IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

Recombinant Human Bone Morphogenetic Protein-2 Priming of Mesenchymal Stem Cells Ameliorate Acute Lung Injury by Inducing Regulatory T Cells

  • Jooyeon Lee (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University) ;
  • Jimin Jang (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University) ;
  • Sang-Ryul Cha (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University) ;
  • Se Bi Lee (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University) ;
  • Seok-Ho Hong (Department of Internal Medicine, School of Medicine, Kangwon National University) ;
  • Han-Sol Bae (Cellular Therapeutics Team, Daewoong Pharmaceutical) ;
  • Young Jin Lee (Cellular Therapeutics Team, Daewoong Pharmaceutical) ;
  • Se-Ran Yang (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University)
  • Received : 2023.09.18
  • Accepted : 2023.12.11
  • Published : 2023.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Mesenchymal stromal/stem cells (MSCs) possess immunoregulatory properties and their regulatory functions represent a potential therapy for acute lung injury (ALI). However, uncertainties remain with respect to defining MSCs-derived immunomodulatory pathways. Therefore, this study aimed to investigate the mechanism underlying the enhanced effect of human recombinant bone morphogenic protein-2 (rhBMP-2) primed ES-MSCs (MSCBMP2) in promoting Tregs in ALI mice. MSC were preconditioned with 100 ng/ml rhBMP-2 for 24 h, and then administrated to mice by intravenous injection after intratracheal injection of 1 mg/kg LPS. Treating MSCs with rhBMP-2 significantly increased cellular proliferation and migration, and cytokines array reveled that cytokines release by MSCBMP2 were associated with migration and growth. MSCBMP2 ameliorated LPS induced lung injury and reduced myeloperoxidase activity and permeability in mice exposed to LPS. Levels of inducible nitric oxide synthase were decreased while levels of total glutathione and superoxide dismutase activity were further increased via inhibition of phosphorylated STAT1 in ALI mice treated with MSCBMP2. MSCBMP2 treatment increased the protein level of IDO1, indicating an increase in Treg cells, and Foxp3+CD25+ Treg of CD4+ cells were further increased in ALI mice treated with MSCBMP2. In co-culture assays with MSCs and RAW264.7 cells, the protein level of IDO1 was further induced in MSCBMP2. Additionally, cytokine release of IL-10 was enhanced while both IL-6 and TNF-α were further inhibited. In conclusion, these findings suggest that MSCBMP2 has therapeutic potential to reduce massive inflammation of respiratory diseases by promoting Treg cells.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2017M3A9B4051542, 2020R1A2C2010712, 2020R1A5A8019180 and 2022M3A9E4016936, RS-2023-00225239), Particulate Matter Management Specialized Graduate Program through the Korea Environmental Industry & Technology Institute(KEITI) funded by the Ministry of Environment(MOE) and Daewoong Pharmaceutical (120210855).

References

  1. Villarino AV, Kanno Y, Ferdinand JR, O'Shea JJ. Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol 2015;194:21-27.
  2. Williams GW, Berg NK, Reskallah A, Yuan X, Eltzschig HK. Acute respiratory distress syndrome. Anesthesiology 2021;134:270-282.
  3. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19. J Infect 2020;80:607-613.
  4. Sauer A, Peukert K, Putensen C, Bode C. Antibiotics as immunomodulators: a potential pharmacologic approach for ARDS treatment. Eur Respir Rev 2021;30:210093.
  5. Pierce LM, Kurata WE. Priming with toll-like receptor 3 agonist poly(I:C) enhances content of innate immune defense proteins but not microRNAs in human mesenchymal stem cell-derived extracellular vesicles. Front Cell Dev Biol 2021;9:676356.
  6. Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, Cosgrove K, Vojnik R, Calfee CS, Lee JW, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med 2015;3:24-32.
  7. Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, Rogers AJ, Gotts JE, Wiener-Kronish JP, Bajwa EK, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir Med 2019;7:154-162.
  8. Fukumitsu M, Suzuki K. Mesenchymal stem/stromal cell therapy for pulmonary arterial hypertension: comprehensive review of preclinical studies. J Cardiol 2019;74:304-312.
  9. Han J, Li Y, Li Y. Strategies to enhance mesenchymal stem cell-based therapies for acute respiratory distress syndrome. Stem Cells Int 2019;2019:5432134.
  10. Li O, Tormin A, Sundberg B, Hyllner J, Le Blanc K, Scheding S. Human embryonic stem cell-derived mesenchymal stroma cells (hES-MSCs) engraft in vivo and support hematopoiesis without suppressing immune function: implications for off-the shelf ES-MSC therapies. PLoS One 2013;8:e55319.
