Immunomodulation mechanisms of MSCs. MSCs modulate the immune responses of the target immune cells, using cell-cell interactions and the secretion of soluble molecules
Note. Adapted with permission from “Mesenchymal stromal cells as potential immunomodulatory players in severe acute respiratory distress syndrome induced by SARS-CoV-2 infection” by Mallis P, Michalopoulos E, Chatzistamatiou T, Stavropoulos-Giokas C. World J Stem Cells. 2020;12:731–51 (https://doi.org/10.4252/wjsc.v12.i8.731). CC BY.
Declarations
Author contributions
PM wrote the initial draft of the manuscript. EM and TC revised the manuscript. CSG made the final approval for the manuscript.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Ullah I, Subbarao RB, Rho GJ.Human mesenchymal stem cells-current trends and future prospective. Biosci Rep.2015;35:e00191. [DOI] [PubMed] [PMC]
Wei X, Yang X, Han ZP, Qu FF, Shao L, Shi YF.Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin.2013;34:747–54. [DOI] [PubMed] [PMC]
Berebichez-Fridman R, Montero-Olvera PR.Sources and clinical applications of mesenchymal stem cells: state-of-the-art review. Sultan Qaboos Univ Med J.2018;18:e264–77. [DOI] [PubMed] [PMC]
Hass R, Kasper C, Böhm S, Jacobs R.Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal.2011;9:12. [DOI] [PubMed] [PMC]
Via AG, Frizziero A, Oliva F.Biological properties of mesenchymal stem cells from different sources. Muscles Ligaments Tendons J.2012;2:154–62. [PubMed] [PMC]
Chen JY, Mou XZ, Du XC, Xiang C.Comparative analysis of biological characteristics of adult mesenchymal stem cells with different tissue origins. Asian Pac J Trop Med.2015;8:739–46. [DOI] [PubMed]
Stewart MC, Stewart AA.Mesenchymal stem cells: characteristics, sources, and mechanisms of action. Vet Clin North Am Equine Pract.2011;27:243–61. [DOI] [PubMed]
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;8:315–7. [DOI] [PubMed]
Viswanathan S, Shi Y, Galipeau J, Krampera M, Leblanc K, Martin I, et al. Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT®) Mesenchymal Stromal Cell committee position statement on nomenclature. Cytotherapy.2019;21:1019–24. [DOI] [PubMed]
Sipp D, Robey PG, Turner L.Clear up this stem-cell mess. Nature.2018;561:455–457. [DOI] [PubMed]
Caplan AI.Mesenchymal stem cells: time to change the name!Stem Cells Transl Med. 2017;6:1445–51. [DOI] [PubMed] [PMC]
Wexler SA, Donaldson C, Denning-Kendall P, Rice C, Bradley B, Hows JM.Adult bone marrow is a rich source of human mesenchymal ‘stem’ cells but umbilical cord and mobilized adult blood are not. Br J Haematol.2003;12:368–74. [DOI]
Elahi KC, Klein G, Avci-Adali M, Sievert KD, MacNeil S, Aicher WK.Human mesenchymal stromal cells from different sources diverge in their expression of cell surface proteins and display distinct differentiation patterns. Stem Cells Int.2016;2016:5646384. [DOI] [PubMed] [PMC]
Weiss ARR, Dahlke MH.Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Front Immunol.2019;10:1191. [DOI] [PubMed] [PMC]
Ryan JM, Barry FP, Murphy JM, Mahon BP.Mesenchymal stem cells avoid allogeneic rejection. J Inflamm (Lond).2005;2:8. [DOI] [PubMed] [PMC]
Zhao QJ, Ren HY, Han ZC.Mesenchymal stem cells: immunomodulatory capability and clinical potential in immune diseases. J Cell Immunother.2016;2:3–20. [DOI]
Harrell CR, Jovicic N, Djonov V, Arsenijevic N, Volarevic V.Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells.2019;8:1605. [DOI]
Seo Y, Kang MJ, Kim HS.Strategies to potentiate paracrine therapeutic efficacy of mesenchymal stem cells in inflammatory diseases. Int J Mol Sci.2021;22:3397. [DOI] [PubMed] [PMC]
