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Muse Cells pp 115-129 | Cite as

Immunomodulatory Properties and Potential Therapeutic Benefits of Muse Cells Administration in Diabetes

  • Marcelo Javier Perone
  • María Laura Gimeno
  • Florencia Fuertes
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1103)

Abstract

It is well established the link between inflammation and the development of insulin resistance and pathogenesis of type 2 diabetes. Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β cells mediated by autoreactive T lymphocytes and pro-inflammatory agents. Therefore, developing new strategies to efficiently control dysregulated inflammation could have substantial benefits in the treatment of diabetes. Recently, a novel population of non-tumorigenic pluripotent stem cells, named multilineage-differentiating stress-enduring (Muse) cells, was discovered. Muse cells secrete significant amounts of TGF-β1, a key cytokine governing down-modulation of T lymphocytes and macrophages. In this chapter, we discuss the immunomodulatory properties of Muse cells as well as the molecular mechanism of TGF-β1 as mediator of Muse cell action. We also describe the role of certain cytokines/growth factors highly expressed in Muse cells as potential mediators of their effects. Finally, we provide evidence of the beneficial effects of adipose tissue-derived Muse cells in an experimental mice model of type 1 diabetes.

Keywords

Stem cells Inflammation Tissue regeneration TGF-β1 Interleukins T lymphocytes Macrophages Adipose-derived stem cells 

