Generic placeholder image

Recent Patents on Inflammation & Allergy Drug Discovery

Author(s): Mudasir B. Gugjoo*, Shahid Hussain, Amarpal, Riaz A. Shah and Kuldeep Dhama

DOI: 10.2174/1872213X14666200130100236

Cite As
Mesenchymal Stem Cell-Mediated Immuno-Modulatory and Anti- Inflammatory Mechanisms in Immune and Allergic Disorders

Page: [3 - 14] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Background: Mesenchymal Stem Cells (MSCs) are present in almost all the tissues of the body and act as the backbone of the internal tissue homeostasis. Among their various characteristic features, immuno-modulatory and/ anti-inflammatory properties play an important role in therapeutics.

Objective: The current topic focuses on the characterization and immuno-modulatory and/ antiinflammatory properties of MSCs. To present and discuss the current status of MSCs immunomodulatory properties.

Methods: Available literature on MSCs properties and patents have been detailed, critically interpreted, and discussed based upon available literature. The main focus has been on their characteristic immunomodulatory and anti-inflammatory properties though some of the basic characterization markers have also been detailed. The databases searched for the literature include PubMed, Med Line, PubMed Central, Science Direct and a few other scientific databases.

Results: MSCs are present in a very limited concentration in the tissues, and as such their culture expansion becomes imperative. MSCs immuno-modulatory and anti-inflammatory roles are achieved through direct cell-cell contact and / by the release of certain factors. Such properties are controlled by micro-environment upon which currently very limited control can be exerted. Besides, further insights in the xeno-protein free culture media as against the fetal bovine serum is required.

Conclusion: MSCs have been well-isolated, cultured and characterized from numerous tissues of the body. The majority of the studies have shown MSCs as immuno-compromised with immunomodulatory and / or anti-inflammatory properties except some of the latest studies that have failed to achieve the desired results and thus, demand further research. Further research is required in the area to translate the results into clinical application.

Keywords: Anti-inflammatory, application, characterization, culture, immuno-modulatory, mesenchymal stem cell.

[1]
Gade NE, Pratheesh MD, Nath A, Dubey PK. Amarpal, Sharma B, et al.Molecular and cellular characterization of buffalo bone marrow-derived mesenchymal stem cells. Reprod Domest Anim 2013; 48(3): 358-67.
[http://dx.doi.org/10.1111/j.1439-0531.2012.02156.x] [PMID: 23679988 ]
[2]
Gugjoo MB, Sharma GT, Aithal HP, Kinjavdekar P. Amarpal. Cartilage tissue engineering: Role of mesenchymal stem cells along with growth factors & scaffolds. Indian J Med Res 2016; 144(3): 339-47.
[http://dx.doi.org/10.4103/0971-5916.198724] [PMID: 28139532]
[3]
Gugjoo MB. Amarpal. Mesenchymal stem cell research in sheep: Current status and future prospects. Small Rumin Res 2018; 169: 46-56.
[http://dx.doi.org/10.1016/j.smallrumres.2018.08.002]
[4]
Barry FP, Murphy JM. Mesenchymal stem cells: Clinical applications and biological characterization. Int J Biochem Cell Biol 2004; 36(4): 568-84.
[http://dx.doi.org/10.1016/j.biocel.2003.11.001] [PMID: 15010324 ]
[5]
Brevini TA, Antonini S, Pennarossa G, Gandolfi F. Recent progress in embryonic stem cell research and its application in domestic species. Reprod Domest Anim 2008; 43(2)(Suppl. 2): 193-9.
[http://dx.doi.org/10.1111/j.1439-0531.2008.01161.x] [PMID: 18638123 ]
[6]
Gugjoo MB. Amarpal, Abdelbaset-Ismail A, Aithal HP, Kinjavdekar P, Pawde AM, et al.Mesenchymal stem cells with IGF-1 and TGF- β1 in laminin gel for osteochondral defects in rabbits. Biomed Pharmacother 2017; 93: 1165-74.
[http://dx.doi.org/10.1016/j.biopha.2017.07.032] [PMID: 28738525 ]
[7]
Gugjoo MB. Amarpal, Makhdoomi DM, Sharma GT. Equine mesenchyaml stem cells: Properties, sources, characterization and potential therapeutic applications. J Equine Vet Sci 2019; 72: 16-27.
[http://dx.doi.org/10.1016/j.jevs.2018.10.007] [PMID: 30929778]
[8]
Gugjoo MB. Amarpal, Chandra V, Wani MY, Dhama K, Sharma GT. Mesenchymal stem cell research in veterinary medicine. Curr Stem Cell Res Ther 2018; 13(8): 645-57. a.
[http://dx.doi.org/10.2174/1574888X13666180517074444] [PMID: 29769009]
[9]
Gugjoo MB, Fazili MR, Gayas MA, Ahmad RA, Dhama K. Animal mesenchymal stem cell research in cartilage regenerative medicine -a review. Vet Q 2019; 39(1): 95-120. a.
[http://dx.doi.org/10.1080/01652176.2019.1643051] [PMID: 31291836]
[10]
Jianxia Hu, Zhao G, Zhang L, Qiao C, Di A, Gao H, Xu H. Safety and therapeutic effect of mesenchymal stem cell infusion on moderate to severe ulcerative colitis. Exp Ther Med 2016; 12(5): 2983-9.
[http://dx.doi.org/10.3892/etm.2016.3724] [PMID: 27882104 ]
[11]
Kagia A, Tzetis M, Kanavakis E, Perrea D, Sfougataki I, Mertzanian A, et al. Therapeutic effects of mesenchymal stem cells derived from bone marrow, umbilical cord blood, and pluripotent stem cells in a mouse model of chemically induced inflammatory bowel disease. Inflammation 2019; 42(5): 1730-40.