De Miguel MP, Fuentes-Julián S, Blázquez-Martïnez A, Pascual CY, Aller MA, Arias J, et al. Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med.2012;12:574–91. [DOI] [PubMed]
Rees AJ.Monocyte and macrophage biology: an overview. Semin Nephrol.2010;30:216–33. [DOI] [PubMed]
Auffray C, Sieweke MH, Geissmann F.Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol.2009;27:669–92. [DOI] [PubMed]
Chen L, Tredget EE, Wu PY, Wu Y.Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One.2008;3:e1886. [DOI] [PubMed] [PMC]
Chen PM, Liu KJ, Hsu PJ, Wei CF, Bai CH, Ho LJ, et al. Induction of immunomodulatory monocytes by human mesenchymal stem cell-derived hepatocyte growth factor through ERK1/2. J Leukoc Biol.2014;96:295–303. [DOI] [PubMed]
Min H, Xu L, Parrott R, Overall CC, Lillich M, Rabjohns EM, et al. Mesenchymal stromal cells reprogram monocytes and macrophages with processing bodies. Stem Cells.2021;39:115–28. [DOI] [PubMed]
Gao S, Mao F, Zhang B, Zhang L, Zhang X, Wang M, et al. Mouse bone marrow-derived mesenchymal stem cells induce macrophage M2 polarization through the nuclear factor-κB and signal transducer and activator of transcription 3 pathways. Exp Biol Med (Maywood).2014;239:366–75. [DOI] [PubMed]
Zhang QZ, Su WR, Shi SH, Wilder-Smith P, Xiang AP, Wong A, et al. Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing. Stem Cells.2010;28:1856–68. [DOI] [PubMed] [PMC]
Mallis P, Boulari D, Michalopoulos E, Dinou A, Spyropoulou-Vlachou M, Stavropoulos-Giokas C.Evaluation of HLA-G expression in multipotent mesenchymal stromal cells derived from vitrified Wharton’s Jelly tissue. Bioengineering (Basel).2018;5:95. [DOI]
Bernardo ME, Fibbe WE.Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell.2013;13:392–402. [DOI] [PubMed]
Yagi H, Soto-Gutierrez A, Parekkadan B, Kitagawa Y, Tompkins RG, Kobayashi N, et al. Mesenchymal stem cells: Mechanisms of immunomodulation and homing. Cell Transplant.2010;19:667–79. [DOI] [PubMed] [PMC]
Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med.2009;15:42–9. [DOI] [PubMed] [PMC]
Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol.2018;233:6425–40. [DOI]
Bernardo ME, Fibbe WE.Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell.2013;13:392–402. [DOI] [PubMed]
Gur-Wahnon D, Borovsky Z, Beyth S, Liebergall M, Rachmilewitz J.Contact-dependent induction of regulatory antigen-presenting cells by human mesenchymal stem cells is mediated via STAT3 signaling. Exp Hematol.2007;35:426–33. [DOI] [PubMed]
Patente TA, Pinho MP, Oliveira AA, Evangelista GCM, Bergami-Santos PC, Barbuto JAM.Human dendritic cells: their heterogeneity and clinical application potential in cancer immunotherapy. Front Immunol.2019;9:3176. [DOI] [PubMed] [PMC]
Mellman I, Steinman RM.Dendritic cells: specialized and regulated antigen processing machines. Cell.2001;106:255–8. [DOI] [PubMed]
Lu Z, Chang W, Meng S, Xu X, Xie J, Guo F, et al. Mesenchymal stem cells induce dendritic cell immune tolerance via paracrine hepatocyte growth factor to alleviate acute lung injury. Stem Cell Res Ther.2019;10:372. [DOI] [PubMed] [PMC]
Djouad F, Charbonnier LM, Bouffi C, Louis-Plence P, Bony C, Apparailly F, et al. Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells.2007;25:2025–32. [DOI] [PubMed]
English K, Barry FP, Mahon BP.Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation. Immunol Lett.2008;115:50–8. [DOI] [PubMed]
Spaggiari GM, Abdelrazik H, Becchetti F, Moretta L.MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood.2009;113:6576–83. [DOI] [PubMed]
