Immunomodulatory Properties of Mesenchymal Stromal Cells: Still Unresolved “Yin and Yang”

Author(s): Alessandro Poggi* , Maria R. Zocchi .

Journal Name: Current Stem Cell Research & Therapy

Volume 14 , Issue 4 , 2019

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Abstract:

Mesenchymal stromal cells (MSC) are mesodermal elements characterized by the ability to differentiate into several types of cells present mainly in connective tissues. They play a key function in tissue homeostasis and repair. Furthermore, they exert a strong effect on both innate and adaptive immune response. The main current of thought considers MSC as strong inhibitors of the immune system. Indeed, the first description of MSC immunomodulation pointed out their inability to induce alloimmune responses and their veto effects on mixed lymphocyte reactions. This inhibition appears to be mediated both by direct MSC interaction with immune cells and by soluble factors. Unfortunately, evidence to support this notion comes almost exclusively from in vitro experiments. In complex experimental systems, it has been shown that MSC can exert immunosuppressive effects also in vivo, either in murine models or in transplanted patients to avoid the graft versus host disease. However, it is still debated how the small number of administered MSC can regulate efficiently a large number of host effector lymphocytes. In addition, some reports in the literature indicate that MSC can trigger rather than inhibit lymphocyte activation when a very low number of MSC are co-cultured with lymphocytes. This would imply that the ratio between the number of MSC and immune cells is a key point to forecast whether MSC will inhibit or activate the immune system. Herein, we discuss the conflicting results reported on the immunomodulatory effects of MSC to define which features are relevant to understand their behavior and cross-talk with immune cells.

Keywords: MSC, immunosuppression, Treg, microenvironment, survival signals, alloresponse.

[1]
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(4): 315-7.
[2]
Horwitz EM, Le Blanc K, Dominici M, et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 2005; 7(5): 393-5.
[3]
Caplan AI. Mesenchymal stem cells. J Orthop Res 1999; 9(5): 641-50.
[4]
Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer 2016; 16(9): 582-98.
[5]
Poggi A, Musso A, Dapino I, Zocchi MR. Mechanisms of tumor escape from immune system: Role of mesenchymal stromal cells. Immunol Lett 2014; 159(1-2): 55-72.
[6]
Turley SJ, Cremasco V, Astarita JL. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol 2015; 15(11): 669-82.
[7]
Poggi A, Giuliani M. Mesenchymal stromal cells can regulate the immune response in the tumor microenvironment. Vaccines (Basel) 2016; 4(4): pii: E41.
[8]
Raffaghello L, Dazzi F. Classification and biology of tumour associated stromal cells. Immunol Lett 2015; 168(2): 175-82.
[9]
Haniffa MA, Collin MP, Buckley CD, Dazzi F. Mesenchymal stem cells: The fibroblasts’ new clothes? Haematologica 2009; 94(2): 258-63.
[10]
Lee ST, Jang JH, Cheong JW, et al. Treatment of high-risk acute myelogenous leukaemia by myeloablative chemoradiotherapy follone by co-infusion of T cell-depleted haematopoietic stem cells and culture-expanded marrow mesenchymal stem cells from a related donor with one fully mismatched human leucocyte antigen haplotype. Br J Haematol 2002; 118(4): 1128-31.
[11]
Kim N, Im KI, Lim JY, et al. Mesenchymal stem cells for the treatment and prevention of graft-versus-host disease: experiments and practice. Ann Hematol 2013; 92(10): 1295-308.
[12]
Horwitz EM, Gordon PL, Koo WK, 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 Sci USA Acad 2002; 99(13): 8932-7.
[13]
Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363(9419): 1439-41.
[14]
Jasperson LK, Bucher C, Panoskaltsis-Mortari A, Mellor AL, Munn DH, Blazar BR. Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of Graftversus-Host Disease (GVHD) lethality. Blood 2009; 114(24): 5062-70.