[http://dx.doi.org/10.1007/s10753-019-01033-x] [PMID: 31227956]
[12]
Gugjoo MB. Amarpal, Fazili MR, Shah RA, Sharma GT. Mesenchymal stem cell: Basic research and potential applications in cattle and buffalo. J Cell Physiol 2019; 234(6): 8618-35. b.
[http://dx.doi.org/10.1002/jcp.27846] [PMID: 30515790]
[13]
Zuk P, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ. Multilineage cells from human adipose tissue: Implications for cell-based therapies. Tissue Eng 2001; 7(2): 211-28.
[http://dx.doi.org/10.1089/107632701300062859] [PMID: 11304456]
[14]
Stewart MC, Stewart AA. Mesenchymal stem cells: Characteristics, sources, and mechanisms of action. Vet Clin North Am Equine Pract 2011; 27(2): 243-61.
[http://dx.doi.org/10.1016/j.cveq.2011.06.004] [PMID: 21872757 ]
[15]
Gugjoo MB, Amarpal A, Sharma GT. Mesenchymal stem cell basic research and applications in dog medicine. J Cell Physiol 2019; 234(10): 16779-811.
[http://dx.doi.org/10.1002/jcp.28348] [PMID: 30790282 ]
[16]
Cardoso MT, Pinheiro AO, Vidane AS, Casals JB, de Oliveira VC, Gonçalves NJN, et al. Characterization of teratogenic potential and gene expression in canine and feline amniotic membrane-derived stem cells. Reprod Domest Anim 2017; 52(Suppl. 2): 58-64.
[http://dx.doi.org/10.1111/rda.12832] [PMID: 27774699]
[17]
Caplan AI. Mesenchymal stem cells. J Orthop Res 1991; 9(5): 641-50.
[http://dx.doi.org/10.1002/jor.1100090504] [PMID: 1870029 ]
[18]
Bianco P, Robey PG, Simmons PJ. Mesenchymal stem cells: Revisiting history, concepts, and assays. Cell Stem Cell 2008; 2(4): 313-9.
[http://dx.doi.org/10.1016/j.stem.2008.03.002] [PMID: 18397751 ]
[19]
Friedenstein AJ. Osteogenic Stem Cells in Bone Marrow. In: Heersche JNM, Kanis JA, EdsBone and Mineral Research. Elsevier:Amsterdam, . 1990; pp. 243-72.
[http://dx.doi.org/10.1016/B978-0-444-81371-8.50012-1]
[20]
Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 2008; 3(3): 301-13.
[http://dx.doi.org/10.1016/j.stem.2008.07.003] [PMID: 18786417 ]
[21]
Charbord P, Livne E, Gross G, Häupl T, Neves NM, Marie P, et al. Human bone marrow mesenchymal stem cells: A systematic reappraisal via the genostem experience. Stem Cell Rev Rep 2011; 7(1): 32-42.
[http://dx.doi.org/10.1007/s12015-010-9125-6] [PMID: 20198518]
[22]
Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem 2006; 98(5): 1076-84.
[http://dx.doi.org/10.1002/jcb.20886] [PMID: 16619257]
[23]
Caplan AI. MSCs as Therapeutics. In: Hematti P, Keating A, EditorsStem cell biology and regenerative medicine: Mesenchymal stromal cells: Biology and Clinical Applications. Human Press: New York 2012; pp. 79-90.
[24]
Prockop DJ, Oh JY. Mesenchymal stem/stromal cells (MSCs): Role as guardians of inflammation. Mol Ther 2012; 20(1): 14-20.
[http://dx.doi.org/10.1038/mt.2011.211] [PMID: 22008910]
[25]
Villatoro AJ, Alcoholado C, Martín-Astorga MC, Fernández V, Cifuentes M, Becerra J. Comparative analysis and characterization of soluble factors and exosomes from cultured adipose tissue and bone marrow mesenchymal stem cells in canine species. Vet Immunol Immunopathol 2019; 208: 6-15.
[http://dx.doi.org/10.1016/j.vetimm.2018.12.003] [PMID: 30712794 ]
[26]
Toupadakis CA, Wong A, Genetos DC, Cheung WK, Borjesson DL, Ferraro GL, et al. Comparison of the osteogenic potential of equine mesenchymal stem cells from bone marrow, adipose tissue, umbilical cord blood, and umbilical cord tissue. Am J Vet Res 2010; 71(10): 1237-45.
[http://dx.doi.org/10.2460/ajvr.71.10.1237] [PMID: 20919913]
[27]
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy Position Statement. Cytotherapy 2006; 8(4): 315-7.
[http://dx.doi.org/10.1080/14653240600855905] [PMID: 16923606 ]
[28]
Schnabel LV, Lynch ME, van der Meulen MC, Yeager AE, Kornatowski MA, Nixon AJ. Mesenchymal stem cells and insulin-like growth factor-I gene-enhanced mesenchymal stem cells improve structural aspects of healing in equine flexor digitorum superficialis tendons. J Orthop Res 2009; 27(10): 1392-8.
[http://dx.doi.org/10.1002/jor.20887] [PMID: 19350658 ]
[29]
De Schauwer C, Meyer E, Van de Walle GR, Van Soom A. Markers of stemness in equine mesenchymal stem cells: A plea for uniformity. Theriogenology 2011; 75(8): 1431-43.
[http://dx.doi.org/10.1016/j.theriogenology.2010.11.008] [PMID: 21196039]
[30]
Gugjoo MB. Isolation, culturing and characterization of New Zealand White rabbit mesenchymal stem cells derived from bone marrow. Asian J Anim Vet Adv 2015; 10(10): 537-48.