Liu Y, Yin Z, Zhang R, Yan K, Chen L, Chen F, et al. MSCs inhibit bone marrow-derived DC maturation and function through the release of TSG-6. Biochem Biophys Res Commun.2014;450:1409–15. [DOI] [PubMed]
Scalavino V, Liso M, Serino G.Role of microRNAs in the regulation of dendritic cell generation and function. Int J Mol Sci.2020;21:1319. [DOI]
Chen W, Huang Y, Han J, Yu L, Li Y, Lu Z, et al. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol Res.2016;64:831–40. [DOI] [PubMed]
Martin-Rufino JD, Espinosa-Lara N, Osugui L, Sanchez-Guijo F.Targeting the immune system with mesenchymal stromal cell-derived extracellular vesicles: what is the cargo’s mechanism of action?Front Bioeng Biotechnol. 2019;7:308. [DOI] [PubMed] [PMC]
Reis M, Mavin E, Nicholson L, Green K, Dickinson AM, Wang XN.Mesenchymal stromal cell-derived extracellular vesicles attenuate dendritic cell maturation and function. Front Immunol.2018;9:2538. [DOI] [PubMed] [PMC]
Favaro E, Carpanetto A, Caorsi C, Giovarelli M, Angelini C, Cavallo-Perin P, et al. Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients. Diabetologia.2016;59:325–33. [DOI] [PubMed]
Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S.Functions of natural killer cells. Nat Immunol.2008;9:503–10. [DOI] [PubMed]
Finton KA, Strong RK.Structural insights into activation of antiviral NK cell responses. Immunol Rev.2012;250:239–57. [DOI] [PubMed] [PMC]
Casado JG, Tarazona R, Sanchez-Margallo FM.NK and MSCs crosstalk: the sense of immunomodulation and their sensitivity. Stem Cell Rev Rep.2013;9:184–9. [DOI] [PubMed]
Najar M, Fayyad-Kazan M, Meuleman N, Bron D, Fayyad-Kazan H, Lagneaux L.Mesenchymal stromal cells of the bone marrow and natural killer cells: cell interactions and cross modulation. J Cell Commun Signal.2018;12:673–88. [DOI] [PubMed] [PMC]
Sangiorgi B, Panepucci RA.Modulation of immunoregulatory properties of mesenchymal stromal cells by Toll-like receptors: potential applications on GVHD. Stem Cells Int.2016;2016:9434250. [DOI] [PubMed] [PMC]
Holt D, Ma X, Kundu N, Fulton A.Prostaglandin E2 (PGE2) suppresses natural killer cell function primarily through the PGE2 receptor EP4. Cancer Immunol Immunother.2011;60:1577–86. [DOI] [PubMed] [PMC]
Najar M, Fayyad-Kazan M, Meuleman N, Bron D, Fayyad-Kazan H, Lagneaux L.Immunological impact of Wharton’s Jelly mesenchymal stromal cells and natural killer cell co-culture. Mol Cell Biochem.2018;447:111–24. [DOI] [PubMed]
Hughes PD, Cohney SJ.Modifiers of complement activation for prevention of antibody-mediated injury to allografts. Curr Opin Organ Transplant.2011;16:425–33. [DOI] [PubMed]
Li Y, Lin F.Mesenchymal stem cells are injured by complement after their contact with serum. Blood.2012;120:3436–43. [DOI] [PubMed] [PMC]
Janssen BJ, Huizinga EG, Raaijmakers HC, Roos A, Daha MR, Nilsson-Ekdahl K, et al. Structures of complement component C3 provide insights into the function and evolution of immunity. Nature.2005;437:505–11. [DOI] [PubMed]
Le Blanc K, Mougiakakos D.Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol.2012;12:383–96. [DOI] [PubMed]
Moll G, Jitschin R, von Bahr L, Rasmusson-Duprez I, Sundberg B, Lönnies L, et al. Mesenchymal stromal cells engage complement and complement receptor bearing innate effector cells to modulate immune responses. PLoS One.2011;6:e21703. [DOI] [PubMed] [PMC]
Tu Z, Li Q, Bu H, Lin F.Mesenchymal stem cells inhibit complement activation by secreting factor H. Stem Cells Dev.2010;19:1803–9. [DOI] [PubMed] [PMC]
Haddad R, Saldanha-Araujo F.Mechanisms of T-cell immunosuppression by mesenchymal stromal cells: what do we know so far?Biomed Res Int. 2014;2014:216806. [DOI] [PubMed] [PMC]
