International Journal of Stem Cells

Korean Society for Stem Cell Research (한국줄기세포학회)
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Diesel Exhaust Particles Impair Therapeutic Effect of Human Wharton's Jelly-Derived Mesenchymal Stem Cells against Experimental Colitis through ROS/ERK/cFos Signaling Pathway

  • Hyun Sung Park (Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Mi-Kyung Oh (Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University) ;
  • Joong Won Lee (Division of Allergy and Respiratory Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health) ;
  • Dong-Hoon Chae (Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University) ;
  • Hansol Joo (Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Ji Yeon Kang (Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Hye Bin An (Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University) ;
  • Aaron Yu (Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University) ;
  • Jae Han Park (Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University) ;
  • Hee Min Yoo (Biometrology Group, Korea Research Institute of Standards and Science (KRISS)) ;
  • Hyun Jun Jung (Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine) ;
  • Uimook Choi (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH) ;
  • Ji-Won Jung (Division of Allergy and Respiratory Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health) ;
  • In-Sook Kim (Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Il-Hoan Oh (Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Kyung-Rok Yu (Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University)
  • Received : 2021.10.06
  • Accepted : 2021.11.10
  • Published : 2022.05.30
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Abstract

Background and Objectives: Epidemiological investigations have shown positive correlations between increased diesel exhaust particles (DEP) in ambient air and adverse health outcomes. DEP are the major constituent of particulate atmospheric pollution and have been shown to induce proinflammatory responses both in the lung and systemically. Here, we report the effects of DEP exposure on the properties of human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs), including stemness, regeneration, and immunomodulation. Methods and Results: Non-apoptotic concentrations of DEP (10 ㎍/ml) inhibited the migration and osteogenic differentiation capacity of WJ-MSCs. Gene expression profiling showed that DEP increased intracellular reactive oxygen species (ROS) and expression of pro-inflammatory and metabolic-process-related genes including cFos. Furthermore, WJ-MSCs cultured with DEP showed impaired suppression of T cell proliferation that was reversed by inhibition of ROS or knockdown of cFos. ERK inhibition assay revealed that DEP-induced ROS regulated cFos through activation of ERK but not NF-κB signaling. Overall, low concentrations of DEP (10 ㎍/ml) significantly suppressed the stemness and immunomodulatory properties of WJ-MSCs through ROS/ERK/cFos signaling pathways. Furthermore, WJ-MSCs cultured with DEP impaired the therapeutic effect of WJ-MSCs in experimental colitis mice, but was partly reversed by inhibition of ROS. Conclusions: Taken together, these results indicate that exposure to DEP enhances the expression of pro-inflammatory cytokines and immune responses through a mechanism involving the ROS/ERK/cFos pathway in WJ-MSCs, and that DEP-induced ROS damage impairs the therapeutic effect of WJ-MSCs in colitis. Our results suggest that modulation of ROS/ERK/cFos signaling pathways in WJ-MSCs might be a novel therapeutic strategy for DEP-induced diseases.

Keywords

Acknowledgement

This research was supported by the Basic Research Program through the National Research Foundation of Korea (NRF) (2019R1C1C1008896) funded by the Korean government.