[http://dx.doi.org/10.3923/ajava.2015.537.548]
[31]
Fisk, N.M., Wolvetang, E.J. Method for differentiating pluripotent stem cell induced from mesenchymal stem cell into osteoblast.US10053669 (2013).
[32]
Munoz, C.J.R., Diaz, T.J.M., Herenci, B.C., Rodriguez, O.M.E.,Montes, D.G.A.R., Martinez-Moreno, J.M., Pena, Y.A., Portillo,M.R., Garcia, P.A., Gundlach, K., Büchel, P.M.J., Steppan, S., Passlick-Deetjen, J. Improved differentiation of mesenchymal stem cells into osteoblasts. EP2899266 (2015).
[33]
Zhiyuan L, Sihao D, Wenyu C, Dahua L, Yang X. One neural stem cell cryopreservation solution and method of use. CN104542576 (2015).
[34]
Henghui Z, Bo D, Haibo W, Dandan Z, Yong Y, Ping F. Species for early predict mesenchymal stem cell osteogenic differentiation potential gene detection kit. CN107475402 (2017).
[35]
Guest DJ, Smith MR, Allen WR. Monitoring the fate of autologous and allogeneic mesenchymal progenitor cells injected into the superficial digital flexor tendon of horses: Preliminary study. Equine Vet J 2008; 40(2): 178-81.
[http://dx.doi.org/10.2746/042516408X276942] [PMID: 18267891 ]
[36]
Ranera B, Lyahyai J, Romeroa A, Vázquez FJ, Remacha AR, Bernal ML, et al. Immunophenotype and gene expression profiles of cell surface markers of mesenchymal stem cells derived from equine bone marrow and adipose tissue. Vet Immunol Immunopathol 2011; 144(1-2): 147-54.
[http://dx.doi.org/10.1016/j.vetimm.2011.06.033] [PMID: 21782255 ]
[37]
De Schauwer C, Piepers S, Van de Walle GR, Demeyere K, Hoogewijs MK, Govaere JL, et al. In search for cross-reactivity to immunophenotype equine mesenchymal stromal cells by multicolor flow cytometry. Cytometry A 2012; 81(4): 312-23.
[http://dx.doi.org/10.1002/cyto.a.22026] [PMID: 22411893 ]
[38]
Martinello T, Bronzini I, MacCatrozzo L, Iacopetti I, Sampaolesi M, Mascarello F, et al. Cryopreservation does not affect the stem characteristics of multipotent cells isolated from equine peripheral blood. Tissue Eng Part C Methods 2010; 16(4): 771-81.
[http://dx.doi.org/10.1089/ten.tec.2009.0512] [PMID: 19839741]
[39]
Vieira NM, Brandalise V, Zucconi E, Secco M, Strauss BE, Zatz M. Isolation, characterization, and differentiation potential of canine adipose-derived stem cells. Cell Transplant 2010; 19(3): 279-89.
[http://dx.doi.org/10.3727/096368909X481764] [PMID: 19995482 ]
[40]
Ghaneialvar H, Soltani L, Rahmani HR, Lotfi AS, Soleimani M. Characterization and classification of mesenchymal stem cells in several species using surface markers for cell therapy purposes. Indian J Clin Biochem 2018; 33(1): 46-52.
[http://dx.doi.org/10.1007/s12291-017-0641-x]
[41]
Colleoni S, Bottani E, Tessaro I, et al. Isolation, growth and differentiation of equine mesenchymal stem cells: Effect of donor, source, amount of tissue and supplementation with basic fibroblast growth factor. Vet Res Commun 2009; 33(8): 811-21.
[http://dx.doi.org/10.1007/s11259-009-9229-0] [PMID: 19472068 ]
[42]
Radcliffe CH, Flaminio MJ, Fortier LA. Temporal analysis of equine bone marrow aspirate during establishment of putative mesenchymal progenitor cell populations. Stem Cells Dev 2010; 19(2): 269-82.
[http://dx.doi.org/10.1089/scd.2009.0091] [PMID: 19604071 ]
[43]
Mosna F, Sensebé L, Krampera M. Human bone marrow and adipose tissue mesenchymal stem cells: A user’s guide. Stem Cells Dev 2010; 19(10): 1449-70.
[http://dx.doi.org/10.1089/scd.2010.0140] [PMID: 20486777 ]
[44]
Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev 2012; 21(14): 2724-52.
[http://dx.doi.org/10.1089/scd.2011.0722] [PMID: 22468918]
[45]
Schwarz C, Leicht U, Rothe C, Drosse I, Luibl V, Röcken M, et al. Effects of different media on proliferation and differentiation capacity of canine, equine and porcine adipose derived stem cells. Res Vet Sci 2012; 93(1): 457-62.
[http://dx.doi.org/10.1016/j.rvsc.2011.08.010] [PMID: 21940026 ]
[46]
Bieback K. Platelet lysate as replacement for fetal bovine serum in mesenchymal stromal cell cultures. Transfus Med Hemother 2013; 40(5): 326-35.
[http://dx.doi.org/10.1159/000354061] [PMID: 24273486 ]
[47]
Yifei W, Xiaofeng L, Qiaoli W, Qiuying L. Serum-free medium for human umbilical cord mesenchymal stem cells and preparation method thereof. CN105112365 (2018).
[48]
Schubert S, Brehm W, Hillmann A, Burk J. Serum-free human MSC medium supports consistency in human but not in equine adipose-derived multipotent mesenchymal stromal cell culture. Cytometry A 2018; 93(1): 60-72.
[http://dx.doi.org/10.1002/cyto.a.23240] [PMID: 28926198 ]
[49]
Basciano L, Nemos C, Foliguet B, de Isla N, de Carvalho M, Tran N, et al. Long term culture of mesenchymal stem cells in hypoxia promotes a genetic program maintaining their undifferentiated and multipotent status. BMC Cell Biol 2011; 12(1): 12.