  11. Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors 2004;22:233-241.
  12. Huang CC, Kang M, Lu Y, Shirazi S, Diaz JI, Cooper LF, Gajendrareddy P, Ravindran S. Functionally engineered extracellular vesicles improve bone regeneration. Acta Biomater 2020;109:182-194.
  13. Cai H, Zou J, Wang W, Yang A. BMP2 induces hMSC osteogenesis and matrix remodeling. Mol Med Rep 2021;23:125.
  14. Yin X, Liang Z, Yun Y, Pei L. Intravenous transplantation of BMP2-transduced endothelial progenitor cells attenuates lipopolysaccharide-induced acute lung injury in rats. Cell Physiol Biochem 2015;35:2149-2158.
  15. Wang K, Gong J, Pei L, Shan S, Tan W. The effect of rhBMP-2 on pulmonary arterioles remodeling in endotoxin-induced acute lung injury in rats. Clin Exp Med 2013;13:187-192.
  16. Cipolla EM, Alcorn JF. Repair of the lung by regulatory T cells. Am J Respir Cell Mol Biol 2020;63:405-407.
  17. Forteza MJ, Polyzos KA, Baumgartner R, Suur BE, Mussbacher M, Johansson DK, Hermansson A, Hansson GK, Ketelhuth DF. Activation of the regulatory t-cell/indoleamine 2,3-dioxygenase axis reduces vascular inflammation and atherosclerosis in hyperlipidemic mice. Front Immunol 2018;9:950.
  18. Hwang SL, Chung NP, Chan JK, Lin CL. Indoleamine 2, 3-dioxygenase (IDO) is essential for dendritic cell activation and chemotactic responsiveness to chemokines. Cell Res 2005;15:167-175.
  19. Park JR, Lee H, Kim SI, Yang SR. The tri-peptide GHK-Cu complex ameliorates lipopolysaccharide-induced acute lung injury in mice. Oncotarget 2016;7:58405-58417.
  20. Rahman I, Kode A, Biswas SK. Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc 2006;1:3159-3165.
  21. Park JR, Kim E, Yang J, Lee H, Hong SH, Woo HM, Park SM, Na S, Yang SR. Isolation of human dermis derived mesenchymal stem cells using explants culture method: expansion and phenotypical characterization. Cell Tissue Bank 2015;16:209-218.
  22. Baghaei K, Hashemi SM, Tokhanbigli S, Asadi Rad A, Assadzadeh-Aghdaei H, Sharifian A, Zali MR. Isolation, differentiation, and characterization of mesenchymal stem cells from human bone marrow. Gastroenterol Hepatol Bed Bench 2017;10:208-213.
  23. Gabrielyan A, Quade M, Gelinsky M, Rosen-Wolff A. IL-11 and soluble VCAM-1 are important components of hypoxia conditioned media and crucial for mesenchymal stromal cells attraction. Stem Cell Res 2020;45:101814.
  24. Zepp JA, Zacharias WJ, Frank DB, Cavanaugh CA, Zhou S, Morley MP, Morrisey EE. Distinct mesenchymal lineages and niches promote epithelial self-renewal and myofibrogenesis in the lung. Cell 2017;170:1134-1148.e10.
  25. Phipps MC, Xu Y, Bellis SL. Delivery of platelet-derived growth factor as a chemotactic factor for mesenchymal stem cells by bone-mimetic electrospun scaffolds. PLoS One 2012;7:e40831.
  26. Chabot V, Dromard C, Rico A, Langonne A, Gaillard J, Guilloton F, Casteilla L, Sensebe L. Urokinase-type plasminogen activator receptor interaction with β1 integrin is required for platelet-derived growth factor-AB-induced human mesenchymal stem/stromal cell migration. Stem Cell Res Ther 2015;6:188.
  27. Forte G, Minieri M, Cossa P, Antenucci D, Sala M, Gnocchi V, Fiaccavento R, Carotenuto F, De Vito P, Baldini PM, et al. Hepatocyte growth factor effects on mesenchymal stem cells: proliferation, migration, and differentiation. Stem Cells 2006;24:23-33.
  28. He S, Shen L, Wu Y, Li L, Chen W, Hou C, Yang M, Zeng W, Zhu C. Effect of brain-derived neurotrophic factor on mesenchymal stem cell-seeded electrospinning biomaterial for treating ischemic diabetic ulcers via milieu-dependent differentiation mechanism. Tissue Eng Part A 2015;21:928-938.