[15]
Silva LHA, Antunes MA, Dos Santos CC, Weiss DJ, Cruz FF, Rocco PRM. Strategies to improve the therapeutic effects of mesenchymal stromal cells in respiratory diseases. Stem Cell Res Ther 2018; 9(1): 45.
[16]
Arsenijevic A, Harrell CR, Fellabaum C, Volarevic V. Mesenchymal Stem Cells as New Therapeutic Agents for the Treatment of Primary Biliary Cholangitis. Anal Cell Pathol (Amst) 2017; 2017: 7492836.
[17]
Broglie L, Margolis D, Medin JA. Yin and Yang of mesenchymal stem cells and aplastic anemia. World J Stem Cells 2017; 9(12): 219-26.
[18]
Salem GA, Selby GB. Stem cell transplant in inflammatory bowel disease: a promising modality of treatment for a complicated disease course. Stem Cell Investig 2017; 4: 95.
[19]
Tsuchiya A, Kojima Y, Ikarashi S, et al. Clinical trials using mesenchymal stem cells in liver diseases and inflammatory bowel diseases. Inflamm Regen 2017; 37: 16.
[20]
Li X, Yue S, Luo Z. Mesenchymal stem cells in idiopathic pulmonary fibrosis. Oncotarget 2017; 8(60): 102600-16.
[21]
Oloyo AK, Ambele MA, Pepper MS. Contrasting views on the role of mesenchymal stromal/stem cells in tumour growth: A systematic review of experimental design. Adv Exp Med Biol 2018; 1083: 103-24.
[22]
Barron CC, Lalu MM, Stewart DJ, et al. Assessment of safety and efficacy of mesenchymal stromal cell therapy in preclinical models of acute myocardial infarction: a systematic review protocol. Canadian Perioperative Anesthesia Clinical Trials Group. Syst Rev 2017; 6(1): 226.
[23]
Forostyak S, Sykova E. Neuroprotective potential of cell-based therapies in ALS: From bench to bedside. Front Neurosci 2017; 11: 591.
[24]
Ibraheim H, Giacomini C, Kassam Z, Dazzi F, Powell N. Advances in mesenchymal stromal cell therapy in the management of Crohn’s disease. Expert Rev Gastroenterol Hepatol 2018; 12(2): 141-53.
[25]
Steinhoff G, Nesteruk J, Wolfien M, et al. Stem cells and heart disease - Brake or accelerator? Adv Drug Deliv Rev 2017; 120: 2-24.
[26]
Augustine S, Avey MT, Harrison B, et al. Mesenchymal stromal cell therapy in bronchopulmonary dysplasia: Systematic review and meta-analysis of preclinical studies. Stem Cells Transl Med 2017; 6(12): 2079-93.
[27]
Parekkadan B, Milwid JM. Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng 2010; 12: 87-117.
[28]
Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105(4): 1815-22.
[29]
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(10): 3838-43.
[30]
Zocchi MR, Catellani S, Canevali P, et al. High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D-ligands recognition in Hodgkin lymphomas. Blood 2012; 119(6): 1479-89.
[31]
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(3): 1327-33.
[32]
Le Blanc K. Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy 2003; 5(6): 485-9.
[33]
Bunpetch V, Wu H, Zhang S, Ouyang H. From “Bench to bedside”: Current advancement on large-scale production of mesenchymal stem cells. Stem Cells Dev 2017; 26(22): 1662-73.
[34]
Oliveira MS, Saldanha-Araujo F, Goes AM, Costa FF, de Carvalho JL. Stem cells in cardiovascular diseases: Turning bad days into good ones. Drug Discov Today 2017; 22(11): 1730-9.
[35]
Oryan A, Kamali A, Moshiri A, Baghaban Eslaminejad M. Role of mesenchymal stem cells in bone regenerative medicine: What is the evidence? Cells Tissues Organs 2017; 204(2): 59-83.
[36]
Scarfe L, Brillant N, Kumar JD, et al. Preclinical imaging methods for assessing the safety and efficacy of regenerative medicine therapies. NPJ Regen Med 2015; 34(12): 1608.