[http://dx.doi.org/10.1186/1471-2121-12-12] [PMID: 21450070 ]
[50]
Cicione C, Muiños-López E, Hermida-Gómez T, Fuentes-Boquete I, Díaz-Prado S, Blanco FJ. Effects of severe hypoxia on bone marrow mesenchymal stem cells differentiation potential. Stem Cells Int 2013; 2013 232896
[http://dx.doi.org/10.1155/2013/232896] [PMID: 24082888 ]
[51]
Jiang C, Liu J, Zhao J, Xiao L, An S, Gou Y, et al. Effects of hypoxia on the immunomodulatory properties of human gingiva-derived mesenchymal stem cells. J Dent Res 2015; 94(1): 69-77.
[http://dx.doi.org/10.1177/0022034514557671] [PMID: 25403565 ]
[52]
Lan YW, Choo KB, Chen CM, Hung TH, Chen YB, Hsieh CH, et al. Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis. Stem Cell Res Ther 2015; 6: 97.
[http://dx.doi.org/10.1186/s13287-015-0081-6] [PMID: 25986930 ]
[53]
in ’t Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, Kruisselbrink AB, van Bezooijen RL, et al. Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica 2003; 88(8): 845-52.
[PMID: 12935972 ]
[54]
Gao F, Chiu SM, Motan DAL, Zhang Z, Chen L, Ji H-L, et al. Mesenchymal stem cells and immunomodulation: Current status and future prospects. Cell Death Dis 2016; 7 e2062
[http://dx.doi.org/10.1038/cddis.2015.327] [PMID: 26794657 ]
[55]
Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Adreini A, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 2006; 24(2): 386-98.
[http://dx.doi.org/10.1634/stemcells.2005-0008] [PMID: 16123384 ]
[56]
Carrade DD, Borjesson DL. Immunomodulation by mesenchymal stem cells in veterinary species. Comp Med 2013; 63(3): 207-17.
[PMID: 23759523 ]
[57]
Bçrziòð U, Matise-VanHoutana I, Pçtersone I, Dûrîtis I, Òikuïðins S, Bogdanova-Jâtniece A, et al. Characterisation and in vivo safety of canine adipose-derived stem cells. Proc Latvian Acad Sci 2018; 72(3): 160-71.
[58]
Enciso N, Ostronoff LLK, Mejías G, León LG, Fermín ML, Merino E, et al. Stem cell factor supports migration in canine mesenchymal stem cells. Vet Res Commun 2018; 42(1): 29-38.
[http://dx.doi.org/10.1007/s11259-017-9705-x] [PMID: 29297135 ]
[59]
Angelone M, Conti V, Biacca C, Battaglia B, Pecorari L, Piana F, et al. The contribution of adipose tissue-derived mesenchymal stem cells and platelet-rich plasma to the treatment of chronic equine laminitis: A proof of concept. Int J Mol Sci 2017; 18(10): 2122.
[http://dx.doi.org/10.3390/ijms18102122] [PMID: 29019941 ]
[60]
Koc ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI, et al. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 2000; 18(2): 307-16.
[http://dx.doi.org/10.1200/JCO.2000.18.2.307] [PMID: 10637244]
[61]
Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY, et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci USA 2002; 99(13): 8932-7.
[http://dx.doi.org/10.1073/pnas.132252399] [PMID: 12084934]
[62]
Kang JW, Kang K-S, Koo HC, Park JR, Choi EW, Park YH. Soluble factors-mediated immunomodulatory effects of canine adipose tissue-derived mesenchymal stem cells. Stem Cells Dev 2008; 17(4): 681-93.
[http://dx.doi.org/10.1089/scd.2007.0153] [PMID: 18717642 ]
[63]
Kim HS, Kim KH, Kim SH, Kim YS, Koo KT, Kim TI, et al. Immunomodulatory effect of canine periodontal ligament stem cells on allogenic and xenogenic peripheral blood mononuclear cells. J Periodontal Implant Sci 2010; 40(6): 265-70.
[http://dx.doi.org/10.5051/jpis.2010.40.6.265] [PMID: 21246016 ]
[64]
Lee WS, Suzuki Y, Graves SS, Iwata M, Venkataraman GM, Mielcarek M, et al. Canine bone marrow-derived mesenchymal stromal cells suppress alloreactive lymphocyte proliferation in vitro but fail to enhance engraftment in canine bone marrow transplantation. Biol Blood Marrow Transplant 2011; 17(4): 465-75.
[http://dx.doi.org/10.1016/j.bbmt.2010.04.016] [PMID: 20457265 ]
[65]
Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: Pathological and therapeutic implications. Nat Immunol 2014; 15(11): 1009-16.
[http://dx.doi.org/10.1038/ni.3002] [PMID: 25329189]
[66]
Wheat WH, Chow L, Kurihara JN, Regan DP, Coy JW, Webb TL, et al. Suppression of canine dendritic cell activation/maturation and inflammatory cytokine release by mesenchymal stem cells occurs through multiple distinct biochemical pathways. Stem Cells Dev 2017; 26(4): 249-62.
[http://dx.doi.org/10.1089/scd.2016.0199] [PMID: 27842458 ]
[67]
Liotta F, Angeli R, Cosmi L, Fili L, Manuelli C, Frosali F, et al. Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells 2008; 26(1): 279-89.
[http://dx.doi.org/10.1634/stemcells.2007-0454] [PMID: 17962701 ]
[68]
Tomchuck SL, Zwezdaryk KJ, Coffelt SB, Waterman RS, Danka ES, Scandurro AB. Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem Cells 2008; 26(1): 99-107.