Davies LC, Heldring N, Kadri N, Le Blanc K.Mesenchymal stromal cell secretion of programmed death-1 ligands regulates T cell mediated immunosuppression. Stem Cells.2017;35:766–76. [DOI] [PubMed] [PMC]
Sreeramkumar V, Fresno M, Cuesta N.Prostaglandin E2 and T cells: friends or foes?Immunol Cell Biol. 2012;90:579–86. [DOI] [PubMed] [PMC]
Ricciotti E, FitzGerald GA.Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol.2011;31: 986–1000. [DOI] [PubMed] [PMC]
Ryan JM, Barry F, Murphy JM, Mahon BP.Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol.2007;149: 353–63. [DOI] [PubMed] [PMC]
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;2:141–50. [DOI] [PubMed]
Wang L, Zhao Y, Shi S.Interplay between mesenchymal stem cells and lymphocytes: implications for immunotherapy and tissue regeneration. J Dent Res.2012;91:1003–10. [DOI] [PubMed] [PMC]
Franquesa M, Hoogduijn MJ, Bestard O, Grinyó JM.Immunomodulatory effect of mesenchymal stem cells on B cells. Front Immunol.2012;3:212. [DOI] [PubMed] [PMC]
Fan L, Hu C, Chen J, Cen P, Wang J, Li L.Interaction between mesenchymal stem cells and B-cells. Int J Mol Sci.2016;17:650. [DOI]
Asari S, Itakura S, Ferreri K, Liu CP, Kuroda Y, Kandeel F, et al. Mesenchymal stem cells suppress B-cell terminal differentiation. Exp Hematol.2009;37:604–15. [DOI] [PubMed] [PMC]
Naji A, Rouas-Freiss N, Durrbach A, Carosella ED, Sensébé L, Deschaseaux F.Concise review: combining human leukocyte antigen G and mesenchymal stem cells for immunosuppressant biotherapy. Stem Cells.2013;31:2296–303. [DOI] [PubMed]
Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis.2016;7:e2062. [DOI] [PubMed] [PMC]
Gieseke F, Böhringer J, Bussolari R, Dominici M, Handgretinger R, Müller I.Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells. Blood.2010;116:3770–9. [DOI] [PubMed]
Machado Cde V, Telles PD, Nascimento IL.Immunological characteristics of mesenchymal stem cells. Rev Bras Hematol Hemoter.2013;35:62–7. [DOI] [PubMed] [PMC]
Wang LT, Ting CH, Yen ML, Liu KJ, Sytwu HK, Wu KK, et al. Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials. J Biomed Sci.2016;23:76. [DOI] [PubMed] [PMC]
Battiwalla M, Hematti P.Mesenchymal stem cells in hematopoietic stem cell transplantation. Cytotherapy.2009;11:503–15. [DOI] [PubMed] [PMC]
Koç ON, Peters C, Aubourg P, Raghavan S, Dyhouse S, DeGasperi R, et al. Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases. Exp Hematol.1999;27:1675–81. [DOI] [PubMed]
Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK, et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant.2005;11:389–98. [DOI] [PubMed]
Koç 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;18:307–16. [DOI] [PubMed]
Kallekleiv M, Larun L, Bruserud Ø, Hatfield KJ.Co-transplantation of multipotent mesenchymal stromal cells in allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis. Cytotherapy.2016;18:172–85. [DOI] [PubMed]
Ball LM, Bernardo ME, Roelofs H, Lankester A, Cometa A, Egeler RM, et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood.2007;110:2764–7. [DOI] [PubMed]
Macmillan ML, Blazar BR, DeFor TE, Wagner JE.Transplantation of ex-vivo culture-expanded parental haploidentical mesenchymal stem cells to promote engraftment in pediatric recipients of unrelated donor umbilical cord blood: results of a phase I-II clinical trial. Bone Marrow Transplant.2009;43: 447–54. [DOI] [PubMed]
Le Blanc K, Samuelsson H, Gustafsson B, Remberger M, Sundberg B, Arvidson J, et al. Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia.2007;21: 1733–8. [DOI] [PubMed]