  29. Li A, Xia X, Yeh J, Kua H, Liu H, Mishina Y, Hao A, Li B. PDGF-AA promotes osteogenic differentiation and migration of mesenchymal stem cell by down-regulating PDGFRα and derepressing BMP-Smad1/5/8 signaling. PLoS One 2014;9:e113785.
  30. Belotti D, Capelli C, Resovi A, Introna M, Taraboletti G. Thrombospondin-1 promotes mesenchymal stromal cell functions via TGFβ and in cooperation with PDGF. Matrix Biol 2016;55:106-116.
  31. Kawata K, Koga H, Tsuji K, Miyatake K, Nakagawa Y, Yokota T, Sekiya I, Katagiri H. Extracellular vesicles derived from mesenchymal stromal cells mediate endogenous cell growth and migration via the CXCL5 and CXCL6/CXCR2 axes and repair menisci. Stem Cell Res Ther 2021;12:414.
  32. Noronha NC, Mizukami A, Caliari-Oliveira C, Cominal JG, Rocha JL, Covas DT, Swiech K, Malmegrim KC. Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies. Stem Cell Res Ther 2019;10:131.
  33. Lourenco S, Teixeira VH, Kalber T, Jose RJ, Floto RA, Janes SM. Macrophage migration inhibitory factor-CXCR4 is the dominant chemotactic axis in human mesenchymal stem cell recruitment to tumors. J Immunol 2015;194:3463-3474.
  34. Cao G, O'Brien CD, Zhou Z, Sanders SM, Greenbaum JN, Makrigiannakis A, DeLisser HM. Involvement of human PECAM-1 in angiogenesis and in vitro endothelial cell migration. Am J Physiol Cell Physiol 2002;282:C1181-C1190.
  35. Kruger K, Schmid S, Paulsen F, Ignatius A, Klinger P, Hotfiel T, Swoboda B, Gelse K. Trefoil factor 3 (TFF3) is involved in cell migration for skeletal repair. Int J Mol Sci 2019;20:4277.
  36. Sivanathan KN, Gronthos S, Rojas-Canales D, Thierry B, Coates PT. Interferon-gamma modification of mesenchymal stem cells: implications of autologous and allogeneic mesenchymal stem cell therapy in allotransplantation. Stem Cell Rev Rep 2014;10:351-375.
  37. Yang W, Zhang S, Ou T, Jiang H, Jia D, Qi Z, Zou Y, Qian J, Sun A, Ge J. Interleukin-11 regulates the fate of adipose-derived mesenchymal stem cells via STAT3 signalling pathways. Cell Prolif 2020;53:e12771.
  38. Zhang JM, Feng FE, Wang QM, Zhu XL, Fu HX, Xu LP, Liu KY, Huang XJ, Zhang XH. Platelet-derived growth factor-BB protects mesenchymal stem cells (MSCs) derived from immune thrombocytopenia patients against apoptosis and senescence and maintains MSC-mediated immunosuppression. Stem Cells Transl Med 2016;5:1631-1643.
  39. Dorronsoro A, Lang V, Ferrin I, Fernandez-Rueda J, Zabaleta L, Perez-Ruiz E, Sepulveda P, Trigueros C. Intracellular role of IL-6 in mesenchymal stromal cell immunosuppression and proliferation. Sci Rep 2020;10:21853.
  40. Xia W, Xie C, Jiang M, Hou M. Improved survival of mesenchymal stem cells by macrophage migration inhibitory factor. Mol Cell Biochem 2015;404:11-24.
  41. Liu XH, Bai CG, Xu ZY, Huang SD, Yuan Y, Gong DJ, Zhang JR. Therapeutic potential of angiogenin modified mesenchymal stem cells: angiogenin improves mesenchymal stem cells survival under hypoxia and enhances vasculogenesis in myocardial infarction. Microvasc Res 2008;76:23-30.
  42. Tomonaga T, Izumi H, Yoshiura Y, Nishida C, Yatera K, Morimoto Y. Examination of surfactant protein D as a biomarker for evaluating pulmonary toxicity of nanomaterials in rat. Int J Mol Sci 2021;22:4635.
  43. Chow CW, Herrera Abreu MT, Suzuki T, Downey GP. Oxidative stress and acute lung injury. Am J Respir Cell Mol Biol 2003;29:427-431.
  44. Kellner M, Noonepalle S, Lu Q, Srivastava A, Zemskov E, Black SM. Ros signaling in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Adv Exp Med Biol 2017;967:105-137.