[http://dx.doi.org/10.1634/stemcells.2007-0563] [PMID: 17916800 ]
[69]
DelaRosa O, Lombardo E. Modulation of adult mesenchymal stem cells activity by toll-like receptors: Implications on therapeutic potential. Mediators Inflamm 2018; 2018: 6560.
[http://dx.doi.org/10.1155/2010/865601] [PMID: 20628526 ]
[70]
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(5): 2321-8.
[http://dx.doi.org/10.4049/jimmunol.0902023] [PMID: 20130212 ]
[71]
Akiyama K, Chen C, Wang D, Xu X, Qu C, Yamaza T, et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 2012; 10(5): 544-55.
[http://dx.doi.org/10.1016/j.stem.2012.03.007] [PMID: 22542159 ]
[72]
Mielcarek M, Storb R, Georges GE, Golubev L, Nikitine A, Hwang B, et al. Mesenchymal stromal cells fail to prevent acute graft-versus-host disease and graft rejection after dog leukocyte antigen-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant 2011; 17(2): 214-25.
[http://dx.doi.org/10.1016/j.bbmt.2010.08.015] [PMID: 20816818 ]
[73]
Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99(10): 3838-43.
[http://dx.doi.org/10.1182/blood.V99.10.3838] [PMID: 11986244]
[74]
Peroni JF, Borjesson DL. Anti-inflammatory and immunomodulatory activities of stem cells. Vet Clin North Am Equine Pract 2011; 27(2): 351-62.
[http://dx.doi.org/10.1016/j.cveq.2011.06.003] [PMID: 21872763 ]
[75]
Carrade DD, Lame MW, Kent MS, Clark KC, Walker NJ, Borjesson DL. Comparative analysis of the immunomodulatory properties of equine adult-derived mesenchymal stem cells. Cell Med 2012; 4(1): 1-11.
[http://dx.doi.org/10.3727/215517912X647217] [PMID: 23152950 ]
[76]
Colbath AC, Dow SW, Phillips JN, McIlwraith CW, Goodrich LR. Autologous and allogeneic equine mesenchymal stem cells exhibit equivalent immunomodulatory properties in vitro. Stem Cells Dev 2017; 26(7): 503-11.
[http://dx.doi.org/10.1089/scd.2016.0266] [PMID: 27958776]
[77]
Cassano JM, Fortier LA, Hicks RB, Harman RM, Van de Walle GR. Equine mesenchymal stromal cells from different tissue sources display comparable immune-related gene expression profiles in response to interferon gamma (IFN)-γ. Vet Immunol Immunopathol 2018; 202: 25-30.
[http://dx.doi.org/10.1016/j.vetimm.2018.06.008] [PMID: 30078595 ]
[78]
Russell KA, Chow NHC, Dukoff D, Gibson TWG, LaMarre J, Betts DH, et al. Characterization and immunomodulatory effects of canine adipose tissue- and bone marrow-derived mesenchymal stromal cells. PLoS One 2016; 11(12) e0167442
[http://dx.doi.org/10.1371/journal.pone.0167442] [PMID: 27907211 ]
[79]
Tso GH, Law HK, Tu W, Chan GC, Lau YL. Phagocytosis of apoptotic cells modulates mesenchymal stem cells osteogenic differentiation to enhance IL-17 and RANKL expression on CD4+ T cells. Stem Cells 2010; 28(5): 939-54.
[http://dx.doi.org/10.1002/stem.406] [PMID: 20222014]
[80]
Yañez R, Lamana ML, García-Castro J, Colmenero I, Ramírez M, Bueren JA. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells 2006; 24(11): 2582-91.
[http://dx.doi.org/10.1634/stemcells.2006-0228] [PMID: 16873762 ]
[81]
Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, et al. Human mesenchymal stem cells modulate B-cell functions. Blood 2006; 107(1): 367-72.
[http://dx.doi.org/10.1182/blood-2005-07-2657] [PMID: 16141348 ]
[82]
Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105(4): 1815-22.
[http://dx.doi.org/10.1182/blood-2004-04-1559] [PMID: 15494428]
[83]
Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 2005; 105(10): 4120-6.
[http://dx.doi.org/10.1182/blood-2004-02-0586] [PMID: 15692068]
[84]
Chiesa S, Morbelli S, Morando S, Massollo M, Marini C, Bertoni A, et al. Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proc Natl Acad Sci USA 2011; 108(42): 17384-9.
[http://dx.doi.org/10.1073/pnas.1103650108] [PMID: 21960443 ]
[85]
Consentius C, Akyüz L, Schmidt-Lucke JA, Tschöpe C, Pinzur L, Ofir R, et al. Mesenchymal stromal cells prevent allostimulation in vivo and control checkpoints of Th1 priming: Migration of human DC to lymph nodes and NK cell activation. Stem Cells 2015; 33(10): 3087-99.
[http://dx.doi.org/10.1002/stem.2104] [PMID: 26184374 ]
[86]
Moretta A. Natural killer cells and dendritic cells: Rendezvous in abused tissues. Nat Rev Immunol 2002; 2(12): 957-64.
[http://dx.doi.org/10.1038/nri956] [PMID: 12461568 ]
[87]
Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 2006; 24(1): 74-85.
[http://dx.doi.org/10.1634/stemcells.2004-0359] [PMID: 16099998 ]
[88]
Cui R, Rekasi H, Hepner-Schefczyk M, Fessmann K, Petri RM, Bruderek K, et al. Human mesenchymal stromal/stem cells acquire immunostimulatory capacity upon cross-talk with natural killer cells and might improve the NK cell function of immunocompromised patients. Stem Cell Res Ther 2016; 7(1): 88.
[http://dx.doi.org/10.1186/s13287-016-0353-9] [PMID: 27388156]
[89]
Michelo C M, Fasse E, van Cranenbroek B, Linda K. Added effects of dexamethasone and mesenchymal stem cells on early natural killer cell activation. Transpl Immunol 2016; 37: 1-9.