References

  1. 1.
    Yañez R, Lamana ML, García-Castro J, Colmenero I, Ramírez M, Bueren JA (2006) Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells 24:2582–2591PubMedCrossRefGoogle Scholar
  2. 2.
    Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M, Ringdén O (2004) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363:1439–1441PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, Borg C, Saas P, Tiberghien P, Rouas-Freiss N et al (2008) Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells 26:212–222PubMedCrossRefGoogle Scholar
  4. 4.
    Ramasamy R, Fazekasova H, Lam EW-F, Soeiro I, Lombardi G, Dazzi F (2007) Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation 83:71–76PubMedCrossRefGoogle Scholar
  5. 5.
    Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L (2008) Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111(3):1327–1333PubMedCrossRefGoogle Scholar
  6. 6.
    Yen BL, Chang CJ, Liu K-J, Chen YC, Hu H-I, Bai C-H, Yen M-L (2009) Brief report--human embryonic stem cell-derived mesenchymal progenitors possess strong immunosuppressive effects toward natural killer cells as well as T lymphocytes. Stem Cells 27:451–456PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Chen K, Wang D, Du WT, Han Z-B, Ren H, Chi Y, Yang SG, Zhu D, Bayard F, Han ZC (2010) Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism. Clin Immunol 135:448–458PubMedCrossRefGoogle Scholar
  8. 8.
    Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L (2006) Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 107:1484–1490PubMedCrossRefGoogle Scholar
  9. 9.
    Hodgetts SI, Beilharz MW, Scalzo AA, Grounds MD (2000) Why do cultured transplanted myoblasts die in vivo? DNA quantification shows enhanced survival of donor male myoblasts in host mice depleted of CD4+ and CD8+ cells or Nk1.1+ cells. Cell Transplant 9:489–502PubMedCrossRefGoogle Scholar
  10. 10.
    Mingliang R, Bo Z, Zhengguo W (2011) Stem cells for cardiac repair: status, mechanisms, and new strategies. Stem Cells Int 2011:1–8.  https://doi.org/10.4061/2011/310928 CrossRefGoogle Scholar
  11. 11.
    Kuroda Y, Kitada M, Wakao S, Nishikawa K, Tanimura Y, Makinoshima H, Goda M, Akashi H, Inutsuka A, Niwa A et al (2010) Unique multipotent cells in adult human mesenchymal cell populations. Proc Natl Acad Sci 107:8639–8643PubMedCrossRefGoogle Scholar
  12. 12.
    Heneidi S, Simerman AA, Keller E, Singh P, Li X, Dumesic DA, Chazenbalk G (2013) Awakened by cellular stress: isolation and characterization of a novel population of pluripotent stem cells derived from Hu-man adipose tissue. PLoS One 8:e64752PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Gimeno ML, Fuertes F, Barcala Tabarrozzi AE, Attorressi AI, Cucchiani R, Corrales L, Oliveira TC, Sogayar MC, Labriola L, Dewey RA, Perone MJ (2017) Pluripotent nontumorigenic adipose tissue-derived Muse-AT cells have immunomodulatory capacity mediated by transforming growth factor-β1. Stem Cells Transl Med 6:161–173PubMedCrossRefGoogle Scholar
  14. 14.
    Wakao S, Kitada M, Kuroda Y, Shigemoto T, Matsuse D, Akashi H, Tanimura Y, Tsuchiyama K, Kikuchi T, Goda M et al (2011) Multiline-age-differentiating stress-enduring (Muse-AT) cells are a primary source of induced pluripotent stem cells in human fibroblasts. Proc Natl Acad Sci 108:9875–9880PubMedCrossRefGoogle Scholar
  15. 15.
    Simerman AA, Dumesic DA, Chazenbalk GD (2014) Pluripotent Muse-AT cells derived from human adipose tissue: a new perspective on regenerative medicine and cell therapy. Clin Transl Med 3:12PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Ogura F, Wakao S, Kuroda Y, Tsuchiyama K, Bagheri M, Heneidi S, Chazenbalk G, Aiba S, Dezawa M (2014) Human adipose tissue possesses a unique population of pluripotent stem cells with nontumorigenic and low telomerase activities: potential implications in regenerative medicine. Stem Cells Dev 23:717–728PubMedCrossRefGoogle Scholar
  17. 17.
    Burrack AL, Martino T, Fife BT (2017) T cell-mediated Beta cell destruction: autoimmunity and alloimmunity in the context of type 1 diabetes. Front Endocrinol 8:343.  https://doi.org/10.3389/fendo.2017.00343 CrossRefGoogle Scholar
  18. 18.
    Rothe H, Hausmann A, Casteels K, Okamura H, Kurimoto M, Burkart V, Mathieu C, Kolb H (1999) IL-18 inhibits diabetes development in nonobese diabetic mice by counterregulation of Th1-dependent destructive insulitis. J Immunol 163:1230–1236PubMedGoogle Scholar
  19. 19.
    Sarikonda G, Pettus J, Phatak S, Sachithanantham S, Miller JF, Wesley JD, Cadag E, Chae J, Ganesan L, Mallios R, Edelman S, Peters B, von Herrath M (2013) CD8 T-cell reactivity to islet antigens is unique to type 1 while CD4 T-cell reactivity exists in both type 1 and type 2 diabetes. J Autoimmun 50:77–82.  https://doi.org/10.1016/j.jaut.2013.12.003 PubMedCrossRefGoogle Scholar
  20. 20.
