 4: 125–41.
Sun LY, Zhang HY, Feng XB, Hou YY, Lu LW, Fan LM. Abnormality of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Lupus 2007; 16: 121–8.
Bocelli-Tyndall C, Bracci L, Spagnoli G, et al. Bone marrow mesenchymal stromal cells (BM-MSCs) from healthy donors and auto-immune disease patients reduce the proliferation of autologous- and allogeneic-stimulated lymphocytes in vitro. Rheumatology 2007; 46: 403–8.
Dinesen L, Wang A, Vianello F, et al. Mesenchymal stem cells administered via novel selective mesenteric artery cannulation for the treatment of severe refractory Crohn's disease. Proceedings of the 4th congress of European Crohn's and Colitis Organisation; 2009 February 5-7; Hamburg, Germany.
Polchert D, Sobinsky J, Douglas GW, et al. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol 2008; 38: 1745–55.
Taddio A, Tommasini A, Valencic E, et al. Failure of interferon-γ pre-treated mesenchymal stem cell treatment in a patient with Crohn's disease. World J Gastroenterol 2015; 21: 4379–84.
Sundin M, Ringdén O, Sundberg B, Nava S, Götherström C, Le Blanc K. No alloantibodies against mesenchymal stromal cells, but presence of anti-fetal calf serum antibodies, after transplantation in allogeneic hematopoietic stem cell recipients. Haematologica 2007; 92: 1208–15.
Forte D, Ciciarello M, Valerii MC, et al. Human cord blood-derived platelet lysate enhances the therapeutic activity of adipose-derived mesenchymal stromal cells isolated from Crohn's disease patients in a mouse model of colitis. Stem Cell Res Ther 2015; 6: 170.
Trojahn Kølle SF, Oliveri RS, Glovinski PV, et al. Pooled human platelet lysate versus fetal bovine serum-investigating the proliferation rate, chromosome stability and angiogenic potential of human adipose tissue-derived stem cells intended for clinical use. Cytotherapy 2013; 15: 1086–97.
Burnouf T, Strunk D, Koh MBC, Schallmoser K. Human platelet lysate: replacing fetal bovine serum as a gold standard for human cell propagation? Biomaterials 2016; 76: 371–87.
Hashmi S, Ahmed M, Murad MH, et al. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis. Lancet Haematol 2016; 3: e45–52.
Chen X, Wang C, Yin J, et al. Efficacy of mesenchymal stem cell therapy for steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis. PLoS ONE 2015; 10: e0136991.
Devine SM, Bartholomew AM, Mahmud N, et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol 2001; 29: 244–55.
Von Bahr L, Batsis I, Moll G, et al. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells 2012; 30: 1575–8.
Ezquer FE, Ezquer ME, Vicencio JM, Calligaris SD. Two complementary strategies to improve cell engraftment in mesenchymal stem cell-based therapy: increasing transplanted cell resistance and increasing tissue receptivity. Cell Adh Migr 2016; 13: 1–10.
Duijvestein M, Molendijk I, Roelofs H, et al. Mesenchymal stromal cell function is not affected by drugs used in the treatment of inflammatory bowel disease. Cytotherapy 2011; 13: 1066–73.
Huang HR, Zan H, Lin Y, Zhong YQ. Effects of azathioprine and infliximab on mesenchymal stem cells derived from the bone marrow of rats in vitro. Mol Med Rep 2014; 9: 1005–12.
Eggenhofer E, Steinmann JF, Renner P, et al. Mesenchymal stem cells together with mycophenolate mofetil inhibit antigen presenting cell and T cell infiltration into allogeneic heart grafts. Transpl Immunol 2011; 24: 157–63.
Eggenhofer E, Renner P, Soeder Y, et al. Features of synergism between mesenchymal stem cells and immunosuppressive drugs in a murine heart transplantation model. Transpl Immunol 2011; 25: 141–7.
Baron F, Storb R. Mesenchymal stromal cells: a new tool against graft-versus-host disease?. Biol Blood Marrow Transplant 2012; 18: 822–40.
Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371: 1579–86.
Baron F, Lechanteur C, Willems E, et al. Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning. Biol Blood Marrow Transplant 2010; 16: 838–47.
Tan J, Wu W, Xu X, et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 2012; 307: 1169–77.
Wakitani S, Okabe T, Horibe S, et al. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med 2011; 5: 146–50.
Otto WR, Wright NA. Mesenchymal stem cells: from experiment to clinic. Fibrogenesis Tissue Repair 2011; 4: 20–34.
Lalu MM, McIntyre L, Pugliese C, et al. Safety of cell therapy with mesenchymal stromal cells (safecell): a systematic review and meta-analysis of clinical trials. PLoS ONE 2012; 7: e47559.
Ren G, Zhao X, Wang Y, et al. CCR2-dependent recruitment of macrophages by tumor-educated mesenchymal stromal cells promotes tumor development and is mimicked by TNFα Cell Stem Cell 2012; 11: 812–24.
Song B, Kim B, Choi S-H, et al. Mesenchymal stromal cells promote tumor progression in fibrosarcoma and gastric cancer cells. Korean J Pathol 2014; 48: 217–24.
Lee RH, Yoon N, Reneau JC, Prockop DJ. Preactivation of human MSCs with TNF-α enhances tumor-suppressive activity. Cell Stem Cell 2012; 11: 825–35.
Abd-Allah SH, Shalaby SM, El-Shal AS, et al. Effect of bone marrow-derived mesenchymal stromal cells on hepatoma. Cytotherapy 2014; 16: 1197–206.
Yang C, Lei D, Ouyang W, et al. Conditioned media from human adipose tissue-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells efficiently induced the apoptosis and differentiation in human glioma cell lines in vitro. Biomed Res Int 2014; 2014: 109389.
Mantovani A. MSCs, macrophages, and cancer: a dangerous ménage-à-trois. Cell Stem Cell 2012; 11: 730–2.
Lazennec G, Jorgensen C. Concise review: adult multipotent stromal cells and cancer: risk or benefit? Stem Cells 2008; 26: 1387–94.
Ning H, Yang F, Jiang M, et al. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study. Leukemia 2008; 22: 593–9.
Chen Z, He X, He X, et al. Bone marrow mesenchymal stem cells ameliorate colitis-Associated tumorigenesis in mice. Biochem Biophys Res Commun 2014; 450: 1402–8.
Ghannam S, Pène J, Moquet-Torcy G, Jorgensen C, Yssel H. Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol 2010; 185: 302–12.
Duffy MM, Ritter T, Ceredig R, Griffin MD. Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther 2011; 2: 34.
Carrión F, Nova E, Luz P, Apablaza F, Figueroa F. Opposing effect of mesenchymal stem cells on Th1 and Th17 cell polarization according to the state of CD4+ T cell activation. Immunol Lett 2011; 135: 10–6.