[37]
Galipeau J, Krampera M, Barrett J, et al. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy 2016; 18(2): 151-9.
[38]
Friedenstein AJ, Chailakhyan RK, Gerasimov UV. Bone marrow osteogenic stem cells: In vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet 1987; 20(3): 263-72.
[39]
Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R. The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration. Cytotherapy 2016; 18(1): 13-24.
[40]
Pachler K, Ketterl N, Desgeorges A, et al. An in vitro potency assay for monitoring the immunomodulatory potential of stromal cell-derived extracellular vesicles. Int J Mol Sci 2017; 18(7): pii: E1413.
[41]
Mougiakakos D, Jitschin R, Johansson CC, Okita R, Kiessling R, Le Blanc K. The impact of inflammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells. Blood 2011; 117(18): 4826-35.
[42]
Uyttenhove C, Pilotte L, Theate I, et al. Evidence for a tumoural immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 2003; 9(10): 1269-74.
[43]
Vig M, Srivastava S, Kandpal U, et al. Inducible oxid nitric synthase in T cells regulates T cell death and immune memory. J Clin Invest 2004; 113(12): 1734-42.
[44]
Ino Y, Yamazaki-Itoh R, Oguro S, et al. Arginase II espressed in cancer-associated fibroblasts indicates tissue hypoxia and predicts poor outcome in patients with pancreatic cancer. PLoS One 2013; 8: e55146.
[45]
Allard D, Allard B, Gaudreau PO, Chrobak P, Stagg J. CD73-adenosine: A next-generation target in immuno-oncology. Immunotherapy 2016; 8(2): 145-63.
[46]
Ohta A. A metabolic immune checkpoint: Adenosine in tumor microenvironment. Front Immunol 2016; 7: 109.
[47]
Harden JL, Egilmez NK. Indoleamine 2,3-dioxygenase and dendritic cell tolerogenicity. Immunol Invest 2012; 41(6-7): 738-64.
[48]
Nguyen NT, Nakahama T, Le DH, Van Son L, Chu HH, Kishimoto T. Aryl hydrocarbon receptor and kynurenine: Recent advances in autoimmune disease research. Front Immunol 2014; 5: 551.
[49]
Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 2006; 24: 99-146.
[50]
Thomas DA, Massagué J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 2005; 8(5): 369-80.
[51]
Lu L, Barbi J, Pan F. The regulation of immune tolerance by FOXP3. Nat Rev Immunol 2017; 17(11): 703-17.
[52]
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(7): 881-8.
[53]
Maccario R, Podestà M, Moretta A, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 2005; 90(4): 516-25.
[54]
Poggi A, Prevosto C, Massaro AM, et al. Interaction between human NK cells and bone marrow stromal cells induces NK cell triggering: role of NKp30 and NKG2D receptors. J Immunol 2005; 175(10): 6352-60.
[55]
Poggi A, Varesano S, Zocchi MR. How to hit mesenchymal stromal cells and make the tumor microenvironment immunostimulant rather than immunosuppressive. Front Immunol 2018; 9: 262.
[56]
Krampera M, Cosmi L, Angeli R, et al. Role for interferon gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 2005; 23(10): 1634-42.
[57]
Kaplani K, Koutsi S, Armenis V, et al. Wound healing related agents: Ongoing research and perspectives. Adv Drug Deliv Rev 2018; pii: S0169-409X(18)30035-8
[58]
Balsamo M, Scordamaglia F, Pietra G, et al. Melanoma associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc Natl Acad Sci USA 2009; 106(49): 20847-52.
[59]
Khan I, Zhang L, Mohammed M, et al. Effects of Wharton’s jelly derived mesenchymal stem cells on neonatal neutrophils. J Inflamm Res 2014; 8: 1-8.
[60]
Brandau S, Jakob M, Bruderek K, et al. Mesenchymal stem cells augment the anti-bacterial activity of neutrophil granulocytes. PLoS One 2014; 9(9): e106903.
[61]
Traggiai Volpi S. Schena F, et al Bone marrowderived 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(2): 562-9.