    Suarez-Pinzon WL, Rabinovitch A (2001) Approaches to type 1 diabetes prevention by intervention in cytokine immunoregulatory circuits. Int J Exp Diabetes Res 2(1):3–17PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Lundh M, Bugliani M, Dahlby T, Chou DH, Wagner B, Ghiasi SM, De Tata V, Chen Z, Lund MN, Davies MJ, Marchetti P, Mandrup-Poulsen T (2017) The immunoproteasome is induced by cytokines and regulates apoptosis in human islets. J Endocrinol 233(3):369–379PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kahn SE, Cooper ME, Del Prato S (2014) Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet 383(9922):1068–1083PubMedCrossRefGoogle Scholar
  23. 23.
    Leiter EH, Schile A (2013) Genetic and pharmacologic models for type 1 diabetes. Curr Protoc Mouse Biol 3(1):9–19PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Lichtman SN, Wang J, Lemasters JJ (1998) LPS receptor CD14 participates in release of TNF alpha in RAW 264.7 and peritoneal cells but not in Kupffer cells. Am J Phys 275(1 Pt 1):G39–G46Google Scholar
  25. 25.
    Stadinski BD, Delong T, Reisdorph N, Reisdorph R, Powell RL, Armstrong M, Piganelli JD, Barbour G, Bradley B, Crawford F, Marrack P, Mahata SK, Kappler JW, Haskins K (2010) Chromogranin a is an auto-antigen in type 1 diabetes. Nat Immunol 11:225–231PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Judkowski V, Pinilla C, Schroder K, Tucker L, Sarvetnick N, Wilson DB (2001) Identification of MHC class II-restricted peptide ligands, including a glutamic acid decarboxylase 65 sequence, that stimulate diabetogenic T cells from transgenic BDC2.5 nonobese diabetic mice. J Immunol 166:908–917PubMedCrossRefGoogle Scholar
  27. 27.
    Castro CN, Barcala Tabarrozzi AE, Winnewisser J, Gimeno ML, Antunica Noguerol M, Liberman AC, Paz DA, Dewey RA, Perone MJ (2014) Curcumin ameliorates autoimmune diabetes. Evidence in accelerated murine models of type 1 diabetes. Clin Exp Immunol 177:149–160PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Ylöstalo JH, Bartosh TJ, Coble K, Prockop DJ (2012) Human mesenchymal stem/stromal cells cultured as spheroids are self-activated to produce prostaglandin E2 that directs stimulated macrophages into an anti-inflammatory phenotype. Stem Cells 30(10):2283–2296PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Nemeth C, Nunnally M, Bitan Y, Nunnally S, Cook RI (2009) Between choice and chance: the role of human factors in acute care equipment decisions. J Patient Saf 5(2):114–121PubMedCrossRefGoogle Scholar
  30. 30.
    Weiss A, Attisano L (2013) The TGF beta superfamily signalling pathway. Wiley Interdiscip Rev Dev Biol 2(1):47–63PubMedCrossRefGoogle Scholar
  31. 31.
    Morikawa M, Derynck R, Miyazono K (2016) TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol 8(5):a021873PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Ayyaz A, Attisano L, Wrana JL (2017) Recent advances in understanding contextual TGFβ signalling. F1000Research 6:749PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669PubMedCrossRefGoogle Scholar
  34. 34.
    Jian H, Shen X, Liu I, Semenov M, He X, Wang XF (2006) Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev 20(6):666–674PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Maeda S, Hayashi M, Komiya S, Imamura T, Miyazono K (2004) Endogenous TGF-beta signalling suppresses maturation of osteoblastic mesenchymal cells. EMBO J 23(3):552–563PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Fingleton B (2017) Matrix metalloproteinases as regulators of inflammatory processes. Biochim Biophys Acta 1864(11 Pt A):2036–2042CrossRefGoogle Scholar
  37. 37.
    Iseki M, Kushida Y, Wakao S, Akimoto T, Mizuma M, Motoi F, Asada R, Shimizu S, Unno M, Chazenbalk G, Dezawa M (2017) Human Muse-AT cells, nontumorigenic pluripotent-like stem cells, have liver regeneration capacity through specific homing and cell replacement in a mouse model of liver fibrosis. Cell Transplant 26:821–840PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Edwards DR, Murphy G, Reynolds JJ, Whitham SE, Docherty AJ, Angel P, Heath JK (1987) Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J 6(7):1899–1904PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Ignotz RA, Massagué J (1986) Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 261(9):4337–4345PubMedGoogle Scholar
  40. 40.
    Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A 83(12):4167–4171PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Uchida N, Kushida Y, Kitada M, Wakao S, Kumagai N, Kuroda Y, Kondo Y, Hirohara Y, Kure S, Chazenbalk G, Dezawa M (2017) Beneficial effects of systemically administered human Muse-AT cells in adriamycin nephropathy. J Am Soc Nephrol 28(10):2946–2960PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    van Baren N, Van den Eynde BJ (2015) Tryptophan-degrading enzymes in tumoral immune resistance. Front Immunol 6:34PubMedPubMedCentralGoogle Scholar
  43. 43.
    Munn DH, Shafizadeh E, Attwood JT, Bondarey I, Pashine A, Mellor AL (1999) Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 189(9):1363–1372PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, Fioretti MC, Puccetti P (2002) T cell apoptosis by tryptophan catabolism. Cell Death Differ 9(10):1069–1077PubMedCrossRefGoogle Scholar
  45. 45.