[http://dx.doi.org/10.1016/j.trim.2016.04.008] [PMID: 27142560 ]
[90]
Poncelet AJ, Vercruysse J, Saliez A, Gianello P. Although pig allogeneic mesenchymal stem cells are not immunogenic in vitro, intracardiac injection elicits an immune response in vivo. Transplantation 2007; 83(6): 783-90.
[http://dx.doi.org/10.1097/01.tp.0000258649.23081.a3] [PMID: 17414713 ]
[91]
Sheng H, Wang Y, Jin Y, Zhang Q, Zhang Y, Wang L, et al. A critical role of IFN gamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res 2008; 18(8): 846-57.
[http://dx.doi.org/10.1038/cr.2008.80] [PMID: 18607390 ]
[92]
Chan JL, Tang KC, Patel AP, Bonilla LM, Pierobon N, Ponzio NM, et al. Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma. Blood 2006; 107(12): 4817-24.
[http://dx.doi.org/10.1182/blood-2006-01-0057] [PMID: 16493000 ]
[93]
Ren G, Roberts AI, Shi Y. Adhesion molecules: Key players in Mesenchymal stem cell-mediated immunosuppression. Cell Adhes Migr 2011; 5(1): 20-2.
[http://dx.doi.org/10.4161/cam.5.1.13491] [PMID: 20935502 ]
[94]
Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2008; 2(2): 141-50.
[http://dx.doi.org/10.1016/j.stem.2007.11.014] [PMID: 18371435 ]
[95]
Dalemans W, Lombardo E. Adipose-derived mesenchymal stem cells for intra-lymphatic administration in autoimmune and inflammatory diseases. KR101900664 (2018).
[96]
McDuffee LA, Pack L, Lores M, Wright GM, Esparza-Gonzalez B, Masaoud E. Osteoprogenitor cell therapy in an equine fracture model. Vet Surg 2012; 41(7): 773-83.
[http://dx.doi.org/10.1111/j.1532-950X.2012.01024.x] [PMID: 22804243 ]
[97]
Lopez MJ, Jarazo J. State of the art: Stem cells in equine regenerative medicine. Equine Vet J 2015; 47(2): 145-54.
[http://dx.doi.org/10.1111/evj.12311] [PMID: 24957845 ]
[98]
Ardanaz N, Vázquez FJ, Romero A, Remacha AR, Barrachina L, Sanz A, et al. Inflammatory response to the administration of mesenchymal stem cells in an equine experimental model: Effect of autologous, and single and repeat doses of pooled allogeneic cells in healthy joints. BMC Vet Res 2016; 12: 65.
[http://dx.doi.org/10.1186/s12917-016-0692-x] [PMID: 27029614 ]
[99]
Cabon Q, Febre M, Gomez N, Cachon T, Pillard P, Carozzo C, et al. Long-term safety and efficacy of single or repeated intra-articular injection of allogeneic neonatal mesenchymal stromal cells for managing pain and lameness in moderate to severe canine osteoarthritis without anti-inflammatory pharmacological support: Pilot Clinical Study. Front Vet Sci 2019; 6: 10.
[http://dx.doi.org/10.3389/fvets.2019.00010] [PMID: 30805348]
[100]
Takeda K, Webb TL, Ning F, Shiraishi Y, Regan DP, Chow L, et al. Mesenchymal stem cells recruit CCR2+ monocytes to suppress allergic airway inflammation. J Immunol 2018; 200(4): 1261-9.
[http://dx.doi.org/10.4049/jimmunol.1700562] [PMID: 29352000]
[101]
Ortiz LA, DuTreil M, Fattman C, et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA 2007; 104(26): 11002-7.
[http://dx.doi.org/10.1073/pnas.0704421104] [PMID: 17569781 ]
[102]
Huh JW, Kim WY, Park YY, et al. Anti-inflammatory role of mesenchymal stem cells in an acute lung injury mouse model. Acute Crit Care 2018; 33(3): 154-61.
[http://dx.doi.org/10.4266/acc.2018.00619] [PMID: 31723879]
[103]
Ohnishi S, Yanagawa B, Tanaka K, Miyahara Y, Obata H, Kataoka M, et al. Transplantation of mesenchymal stem cells attenuates myocardial injury and dysfunction in a rat model of acute myocarditis. J Mol Cell Cardiol 2007; 42(1): 88-97.
[http://dx.doi.org/10.1016/j.yjmcc.2006.10.003] [PMID: 17101147 ]
[104]
Parekkadan B, Van Poll D, Suganuma K, Carter EA, Berthiaume F, Tilles AW, et al. Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS One 2007; 2(9) e941
[http://dx.doi.org/10.1371/journal.pone.0000941] [PMID: 17895982]
[105]
Semedo P, Wang PM, Andreucci TH, Cenedeze MA, Teixeira VP, Reis MA, et al. Mesenchymal stem cells ameliorate tissue damages triggered by renal ischemia and reperfusion injury. Transplant Proc 2007; 39(2): 421-3.
[http://dx.doi.org/10.1016/j.transproceed.2007.01.036] [PMID: 17362746 ]
[106]
Kim SW, Zhang HZ, Guo L, Kim JM, Kim MH. Amniotic mesenchymal stem cells enhance wound healing in diabetic NOD/SCID mice through high angiogenic and engraftment capabilities. PLoS One 2012; 7(7) e41105
[http://dx.doi.org/10.1371/journal.pone.0041105] [PMID: 22815931 ]
[107]
Kim JW, Lee JH, Lyoo YS, Jung DI, Park HM. The effects of topical mesenchymal stem cell transplantation in canine experimental cutaneous wounds. Vet Dermatol 2013; 24(2): 242-53.