Karp JM, Leng Teo GS.Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell.2009;4:206–16. [DOI] [PubMed]
Mäkelä T, Takalo R, Arvola O, Haapanen H, Yannopoulos F, Blanco R, et al. Safety and biodistribution study of bone marrow-derived mesenchymal stromal cells and mononuclear cells and the impact of the administration route in an intact porcine model. Cytotherapy.2015;17:392–402. [DOI] [PubMed]
von Bahr L, Batsis I, Moll G, Hägg M, Szakos A, Sundberg B, 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. [DOI] [PubMed]
Iacobaeus E, Kadri N, Lefsihane K, Boberg E, Gavin C, Törnqvist Andrén A, et al. Short and long term clinical and immunologic follow up after bone marrow mesenchymal stromal cell therapy in progressive multiple sclerosis-A phase I study. J Clin Med.2019;8:2102. [DOI]
Cheung TS, Bertolino GM, Giacomini C, Bornhäuser M, Dazzi F, Galleu A.Mesenchymal stromal cells for graft versus host disease: mechanism-based biomarkers. Front Immunol.2020;11:1338. [DOI] [PubMed] [PMC]
Funke VA, Moreira MC, Vigorito AC.Acute and chronic Graft-versus-host disease after hematopoietic stem cell transplantation. Rev Assoc Med Bras.2016;62Suppl 1:44–50. [DOI] [PubMed]
Blazar BR, Murphy WJ, Abedi M.Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol.2012;12:443–58. [DOI] [PubMed] [PMC]
Zeiser R, Blazar BR.Acute graft-versus-host disease-biologic process, prevention, and therapy. N Engl J Med.2017;377:2167–79. [DOI] [PubMed] [PMC]
Choi SW, Levine JE, Ferrara JL.Pathogenesis and management of graft-versus-host disease. Immunol Allergy Clin North Am.2010;30:75–101. [DOI] [PubMed] [PMC]
Hill L, Alousi A, Kebriaei P, Mehta R, Rezvani K, Shpall E.New and emerging therapies for acute and chronic graft versus host disease. Ther Adv Hematol.2018; 9:21–46. [DOI] [PubMed] [PMC]
Bader P, Kuçi Z, Bakhtiar S, Basu O, Bug G, Dennis M, et al. Effective treatment of steroid and therapy-refractory acute graft-versus host disease with a novel mesenchymal stromal cell product (MSC-FFM). Bone Marrow Transplant.2018;53:852–62. [DOI] [PubMed] [PMC]
Simonetta F, Alvarez M, Negrin RS.Natural killer cells in graft-versus-host-disease after allogeneic hematopoietic cell transplantation. Front Immunol.2017;8:465. [DOI] [PubMed] [PMC]
Pasquini MC.Impact of graft-versus-host disease on survival. Best Pract Res Clin Haematol.2008;21: 193–204. [DOI] [PubMed]
Kuba A, Raida L.Graft versus host disease: from basic pathogenic principles to DNA damage response and cellular senescence. Mediators Inflamm.2018;2018:9451950. [DOI] [PubMed] [PMC]
Elgaz S, Kuçi Z, Kuçi S, Bönig H, Bader P.Clinical use of mesenchymal stromal cells in the treatment of acute graft-versus-host disease. Transfus Med Hemother.2019;46:27–34. [DOI] [PubMed] [PMC]
Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet.2004;363:1439–41. [DOI] [PubMed]
Ringden O, Baygan A, Remberger M, Gustafsson B, Winiarski J, Khoein B, et al. Placenta-derived decidua stromal cells for treatment of severe acute graft-versus-host disease. Stem Cells Transl Med.2018;7:325–31. [DOI] [PubMed] [PMC]
Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant severe, acute graft-versus-host disease: a phase II study. Lancet.2008;371:1579–86. [DOI] [PubMed]
Dotoli GM, De Santis GC, Orellana MD, de Lima Prata K, Caruso SR, Fernandes TR, et al. Mesenchymal stromal cell infusion to treat steroid-refractory acute GvHD III/IV after hematopoietic stem cell transplantation. Bone Marrow Transplant.2017;52:859–62. [DOI] [PubMed]