  45. Lee H, Lee J, Park Y, Kim JH, Eickelberg O, Yang SR. WKYMVm ameliorates acute lung injury via neutrophil antimicrobial peptide derived STAT1/IRF1 pathway. Biochem Biophys Res Commun 2020;533:313-318.
  46. Liang C, Jiang E, Yao J, Wang M, Chen S, Zhou Z, Zhai W, Ma Q, Feng S, Han M. Interferon-γ mediates the immunosuppression of bone marrow mesenchymal stem cells on T-lymphocytes in vitro. Hematology 2018;23:44-49.
  47. Liu Q, Chen X, Liu C, Pan L, Kang X, Li Y, Du C, Dong S, Xiang AP, Xu Y, et al. Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression. Cell Death Dis 2021;12:240.
  48. Li X, Wang Q, Ding L, Wang YX, Zhao ZD, Mao N, Wu CT, Wang H, Zhu H, Ning SB. Intercellular adhesion molecule-1 enhances the therapeutic effects of MSCs in a dextran sulfate sodium-induced colitis models by promoting MSCs homing to murine colons and spleens. Stem Cell Res Ther 2019;10:267.
  49. Riezu-Boj JI, Larrea E, Aldabe R, Guembe L, Casares N, Galeano E, Echeverria I, Sarobe P, Herrero I, Sangro B, et al. Hepatitis C virus induces the expression of CCL17 and CCL22 chemokines that attract regulatory T cells to the site of infection. J Hepatol 2011;54:422-431.
  50. Kim SN, Lee HJ, Jeon MS, Yi T, Song SU. Galectin-9 is involved in immunosuppression mediated by human bone marrow-derived clonal mesenchymal stem cells. Immune Netw 2015;15:241-251.
  51. Wu J, Song D, Li Z, Guo B, Xiao Y, Liu W, Liang L, Feng C, Gao T, Chen Y, et al. Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis. Cell Res 2020;30:794-809.
  52. Kim HN, Shin JY, Kim DY, Lee JE, Lee PH. Priming mesenchymal stem cells with uric acid enhances neuroprotective properties in parkinsonian models. J Tissue Eng 2021;12:20417314211004816.
  53. Ullah M, Liu DD, Thakor AS. Mesenchymal stromal cell homing: mechanisms and strategies for improvement. iScience 2019;15:421-438.
  54. Legrand C, Gilles C, Zahm JM, Polette M, Buisson AC, Kaplan H, Birembaut P, Tournier JM. Airway epithelial cell migration dynamics. MMP-9 role in cell-extracellular matrix remodeling. J Cell Biol 1999;146:517-529.
  55. Pricola KL, Kuhn NZ, Haleem-Smith H, Song Y, Tuan RS. Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism. J Cell Biochem 2009;108:577-588.
  56. Park KS, Bandeira E, Shelke GV, Lasser C, Lotvall J. Enhancement of therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res Ther 2019;10:288.
  57. Zimmermann JA, Hettiaratchi MH, McDevitt TC. Enhanced immunosuppression of t cells by sustained presentation of bioactive interferon-gamma within three-dimensional mesenchymal stem cell constructs. Stem Cells Transl Med 2017;6:223-237.
  58. Taylor MW, Feng GS. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J 1991;5:2516-2522.
  59. Lepiller Q, Soulier E, Li Q, Lambotin M, Barths J, Fuchs D, Stoll-Keller F, Liang TJ, Barth H. Antiviral and immunoregulatory effects of indoleamine-2,3-dioxygenase in hepatitis C virus infection. J Innate Immun 2015;7:530-544.
  60. Salminen A. Role of indoleamine 2,3-dioxygenase 1 (IDO1) and kynurenine pathway in the regulation of the aging process. Ageing Res Rev 2022;75:101573.
  61. Norton DL, Ceppe A, Tune MK, McCravy M, Devlin T, Drummond MB, Carson SS, Vincent BG, Hagan RS, Dang H, et al. Bronchoalveolar Tregs are associated with duration of mechanical ventilation in acute respiratory distress syndrome. J Transl Med 2020;18:427.
  62. Xue Y, Xiao H, Guo S, Xu B, Liao Y, Wu Y, Zhang G. Indoleamine 2,3-dioxygenase expression regulates the survival and proliferation of Fusobacterium nucleatum in THP-1-derived macrophages. Cell Death Dis 2018;9:355.
  63. Blumenthal A, Nagalingam G, Huch JH, Walker L, Guillemin GJ, Smythe GA, Ehrt S, Britton WJ, Saunders BM. M. tuberculosis induces potent activation of IDO-1, but this is not essential for the immunological control of infection. PLoS One 2012;7:e37314.