Acknowledgement
This research was supported by the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. NRF-2017M3A9B4061887). Parts of figures were created with BioRender.com. We would like to express our sincere gratitude to Joony Yim for helping us develop the main findings of this study more clearly.
References
- Stern J, Pier J, Litonjua AA. Asthma epidemiology and risk factors. Semin Immunopathol 2020;42:5-15. https://doi.org/10.1007/s00281-020-00785-1
- Henderson I, Caiazzo E, McSharry C, Guzik TJ, Maffia P. Why do some asthma patients respond poorly to glucocorticoid therapy? Pharmacol Res 2020;160:105189.
- Akkoc T, Genc D. Asthma immunotherapy and treatment approaches with mesenchymal stem cells. Immunotherapy 2020;12:665-674. https://doi.org/10.2217/imt-2019-0194
- Dimarino AM, Caplan AI, Bonfield TL. Mesenchymal stem cells in tissue repair. Front Immunol 2013;4:201.
- Song N, Scholtemeijer M, Shah K. Mesenchymal stem cell immunomodulation: Mechanisms and therapeutic potential. Trends Pharmacol Sci 2020;41:653-664. https://doi.org/10.1016/j.tips.2020.06.009
- Jiang W, Xu J. Immune modulation by mesenchymal stem cells. Cell Prolif 2020;53:e12712.
- Mirershadi F, Ahmadi M, Rezabakhsh A, Rajabi H, Rahbarghazi R, Keyhanmanesh R. Unraveling the therapeutic effects of mesenchymal stem cells in asthma. Stem Cell Res Ther 2020;11:400.
- Shin JW, Ryu S, Ham J, Jung K, Lee S, Chung DH, Kang HR, Kim HY. Mesenchymal stem cells suppress severe asthma by directly regulating Th2 cells and type 2 innate lymphoid cells. Mol Cells 2021;44:580-590. https://doi.org/10.14348/molcells.2021.0101
- Poston RN, Chanez P, Lacoste JY, Litchfield T, Lee TH, Bousquet J. Immunohistochemical characterization of the cellular infiltration in asthmatic bronchi. Am Rev Respir Dis 1992;145:918-921. https://doi.org/10.1164/ajrccm/145.4_Pt_1.918
- Tomita K, Tanigawa T, Yajima H, Fukutani K, Matsumoto Y, Tanaka Y, Sasaki T. Identification and characterization of monocyte subpopulations from patients with bronchial asthma. J Allergy Clin Immunol 1995;96:230-238. https://doi.org/10.1016/S0091-6749(95)70012-9
- Saradna A, Do DC, Kumar S, Fu QL, Gao P. Macrophage polarization and allergic asthma. Transl Res 2018;191:1-14. https://doi.org/10.1016/j.trsl.2017.09.002
- Guilliams M, Thierry GR, Bonnardel J, Bajenoff M. Establishment and maintenance of the macrophage niche. Immunity 2020;52:434-451. https://doi.org/10.1016/j.immuni.2020.02.015
- Keyhanmanesh R, Rahbarghazi R, Aslani MR, Hassanpour M, Ahmadi M. Systemic delivery of mesenchymal stem cells condition media in repeated doses acts as magic bullets in restoring IFN-γ/IL-4 balance in asthmatic rats. Life Sci 2018;212:30-36. https://doi.org/10.1016/j.lfs.2018.09.049
- Jeong EM, Shin JW, Lim J, Kim JH, Kang H, Yin Y, Kim HM, Kim Y, Kim SG, Kang HS, et al. Monitoring glutathione dynamics and heterogeneity in living stem cells. Int J Stem Cells 2019;12:367-379. https://doi.org/10.15283/ijsc18151
- Jeong EM, Yoon JH, Lim J, Shin JW, Cho AY, Heo J, Lee KB, Lee JH, Lee WJ, Kim HJ, et al. Real-time monitoring of glutathione in living cells reveals that high glutathione levels are required to maintain stem cell function. Stem Cell Reports 2018;10:600-614. https://doi.org/10.1016/j.stemcr.2017.12.007
- Chang J, Nie H, Ge X, Du J, Liu W, Li X, Sun Y, Wei X, Xun Z, Li YC. Vitamin D suppresses bleomycininduced pulmonary fibrosis by targeting the local renin-angiotensin system in the lung. Sci Rep 2021;11:16525.