von Dalowski F, Kramer M, Wermke M, Wehner R, Röllig C, Alakel N, et al. Mesenchymal stromal cells for treatment of acute steroid-refractory graft versus host disease: clinical responses and long-term outcome. Stem Cells.2016;34:357–66. [DOI] [PubMed]
Liu Z, Zhang Y, Xiao H, Yao Z, Zhang H, Liu Q, et al. Cotransplantation of bone marrow-derived mesenchymal stem cells in haploidentical hematopoietic stem cell transplantation in patients with severe aplastic anemia: an interim summary for a multicenter phase II trial results. Bone Marrow Transplant.2017;52:704–10. [DOI] [PubMed]
Angum F, Khan T, Kaler J, Siddiqui L, Hussain A.The prevalence of autoimmune disorders in women: a narrative review. Cureus.2020;12:e8094. [DOI] [PubMed] [PMC]
Figueroa FE, Carrión F, Villanueva S, Khoury M.Mesenchymal stem cell treatment for autoimmune diseases: a critical review. Biol Res.2012;45:269–77. [DOI] [PubMed]
Rad F, Ghorbani M, Mohammadi Roushandeh A, Habibi Roudkenar M.Mesenchymal stem cell-based therapy for autoimmune diseases: emerging roles of extracellular vesicles. Mol Biol Rep.2019;46: 1533–49. [DOI] [PubMed]
Tyndall A, Houssiau FA.Mesenchymal stem cells in the treatment of autoimmune diseases. Ann Rheum Dis.2010;69:1413–4. [DOI] [PubMed]
Pistoia V, Raffaghello L.Mesenchymal stromal cells and autoimmunity. Int Immunol.2017;29:49–58. [DOI] [PubMed]
Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W.The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology (Oxford).2017;56:1945–61. [DOI] [PubMed]
Perl A.Systems biology of lupus: mapping the impact of genomic and environmental factors on gene expression signatures, cellular signaling, metabolic pathways, hormonal and cytokine imbalance, and selecting targets for treatment. Autoimmunity.2010;43:32–47. [DOI] [PubMed] [PMC]
Feng X, Li R, Huang J, Zhang H, Zhu L, Hua B, et al. Olf1/EBF associated zinc finger protein interfered with antinuclear antibody production in patients with systemic lupus erythematosus. Arthritis Res Ther.2010;12:R59. [DOI] [PubMed] [PMC]
Feng X, Che N, Liu Y, Chen H, Wang D, Li X, et al. Restored immunosuppressive effect of mesenchymal stem cells on B cells after olfactory 1/early B cell factor-associated zinc-finger protein down-regulation in patients with systemic lupus erythematosus. Arthritis Rheumatol.2014;66:3413–23. [DOI] [PubMed]
Alessandri C, Barbati C, Vacirca D, Piscopo P, Confaloni A, Sanchez M, et al. T lymphocytes from patients with systemic lupus erythematosus are resistant to induction of autophagy. FASEB J.2012;26:4722–32. [DOI] [PubMed] [PMC]
Wang F, Tasset I, Cuervo AM, Muller S.In vivo remodeling of altered autophagy-lysosomal pathway by a phosphopeptide in lupus. Cells.2020;9:2328. [DOI]
Chen J, Wang Q, Feng X, Zhang Z, Geng L, Xu T, et al. Umbilical cord-derived mesenchymal stem cells suppress autophagy of T cells in patients with systemic lupus erythematosus via transfer of mitochondria. Stem Cells Int.2016;2016:4062789. [DOI] [PubMed] [PMC]
Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, et al. Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis.2010;69:1423–9. [DOI] [PubMed]
Boyapati R, Satsangi J, Ho GT.Pathogenesis of Crohn’s disease. F1000Prime Rep.2015;7:44. [DOI] [PubMed] [PMC]
Marks DJ, Rahman FZ, Sewell GW, Segal AW.Crohn’s disease: an immune deficiency state. Clin Rev Allergy Immunol.2010;38:20–31. [DOI] [PubMed] [PMC]
Ruffolo C, Scarpa M, Bassi N.Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med.2010;363:1086–7. [DOI] [PubMed]
Dalal J, Gandy K, Domen J.Role of mesenchymal stem cell therapy in Crohn’s disease. Pediatr Res.2012;71:445–51. [DOI] [PubMed]
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, Abstract 2006, 121.
Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut.2011;60:788–98. [DOI] [PubMed]
Garcïa-Olmo D, Garcïa-Arranz M, Herreros D, Pascual I, Peiro C, Rodrïguez-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. [DOI] [PubMed]
Loma I, Heyman R.Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol.2011;9: 409–16. [DOI] [PubMed] [PMC]
Ghasemi N, Razavi S, Nikzad E.Multiple sclerosis: pathogenesis, symptoms, diagnoses and cell-based therapy. Cell J.2017;19:1–10. [DOI] [PubMed] [PMC]
Pandit L, Murthy JM.Treatment of multiple sclerosis. Ann Indian Acad Neurol.2011;14Suppl 1:S65–9. [DOI] [PubMed] [PMC]
Kassis I, Vaknin-Dembinsky A, Karussis D.Bone marrow mesenchymal stem cells: agents of immunomodulation and neuroprotection. Curr Stem Cell Res Ther.2011;6:63–8. [DOI] [PubMed]
Karussis D.Worldwide status of clinical experimentation with stem cells in neurologic diseases. Neurology.2012;78:1334–6. [DOI] [PubMed]
Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol.2010;67:1187–94. [DOI] [PubMed] [PMC]
Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, 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;11:150–6. [DOI] [PubMed] [PMC]
Gugliandolo A, Bramanti P, Mazzon E.Mesenchymal stem cells: a potential therapeutic approach for amyotrophic lateral sclerosis?Stem Cells Int. 2019;2019:3675627. [DOI] [PubMed] [PMC]
Nabavi SM, Arab L, Jarooghi N, Bolurieh T, Abbasi F, Mardpour S, et al. Safety, feasibility of intravenous and intrathecal injection of autologous bone marrow derived mesenchymal stromal cells in patients with amyotrophic lateral sclerosis: an open label phase I clinical trial. Cell J.2019;20:592–8. [DOI] [PubMed] [PMC]
Oh KW, Moon C, Kim HY, Oh SI, Park J, Lee JH, et al. Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. Stem Cells Transl Med.2015;4:590–7. [DOI] [PubMed] [PMC]
Petrou P, Gothelf Y, Argov Z, Gotkine M, Levy YS, Kassis I, et al. Safety and clinical effects of mesenchymal stem cells secreting neurotrophic factor transplantation in patients with amyotrophic lateral sclerosis: results of phase 1/2 and 2a clinical trials. JAMA Neurol.2016;73:337–44. [DOI] [PubMed]
Mallam E, Kemp K, Wilkins A, Rice C, Scolding N.Characterization of in vitro expanded bone marrow-derived mesenchymal stem cells from patients with multiple sclerosis. Mult Scler.2010;16:909–18. [DOI] [PubMed]
Gugliandolo A, Bramanti P, Mazzon E.Mesenchymal stem cells in multiple sclerosis: recent evidence from pre-clinical to clinical studies. Int J Mol Sci.2020;21:8662. [DOI]
Lu H, Stratton CW, Tang YW.Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle. J Med Virol.2020;92:401–2. [DOI] [PubMed] [PMC]
Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. Int J Antimicrob Agents.2020;55:105924. [DOI] [PubMed] [PMC]
Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol.2020;5:536–44. [DOI] [PubMed] [PMC]
Awadasseid A, Wu Y, Tanaka Y, Zhang W.SARS-CoV-2 variants evolved during the early stage of the pandemic and effects of mutations on adaptation in Wuhan populations. Int J Biol Sci.2021;17:97–106. [DOI] [PubMed] [PMC]
Mallis P, Michalopoulos E, Chatzistamatiou T, Stavropoulos-Giokas C.Mesenchymal stromal cells as potential immunomodulatory players in severe acute respiratory distress syndrome induced by SARS-CoV-2 infection. World J Stem Cells.2020;12:731–51. [DOI] [PubMed] [PMC]
Afarid M, Sanie-Jahromi F.Mesenchymal stem cells and COVID-19: cure, prevention, and vaccination. Stem Cells Int.2021;2021:6666370. [DOI] [PubMed] [PMC]