[http://dx.doi.org/10.1111/vde.12011] [PMID: 23432413 ]
[108]
Ringdén O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lönnies H, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 2006; 81(10): 1390-7.
[http://dx.doi.org/10.1097/01.tp.0000214462.63943.14] [PMID: 16732175 ]
[109]
Kim Y, Jo SH, Kim WH, Kweon O-K. Antioxidant and anti-inflammatory effects of intravenously injected adipose derived mesenchymal stem cells in dogs with acute spinal cord injury. Stem Cell Res Ther 2015; 6: 229.
[http://dx.doi.org/10.1186/s13287-015-0236-5] [PMID: 26612085]
[110]
Abdel Salam AG, Ata HM, Salman TM, Rashed LA, Sabry D, Schaalan MF. Potential therapeutic utility of mesenchymal stem cells in inflammatory bowel disease in mice. Int Immunopharmacol 2014; 22(2): 515-21.
[http://dx.doi.org/10.1016/j.intimp.2014.07.030] [PMID: 25133649 ]
[111]
Tassi SA, Sergio NZ, Misawa MYO, Villar CC. Efficacy of stem cells on periodontal regeneration: Systematic review of pre-clinical studies. J Periodontal Res 2017; 52(5): 793-812.
[http://dx.doi.org/10.1111/jre.12455] [PMID: 28394043 ]
[112]
Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363(9419): 1439-41.
[http://dx.doi.org/10.1016/S0140-6736(04)16104-7] [PMID: 15121408 ]
[113]
Rafei M, Campeau PM, Aguilar-Mahecha A, Buchanan M, Williams P, Birman E, et al. Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. J Immunol 2009; 182(10): 5994-6002.
[http://dx.doi.org/10.4049/jimmunol.0803962] [PMID: 19414750 ]
[114]
Cho KS, Park HK, Park HY, Jung JS, Jeon SG, Kim YK, et al. IFATS collection: Immunomodulatory effects of adipose tissue-derived stem cells in an allergic rhinitis mouse model. Stem Cells 2009; 27(1): 259-65.
[http://dx.doi.org/10.1634/stemcells.2008-0283] [PMID: 18832595]
[115]
Bonfield TL, Koloze M, Lennon DP, Zuchowski B, Yang SE, Caplan AI. Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model. Am J Physiol Lung Cell Mol Physiol 2010; 299(6): L760-70.
[http://dx.doi.org/10.1152/ajplung.00182.2009] [PMID: 20817776 ]
[116]
Bonfield TL, Nolan Koloze MT, Lennon DP, Caplan AI. Defining human mesenchymal stem cell efficacy in vivo. J Inflamm (Lond) 2010; 7: 51.
[http://dx.doi.org/10.1186/1476-9255-7-51] [PMID: 20974000]
[117]
Cho KS, Roh HJ. Immunomodulatory effects of adipose-derived stem cells in airway allergic diseases. Curr Stem Cell Res Ther 2010; 5(2): 111-5.
[http://dx.doi.org/10.2174/157488810791268681] [PMID: 19941459]
[118]
Nemeth K, Keane-Myers A, Brown JM, Metcalfe DD, Gorham JD, Bundoc VG, et al. Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma. Proc Natl Acad Sci USA 2010; 107(12): 5652-7.
[http://dx.doi.org/10.1073/pnas.0910720107] [PMID: 20231466]
[119]
Goodwin M, Sueblinvong V, Eisenhauer P, Ziats NP, LeClair L, Poynter ME, et al. Bone marrow-derived mesenchymal stromal cells inhibitz Th2-mediated allergic airways inflammation in mice. Stem Cells 2011; 29(7): 1137-48.
[http://dx.doi.org/10.1002/stem.656] [PMID: 21544902]
[120]
Crop MJ, Baan CC, Korevaar SS, Ijzermans JN, Pescatori M, Stubbs AP, et al. Inflammatory conditions affect gene expression and function of human adipose tissue-derived mesenchymal stem cells. Clin Exp Immunol 2010; 162(3): 474-86.
[http://dx.doi.org/10.1111/j.1365-2249.2010.04256.x] [PMID: 20846162 ]
[121]
Raicevic G, Najar M, Najimi M, El Taghdouini A, van Grunsven LA, Sokal E, et al. Influence of inflammation on the immunological profile of adult-derived human liver mesenchymal stromal cells and stellate cells. Cytotherapy 2015; 17(2): 174-85.
[http://dx.doi.org/10.1016/j.jcyt.2014.10.001] [PMID: 25455740]
[122]
Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood 2006; 108(6): 2114-20.
[http://dx.doi.org/10.1182/blood-2005-11-011650] [PMID: 16690970]
[123]
Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: Mesenchymal stem cells: Their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 2007; 25(11): 2739-49.
[http://dx.doi.org/10.1634/stemcells.2007-0197] [PMID: 17656645 ]
[124]
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(10): 890-6.
[http://dx.doi.org/10.1016/S0301-472X(03)00110-3] [PMID: 14550804]
[125]
Klyushnenkova E, Mosca JD, Zernetkina V, Majumdar MK, Beggs KJ, Simonetti DW, et al. T Cell responses to allogeneic human mesenchymal stem cells: Immunogenicity, tolerance, and suppression. J Biomed Sci 2005; 12(1): 47-57.
[http://dx.doi.org/10.1007/s11373-004-8183-7] [PMID: 15864738]
[126]
Le Blanc K, Ringdén O. Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med 2007; 262(5): 509-25.
[http://dx.doi.org/10.1111/j.1365-2796.2007.01844.x] [PMID: 17949362]
[127]
Pezzanite LM, Fortier LA, Antczak DF, Cassano JM, Brosnahan MM, Miller D, et al. Equine allogeneic bone marrow-derived mesenchymal stromal cells elicit antibody responses in vivo. Stem Cell Res Ther 2015; 6: 54.