References

  1. Wilson SJ, Miller MR, Newby DE. Effects of diesel exhaust on cardiovascular function and oxidative stress. Antioxid Redox Signal 2018;28:819-836 
  2. Li N, Hao M, Phalen RF, Hinds WC, Nel AE. Particulate air pollutants and asthma. A paradigm for the role of oxidative stress in PM-induced adverse health effects. Clin Immunol 2003;109:250-265 
  3. van Eeden SF, Tan WC, Suwa T, Mukae H, Terashima T, Fujii T, Qui D, Vincent R, Hogg JC. Cytokines involved in the systemic inflammatory response induced by exposure to particulate matter air pollutants (PM(10)). Am J Respir Crit Care Med 2001;164:826-830 
  4. Totlandsdal AI, Cassee FR, Schwarze P, Refsnes M, Lag M. Diesel exhaust particles induce CYP1A1 and pro-inflammatory responses via differential pathways in human bronchial epithelial cells. Part Fibre Toxicol 2010;7:41 
  5. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008;453:65-71 
  6. Yu KR, Kang KS. Aging-related genes in mesenchymal stem cells: a mini-review. Gerontology 2013;59:557-563 
  7. Jimenez-Puerta GJ, Marchal JA, Lopez-Ruiz E, GalvezMartin P. Role of mesenchymal stromal cells as therapeutic agents: potential mechanisms of action and implications in their clinical use. J Clin Med 2020;9:445 
  8. Yu KR, Lee JY, Kim HS, Hong IS, Choi SW, Seo Y, Kang I, Kim JJ, Lee BC, Lee S, Kurtz A, Seo KW, Kang KS. A p38 MAPK-mediated alteration of COX-2/PGE2 regulates immunomodulatory properties in human mesenchymal stem cell aging. PLoS One 2014;9:e102426 
  9. Song N, Scholtemeijer M, Shah K. Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential. Trends Pharmacol Sci 2020;41:653-664 
  10. Kang JY, Oh MK, Joo H, Park HS, Chae DH, Kim J, Lee HR, Oh IH, Yu KR. Xeno-free condition enhances therapeutic functions of human Wharton's jelly-derived mesenchymal stem cells against experimental colitis by upregulated indoleamine 2,3-dioxygenase activity. J Clin Med 2020;9:2913 
  11. Joo H, Oh MK, Kang JY, Park HS, Chae DH, Kim J, Lee JH, Yoo HM, Choi U, Kim DK, Lee H, Kim S, Yu KR. Extracellular vesicles from thapsigargin-treated mesenchymal stem cells ameliorated experimental colitis via enhanced immunomodulatory properties. Biomedicines 2021;9:209 
  12. Fontaine MJ, Shih H, Schafer R, Pittenger MF. Unraveling the mesenchymal stromal cells' paracrine immunomodulatory effects. Transfus Med Rev 2016;30:37-43 
  13. Kim SY, Oh SH, Lee JH, Suh MW, Park MK. Effects of placenta-derived mesenchymal stem cells on the particulate matter-induced damages in human middle ear epithelial cells. Stem Cells Int 2019;2019:4357684 
  14. Munir H, McGettrick HM. Mesenchymal stem cell therapy for autoimmune disease: risks and rewards. Stem Cells Dev 2015;24:2091-2100 
  15. Trapnell C, Pachter L, Salzberg SL. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 2009;25:1105-1111 
  16. Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, Salzberg SL, Wold BJ, Pachter L. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 2010;28:511-515 
  17. Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, Pimentel H, Salzberg SL, Rinn JL, Pachter L. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 2012;7:562-578 
  18. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 1995;57:289-300 
  19. O'Driscoll CA, Owens LA, Gallo ME, Hoffmann EJ, Afrazi A, Han M, Fechner JH, Schauer JJ, Bradfield CA, Mezrich JD. Differential effects of diesel exhaust particles on T cell differentiation and autoimmune disease. Part Fibre Toxicol 2018;15:35 
  20. Meldrum K, Gant TW, Leonard MO. Diesel exhaust particulate associated chemicals attenuate expression of CXCL10 in human primary bronchial epithelial cells. Toxicol In Vitro 2017;45(Pt 3):409-416 
  21. Raudoniute J, Stasiulaitiene I, Kulvinskiene I, Bagdonas E, Garbaras A, Krugly E, Martuzevicius D, Bironaite D, Aldonyte R. Pro-inflammatory effects of extracted urban fine particulate matter on human bronchial epithelial cells BEAS-2B. Environ Sci Pollut Res Int 2018;25:32277-32291 