Harrell CR, Jovicic BP, Djonov V, Volarevic V.Therapeutic potential of mesenchymal stem cells and their secretome in the treatment of SARS-CoV-2-induced acute respiratory distress syndrome. Anal Cell Pathol (Amst).2020;2020:1939768. [DOI] [PubMed] [PMC]
Qin H, Zhao A.Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics. Protein Cell.2020;11:707–22. [DOI] [PubMed] [PMC]
Gorman E, Millar J, McAuley D, O’Kane C.Mesenchymal stromal cells for acute respiratory distress syndrome (ARDS), sepsis, and COVID-19 infection: optimizing the therapeutic potential. Expert Rev Respir Med.2021;15:301–24. [DOI] [PubMed]
Hamdan H, Hashmi SK, Lazarus H, Gale RP, Qu W, El Fakih R.Promising role for mesenchymal stromal cells in coronavirus infectious disease-19 (COVID-19)-related severe acute respiratory syndrome?Blood Rev. 2021;46:100742. [DOI] [PubMed] [PMC]
Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, et al. Transplantation of ACE2– mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis.2020;11:216–28. [DOI] [PubMed] [PMC]
Chatzistamatiou TK, Papassavas AC, Michalopoulos E, Gamaloutsos C, Mallis P, Gontika I, et al. Optimizing isolation culture and freezing methods to preserve Wharton’s jelly’s mesenchymal stem cell (MSC) properties: an MSC banking protocol validation for the Hellenic Cord Blood Bank. Transfusion.2014;54:3108–20. [DOI] [PubMed]
Redondo J, Sarkar P, Kemp K, Heesom KJ, Wilkins A, Scolding NJ, et al. Dysregulation of mesenchymal stromal cell antioxidant responses in progressive multiple sclerosis. Stem Cells Transl Med.2018;7: 748–58. [DOI] [PubMed] [PMC]
Sagar R, Walther-Jallow L, David AL, Götherström C, Westgren M.Fetal mesenchymal stromal cells: an opportunity for prenatal cellular therapy. Curr Stem Cell Rep.2018;4:61–8. [DOI] [PubMed] [PMC]
Ding DC, Chou HL, Chang YH, Hung WT, Liu HW, Chu TY.Characterization of HLA-G and related immunosuppressive effects in human umbilical cord stroma-derived stem cells. Cell Transplant.2016;25:217–28. [DOI] [PubMed]
Hunt JS, Petroff MG, McIntire RH, Ober C.HLA-G and immune tolerance in pregnancy. FASEB J.2005;19:681–93. [DOI] [PubMed]
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. [DOI] [PubMed]
Castro-Manrreza ME, Montesinos JJ.Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications. J Immunol Res.2015;2015:394917. [DOI] [PubMed] [PMC]
Lin L, Du L.The role of secreted factors in stem cells-mediated immune regulation. Cell Immunol.2018;326:24–32. [DOI] [PubMed]
van den Hoogen P, de Jager SCA, Mol EA, Schoneveld AS, Huibers MMH, Vink A, et al. Potential of mesenchymal-and cardiac progenitor cells for therapeutic targeting of B-cells and antibody responses in end-stage heart failure. PLoS One.2019;14:e0227283. [DOI] [PubMed] [PMC]
Cai J, Wu J, Wang J, Li Y, Hu X, Luo S, et al. Extracellular vesicles derived from different sources of mesenchymal stem cells: therapeutic effects and translational potential. Cell Biosci. 2020:10:69. [DOI] [PubMed] [PMC]
Khan RS, Newsome PN.A comparison of phenotypic and functional properties of mesenchymal stromal cells and multipotent adult progenitor cells. Front Immunol. 2019:10:1952. [DOI] [PubMed] [PMC]
Deasy BM, Anderson JE, Zelina S.Regulatory issues in the therapeutic use of stem cells. In: Andrades JA, editor. Regenerative Medicine and Tissue Engineering. London: IntechOpen; 2013.