[http://dx.doi.org/10.1186/s13287-015-0053-x] [PMID: 25889095]
[128]
Owens SD, Kol A, Walker NJ, Borjesson DL. Allogeneic mesenchymal stem cell treatment induces specific alloantibodies in horses. Stem Cells Int 2016; 2016 5830103
[http://dx.doi.org/10.1155/2016/5830103] [PMID: 27648075]
[129]
Djouad F, Fritz V, Apparailly F, Louis-Plence P, Bony C, Sany J, et al. Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor α in collagen-induced arthritis. Arthritis Rheum 2005; 52(5): 1595-603.
[http://dx.doi.org/10.1002/art.21012] [PMID: 15880818 ]
[130]
Sudres M, Norol F, Trenado A, Grégoire S, Charlotte F, Levacher B, et al. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol 2006; 176(12): 7761-7.
[http://dx.doi.org/10.4049/jimmunol.176.12.7761] [PMID: 16751424 ]
[131]
Frisbie DD, Kisiday JD, Kawcak CE, Werpy NM, McIlwraith CW. Evaluation of adipose-derived stromal vascular fraction or bone marrow-derived mesenchymal stem cells for treatment of osteoarthritis. J Orthop Res 2009; 27(12): 1675-80.
[http://dx.doi.org/10.1002/jor.20933] [PMID: 19544397 ]
[132]
Zayed MN, Schumacher J, Misk N, Dhar MS. Effects of pro-inflammatory cytokines on chondrogenesis of equine mesenchymal stromal cells derived from bone marrow or synovial fluid. Vet J 2016; 217: 26-32.
[http://dx.doi.org/10.1016/j.tvjl.2016.05.014] [PMID: 27810206 ]
[133]
Barrachina AR, Remachaa A, Romeroa FJ, Vázquez FJ, Albareda J, Prades M, et al. Effect of inflammatory environment on equine bone marrow derived mesenchymal stem cells immunogenicity and immunomodulatory properties. Vet Immunol Immunopathol 2016; 171: 57-65.
[http://dx.doi.org/10.1016/j.vetimm.2016.02.007] [PMID: 26964718 ]
[134]
Reesink HL, Sutton RM, Shurer CR, Peterson RP, Tan JS, Su J, et al. Galectin-1 and galectin-3 expression in equine Mesenchymal Stromal Cells (MSCs), synovial fibroblasts and chondrocytes, and the effect of inflammation on MSC motility. Stem Cell Res Ther 2017; 8(1): 243.
[http://dx.doi.org/10.1186/s13287-017-0691-2] [PMID: 29096716 ]
[135]
Taylor SE, Smith RKW, Clegg PD. Mesenchymal stem cell therapy in equine musculoskeletal disease: Scientific fact or clinical fiction? Equine Vet J 2007; 39(2): 172-80.
[http://dx.doi.org/10.2746/042516407X180868] [PMID: 17378447]
[136]
Joswig A-J, Mitchell A, Cummings KJ, Levine GJ, Gregory CA, Smith R, et al. Repeated intra-articular injection of allogeneic mesenchymal stem cells causes an adverse response compared to autologous cells in the equine model. Stem Cell Res Ther 2017; 8(1): 42.
[http://dx.doi.org/10.1186/s13287-017-0503-8] [PMID: 28241885]
[137]
Berglund AK, Schnabel LV. Allogeneic major histocompatibility complex-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-major histocompatibility complex antibodies. Equine Vet J 2017; 49(4): 539-44.
[http://dx.doi.org/10.1111/evj.12647] [PMID: 27862236]
[138]
Arzi B, Borjesson DL, Verstraete FJM. Mesenchymal stem cells for oral inflammation treatment. US20160199414 (2016).
[139]
Weiss M, Grumet MH. Encapsulated stem cells for the treatment of inflammatory disease. WO2016086020 (2016).
[140]
Lee JJ. Stem cell carrier and method for bone regeneration with 3D customized CAD/CAM using carrier. EP3034102 (2016).
[141]
Hung SC. Hypoxia-cultured mesenchymal stem cells for treating atherosclerotic lesions. US20160113968 (2016).
[142]
Han HQ, Lu ZY, Zhang BJ, et al. Externally used gel preparation containing human umbilical cord mesenchymal stem cell extract as well as preparation method and application of externally used gel preparation. CN106474155 (2016).
[143]
Günther C, Geiger-Schredelseker S, Hermann F, Huss R, Forster DL. Genetically modified mesenchymal stem cells expressing Alpha-1 Antitrypsin (AAT). EP3242933 (2016).
[144]
Günther C, Theoharis S, Hermann F, Huss R. Genetically modified mesenchymal stem cells expressing an immune responsestimulating cytokine to attract and/or activate immune cells.WO2016026854 (2016).
[145]
Kadouri A, Bar-Ilan A, Melamed E, Offen D, Sadan O, Bahat-Stromza M. Mesenchymal stem cells for the treatment of CNS diseases. US9474787 (2016).
[146]
Bartholomew A, Lee S, Szilagyi E. ctivated mesenchymal stem cells for wound healing and impaired tissue regeneration.US9011840 (2015).
[147]
Gupta PK, House AC, Das AK, et al. Management of osteoarthritis using pooled allogenic mesenchymal stem cells. WO2015022670 (2015).
[148]
Yingying R, Baihua J, Jinqiong H, Rong W, Yuntao D. Human derived mesenchymal stem cell factor, and preparation method and application thereof. CN105543313 (2015).
[149]
Caplan AI, Bonfield TL. Mesenchymal stem cell compositions for the treatment of microbial infections. US20140134140 (2013).