  22. Abu-Elmagd M, Alghamdi MA, Shamy M, Khoder MI, Costa M, Assidi M, Kadam R, Alsehli H, Gari M, Pushparaj PN, Kalamegam G, Al-Qahtani MH. Evaluation of the effects of airborne particulate matter on bone marrow-mesenchymal stem cells (BM-MSCs): cellular, molecular and systems biological approaches. Int J Environ Res Public Health 2017;14:440 
  23. Baeza-Squiban A, Bonvallot V, Boland S, Marano F. Diesel exhaust particles increase NF-kappaB DNA binding activity and c-FOS proto-oncogene expression in human bronchial epithelial cells. Toxicol In Vitro 1999;13:817-822 
  24. Pourazar J, Mudway IS, Samet JM, Helleday R, Blomberg A, Wilson SJ, Frew AJ, Kelly FJ, Sandstrom T. Diesel exhaust activates redox-sensitive transcription factors and kinases in human airways. Am J Physiol Lung Cell Mol Physiol 2005;289:L724-L730 
  25. Donaldson K, Tran L, Jimenez LA, Duffin R, Newby DE, Mills N, MacNee W, Stone V. Combustion-derived nanoparticles: a review of their toxicology following inhalation exposure. Part Fibre Toxicol 2005;2:10 
  26. Tseng CY, Wang JS, Chang YJ, Chang JF, Chao MW. Exposure to high-dose diesel exhaust particles induces intracellular oxidative stress and causes endothelial apoptosis in cultured in vitro capillary tube cells. Cardiovasc Toxicol 2015;15:345-354 
  27. Luu NT, McGettrick HM, Buckley CD, Newsome PN, Rainger GE, Frampton J, Nash GB. Crosstalk between mesenchymal stem cells and endothelial cells leads to downregulation of cytokine-induced leukocyte recruitment. Stem Cells 2013;31:2690-2702 
  28. Vogel CF, Sciullo E, Wong P, Kuzmicky P, Kado N, Matsumura F. Induction of proinflammatory cytokines and C-reactive protein in human macrophage cell line U937 exposed to air pollution particulates. Environ Health Perspect 2005;113:1536-1541 
  29. Li R, Kou X, Xie L, Cheng F, Geng H. Effects of ambient PM2.5 on pathological injury, inflammation, oxidative stress, metabolic enzyme activity, and expression of c-fos and c-jun in lungs of rats. Environ Sci Pollut Res Int 2015;22:20167-20176 
  30. Lee BC, Yu KR. Impact of mesenchymal stem cell senescence on inflammaging. BMB Rep 2020;53:65-73 
  31. Mamessier E, Nieves A, Vervloet D, Magnan A. Diesel exhaust particles enhance T-cell activation in severe asthmatics. Allergy 2006;61:581-588 
  32. Abarrategi A, Gambera S, Alfranca A, Rodriguez-Milla MA, Perez-Tavarez R, Rouault-Pierre K, Waclawiczek A, Chakravarty P, Mulero F, Trigueros C, Navarro S, Bonnet D, Garcia-Castro J. c-Fos induces chondrogenic tumor formation in immortalized human mesenchymal progenitor cells. Sci Rep 2018;8:15615 
  33. Baulig A, Garlatti M, Bonvallot V, Marchand A, Barouki R, Marano F, Baeza-Squiban A. Involvement of reactive oxygen species in the metabolic pathways triggered by diesel exhaust particles in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 2003;285:L671-L679 
  34. Tal TL, Simmons SO, Silbajoris R, Dailey L, Cho SH, Ramabhadran R, Linak W, Reed W, Bromberg PA, Samet JM. Differential transcriptional regulation of IL-8 expression by human airway epithelial cells exposed to diesel exhaust particles. Toxicol Appl Pharmacol 2010;243:46-54 
  35. Hendryx M, Luo J. COVID-19 prevalence and fatality rates in association with air pollution emission concentrations and emission sources. Environ Pollut 2020;265(Pt A):115126 
  36. Baulig A, Blanchet S, Rumelhard M, Lacroix G, Marano F, Baeza-Squiban A. Fine urban atmospheric particulate matter modulates inflammatory gene and protein expression in human bronchial epithelial cells. Front Biosci 2007;12:771-782 
  37. Paital B, Agrawal PK. Air pollution by NO2 and PM2.5 explains COVID-19 infection severity by overexpression of angiotensin-converting enzyme 2 in respiratory cells: a review. Environ Chem Lett 2021;19:25-42 
  38. Avanzini MA, Mura M, Percivalle E, Bastaroli F, Croce S, Valsecchi C, Lenta E, Nykjaer G, Cassaniti I, Bagnarino J, Baldanti F, Zecca M, Comoli P, Gnecchi M. Human mesenchymal stromal cells do not express ACE2 and TMPRSS2 and are not permissive to SARS-CoV-2 infection. Stem Cells Transl Med 2021;10:636-642 
  39. Lee BC, Kang I, Yu KR. Therapeutic features and updated clinical trials of mesenchymal stem cell (MSC)-derived exosomes. J Clin Med 2021;10:711