[62]
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(7): 1753-60.
[63]
Colombo BM, Canevali P, Magnani O, et al. Defective expression and function of the leukocyte associated Ig-like receptor 1 in B lymphocytes from systemic lupus erythematosus patients. PLoS One 2012; 7(2): e31903.
[64]
D, Wittig O, Ayala-Grosso C, Pieruzzini R, Cardier JE. Human olfactory mucosa multipotent mesenchymal stromal cells promote survival, proliferation, and differentiation of human hematopoietic cells. Stem Cells Dev 2012; 21(17): 3187-96.
[65]
Najar M, Rouas R, Raicevic G, et al. Mesenchymal stromal cells promote or suppress the proliferation of T lymphocytes from cord blood and peripheral blood: the importance of low cell ratio and role of interleukin-6. Cytotherapy 2009; 11(5): 570-83.
[66]
Ly JD, Grubb DR, Lawen A. The mitochondrial membrane potential (deltapsi(m)) in apoptosis: An update. Apoptosis 2003; 8(2): 115-28.
[67]
Musso A, Zocchi MR, Poggi A. Relevance of the mevalonate biosynthetic pathway in the regulation of bone marrow mesenchymal stromal cell-mediated effects on T-cell proliferation and B-cell survival. Haematologica 2011; 96(1): 16-23.
[68]
Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood 2006; 107(1): 367-72.
[69]
Lebbink RJ, de Ruiter T, Adelmeijer J, et al. Collagens arefunctional, high affinity ligands for the inhibitory immune receptor LAIR-1. J Exp Med 2006; 203(6): 1419-25.
[70]
Walraven M, Hinz B. Therapeutic approaches to control tissue repair and fibrosis: Extracellular matrix as a game changer. Matrix Biol 2018; pii: S0945-053X(17)30490-0
[71]
Fidler AL, Boudko SP, Rokas A, Hudson BG. The triple helix of collagens - an ancient protein structure that enabled animal multicellularity and tissue evolution. J Cell Sci 2018; 131(7): pii: jcs203950.
[72]
Klinker MW, Marklein RA, Lo Surdo JL, Wei CH, Bauer SR. Morphological features of IFN-γ-stimulated mesenchymal stromal cells predict overall immunosuppressive capacity. Proc Natl Acad Sci USA 2017; 114(13): E2598-607.
[73]
Hoogduijn MJ, Crop MJ, Korevaar SS, et al. Susceptibility of human mesenchymal stem cells to tacrolimus, mycophenolic acid, and rapamycin. Transplantation 2008; 86(9): 1283-91.
[74]
Buron F, Perrin H, Malcus C, et al. Human mesenchymal stem cells and immunosuppressive drug interactions in allogeneic responses: An in vitro study using human cells. Transplant Proc 2009; 41(8): 3347-52.
[75]
Girdlestone J, Pido-Lopez J, Srivastava S, et al. Enhancement of the immunoregulatory potency of mesenchymal stromal cells by treatment with immunosuppressive drugs. Cytotherapy 2015; 17(9): 1188-99.
[76]
Erkers T, Solders M, Verleng L, et al. Frontline Science: Placenta-derived decidual stromal cells alter IL-2R expression and signaling in alloantigen-activated T cells. J Leukoc Biol 2017; 101(3): 623-32.
[77]
Ballester S, Ballester A. Editorial: IL-2/IL-2R axis modulation by mesenchymal stromal cells: Interaction with immunosuppressive drugs? J Leukoc Biol 2017; 101(3): 617-9.
[78]
Ardeshiry Lajimi A, Hagh MF, et al. Feasibility of cell therapy in multiple sclerosis: A systematic review of 83 studies. Int J Hematol Oncol Stem Cell Res 2013; 7(1): 15-33.
[79]
Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol 2012; 11(2): 150-6.
[80]
Dulamea A. Mesenchymal stem cells in multiple sclerosis-translation to clinical trials. J Med Life 2015; 8(1): 24-7.