    Terness P, Bauer TM, Röse L, Dufter C, Watzlik A, Simon H, Opelz G (2002) Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 196(4):447–457PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C, Santamaria P, Fioretti MC, Puccetti P (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176(11):6752–6761PubMedCrossRefGoogle Scholar
  47. 47.
    Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99(10):3838–3843PubMedCrossRefGoogle Scholar
  48. 48.
    Haddad R, Saldanha-Araujo F (2014) Mechanisms of T-cell immuno-suppression by mesenchymal stromal cells: what do we know so far? Biomed Res Int 2014:1–14.  https://doi.org/10.1155/2014/216806 CrossRefGoogle Scholar
  49. 49.
    Kucia M, Jankowski K, Reca R, Wysoczynski M, Bandura L, Allendorf DJ, Zhang J, Ratajczak J, Ratajczak MZ (2004) CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol 35(3):233–245PubMedCrossRefGoogle Scholar
  50. 50.
    Hirbe AC, Morgan EA, Weilbaecher KN (2010) The CXCR4/SDF-1 chemokine axis: a potential therapeutic target for bone metastases? Curr Pharm Des 16(11):1284–1290PubMedCrossRefGoogle Scholar
  51. 51.
    Tanaka T, Nishigaki K, Minatoguchi S, Nawa T, Yamada Y, Kanamori H, Mikami A, Ushikoshi H, Kawasaki M, Dezawa M, Minatoguchi S (2017) Mobilized Muse-AT cells after acute myocardial infarction predict cardiac function and remodelling in the chronic phase. Circ J 82(2):561–571PubMedCrossRefGoogle Scholar
  52. 52.
    Nitzsche F, Müller C, Lukomska B, Jolkkonen J, Deten A, Boltze J (2017) Concise review: MSC adhesion cascade-insights into homing and transendothelial migration. Stem Cells 35(6):1446–1460PubMedCrossRefGoogle Scholar
  53. 53.
    Bayo J, Marrodán M, Aquino JB, Silva M, García MG, Mazzolini G (2014) The therapeutic potential of bone marrow-derived mesenchymal stromal cells on hepatocellular carcinoma. Liver Int 34(3):330–342PubMedCrossRefGoogle Scholar
  54. 54.
    Zhao M, Hu Y, Jin J, Yu Y, Zhang S, Cao J, Zhai Y, Wei R, Shou J, Cai W, Liu S, Yang X, Xu GT, Yang J, Corry DB, Su SB, Liu X, Yang T (2017) Interleukin 37 promotes angiogenesis through TGF-β signalling. Sci Rep 7(1):6113PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Pardali E, Goumans MJ, ten Dijke P (2010) Signalling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol 20:556–567PubMedCrossRefGoogle Scholar
  56. 56.
    Bonfanti R, Bazzigaluppi E, Calori G, Riva MC, Viscardi M, Bognetti E, Meschi F, Bosi E, Chiumello G, Bonifacio E (1998) Parameters associated with residual insulin secretion during the first year of disease in children and adolescents with type 1 diabetes mellitus. Diabet Med 15(10):844–850PubMedCrossRefGoogle Scholar
  57. 57.
    Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH (2008) Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes 57(7):1759–1767PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Di Ianni M, Del Papa B, De Ioanni M, Moretti L, Bonifacio E, Cecchini D, Sportoletti P, Falzetti F, Tabilio A (2008) Mesenchymal cells recruit and regulate T regulatory cells. Exp Hematol 36(3):309–318PubMedCrossRefGoogle Scholar
  59. 59.
    Ghannam S, Bouffi C, Djouad F, Jorgensen C, Noël D (2010) Immuno-suppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther 1(1):2PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Oh W, Kim DS, Yang YS, Lee JK (2008) Immunological properties of umbilical cord blood-derived mesenchymal stromal cells. Cell Immunol 251(2):116–123PubMedCrossRefGoogle Scholar
  61. 61.
    Li L, Hui H, Jia X, Zhang J, Liu Y, Xu Q, Zhu D (2016) Infusion with human bone marrow-derived mesenchymal stem cells improves β-cell function in patients and nonobese mice with severe diabetes. Sci Rep 6:37894PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    International Diabetes Federation (2017) International diabetes federation atlas, 7th edn. Brussels, BelgiumGoogle Scholar
  63. 63.
    Kinoshita K, Kuno S, Ishimine H, Aoi N, Mineda K, Kato H, Doi K, Kanayama K, Feng J, Mashiko T, Kurisaki A, Yoshimura K (2015) Therapeutic potential of adipose-derived SSEA-3-positive Muse-AT cells for treating diabetic skin ulcers. Stem Cells Transl Med 4(2):146–155PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Hakonen E, Ustinov J, Mathijs I, Palgi J, Bouwens L, Miettinen PJ, Otonkoski T (2011) Epidermal growth factor (EGF)-receptor signalling is needed for murine beta cell mass expansion in response to high-fat diet and pregnancy but not after pancreatic duct ligation. Diabetologia 54(7):1735–1743PubMedCrossRefGoogle Scholar
  65. 65.
    Chen H, Gu X, Liu Y, Wang J, Wirt SE, Bottino R, Schorle H, Sage J, Kim SK (2011) PDGF signalling controls age-dependent proliferation in pancreatic β-cells. Nature 478(7369):349–355PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Alessio N, Özcan S, Tatsumi K, Murat A, Peluso G, Dezawa M, Galderisi U (2017) The secretome of MUSE-AT cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation. Cell Cycle 16(1):33–44PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Marcelo Javier Perone
    • 1
  • María Laura Gimeno
    • 1
  • Florencia Fuertes
    • 1
  1. 1.Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) – CONICET – Partner Institute of the Max Planck SocietyBuenos AiresArgentina

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