[81]
Hou ZL, Liu Y, Mao XH, et al. Transplantation of umbilical cord and bone marrow-derived mesenchymal stem cells in a patient with relapsing remitting multiple sclerosis. Cell Adhes Migr 2013; 7(5): 404-7.
[82]
Dahbour S, Jamali F, Alhattab D, et al. Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: clinical, ophthalmological and radiological assessments of safety and efficacy. CNS Neurosci Ther 2017; 23(11): 866-74.
[83]
Poloni A, Maurizi G, Leoni P, et al. Human dedifferentiated adipocytes show similar properties to bone marrow-derived mesenchymal stem cells. Stem Cells 2012; 30(5): 965-74.
[84]
Poloni A, Maurizi G, Ciarlantini M, et al. Interaction between human mature adipocytes and lymphocytes induces T-cell proliferation. Cytotherapy 2015; 17(9): 1292-301.
[85]
Maurizi G, Della Guardia L, Maurizi A, Poloni A. Adipocytes properties and crosstalk with immune system in obesity-related inflammation. J Cell Physiol 2018; 233(1): 88-97.
[86]
Munir H, Ward LSC, Sheriff L, et al. Adipogenic differentiation of mesenchymal stem cells alters their immunomodulatory properties in a tissue-specific manner. Stem Cells 2017; 35(6): 1636-46.
[87]
Adkisson HD, Milliman C, Zhang X, Mauch K, Maziarz RT, Streeter PR. Immune evasion by neocartilage-derived chondrocytes: implications for biologic repair of joint articular cartilage. Stem Cell Res 2010; 4(1): 57-68.
[88]
Lohan P, Treacy O, Lynch K, et al. Culture expanded primary condrocytes have potent immunomodulatory properties and do not induce an allogeneic immune response. Osteoarthritis Cartilage 2016; 24(3): 521-33.
[89]
Pereira RC, Martinelli D, Cancedda R, Gentili C, Poggi A. Human articular chondrocytes regulate immune response by affecting directly T cell proliferation and indirectly inhibiting monocyte differentiation to professional antigen-presenting cellsFront Immunol 2016; 7: 415 eCollection 2016
[90]
Lim CL, Lee YJ, Cho JH, et al. Immunogenicity and immunomodulatory effects of the human chondrocytes, hChonJ. BMC Musculoskelet Disord 2017; 18(1): 199.
[91]
Trabanelli S, La Manna F, Romano M, et al. The human mesenchymal stromal cell-derived osteocyte capacity to modulate dendritic cell functions is strictly dependent on the culture system. J Immunol Res 2015; 2015: 526195.
[92]
Pacifici R. T cells, osteoblasts, and osteocytes: Interacting lineages key for the bone anabolic and catabolic activities of parathyroid hormone. Ann N Y Acad Sci 2016; 1364: 11-24.
[93]
Galleu A, Riffo-Vasquez Y, Trento C, et al. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci Transl Med 2017; 9(416): pii eaam7828.
[94]
Keshtkar S, Azarpira N, Ghahremani MH. Mesenchymal stem cellderived extracellular vesicles: novel frontiers in regenerative medicine. Stem Cell Res Ther 2018; 9(1): 63.
[95]
Aghajani Nargesi A, Lerman LO, Eirin A. Mesenchymal stem cellderived extracellular vesicles for kidney repair: current status and looming challenges. Stem Cell Res Ther 2017; 8(1): 273.
[96]
Giebel B, Kordelas L, Börger V. Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles. Stem Cell Investig 2017; 4: 84.
[97]
Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: Toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci 2017; 18(9): pii E1852.
[98]
Gimona M, Pachler K, Laner-Plamberger S, Schallmoser K, Rohde E. Manufacturing of human extracellular vesicle-based therapeutics for clinical use. Int J Mol Sci 2017; 18(6): pii E1190.


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VOLUME: 14
ISSUE: 4
Year: 2019
Page: [344 - 350]
Pages: 7
DOI: 10.2174/1574888X14666181205115452
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