- Hu X, Tian Y, Qu S, Cao Y, Li S, Zhang W, Zhang Z, Zhang N, Fu Y. Protective effect of TM6 on LPSinduced acute lung injury in mice. Sci Rep 2017;7:572.
- Hu Z, Chen R, Cai Z, Yu L, Fei Y, Weng L, Wang J, Ge X, Zhu T, Wang J, et al. Salmeterol attenuates the inflammatory response in asthma and decreases the pro-inflammatory cytokine secretion of dendritic cells. Cell Mol Immunol 2012;9:267-275. https://doi.org/10.1038/cmi.2011.56
- Kim J, Hematti P. Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp Hematol 2009;37:1445-1453. https://doi.org/10.1016/j.exphem.2009.09.004
- Khan DA. Allergic rhinitis and asthma: epidemiology and common pathophysiology. Allergy Asthma Proc 2014;35:357-361. https://doi.org/10.2500/aap.2014.35.3794
- Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999;103:779-788. https://doi.org/10.1172/JCI5909
- Hou F, Xiao K, Tang L, Xie L. Diversity of macrophages in lung homeostasis and diseases. Front Immunol 2021;12:753940.
- Roszer T. Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediators Inflamm 2015;2015:816460.
- Moreira AP, Hogaboam CM. Macrophages in allergic asthma: fine-tuning their pro- and antiinflammatory actions for disease resolution. J Interferon Cytokine Res 2011;31:485-491. https://doi.org/10.1089/jir.2011.0027
- Tang Z, Gao J, Wu J, Zeng G, Liao Y, Song Z, Liang X, Hu J, Hu Y, Liu M, et al. Human umbilical cord mesenchymal stromal cells attenuate pulmonary fibrosis via regulatory T cell through interaction with macrophage. Stem Cell Res Ther 2021;12:397.
- Fang SB, Zhang HY, Meng XC, Wang C, He BX, Peng YQ, Xu ZB, Fan XL, Wu ZJ, Wu ZC, et al. Small extracellular vesicles derived from human MSCs prevent allergic airway inflammation via immunomodulation on pulmonary macrophages. Cell Death Dis 2020;11:409.
- Murray LA, Chen Q, Kramer MS, Hesson DP, Argentieri RL, Peng X, Gulati M, Homer RJ, Russell T, van Rooijen N, et al. TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. Int J Biochem Cell Biol 2011;43:154-162. https://doi.org/10.1016/j.biocel.2010.10.013
- Nouno T, Okamoto M, Ohnishi K, Kaieda S, Tominaga M, Zaizen Y, Ichiki M, Momosaki S, Nakamura M, Fujimoto K, et al. Elevation of pulmonary CD163+ and CD204+ macrophages is associated with the clinical course of idiopathic pulmonary fibrosis patients. J Thorac Dis 2019;11:4005-4017. https://doi.org/10.21037/jtd.2019.09.03
- Willis GR, Fernandez-Gonzalez A, Anastas J, Vitali SH, Liu X, Ericsson M, Kwong A, Mitsialis SA, Kourembanas S. Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. Am J Respir Crit Care Med 2018;197:104-116. https://doi.org/10.1164/rccm.201705-0925OC
- Luo XY, Meng XJ, Cao DC, Wang W, Zhou K, Li L, Guo M, Wang P. Transplantation of bone marrow mesenchymal stromal cells attenuates liver fibrosis in mice by regulating macrophage subtypes. Stem Cell Res Ther 2019;10:16.
- Braza F, Dirou S, Forest V, Sauzeau V, Hassoun D, Chesne J, Cheminant-Muller MA, Sagan C, Magnan A, Lemarchand P. Mesenchymal stem cells induce suppressive macrophages through phagocytosis in a mouse model of asthma. Stem Cells 2016;34:1836-1845. https://doi.org/10.1002/stem.2344
- Song X, Xie S, Lu K, Wang C. Mesenchymal stem cells alleviate experimental asthma by inducing polarization of alveolar macrophages. Inflammation 2015;38:485-492. https://doi.org/10.1007/s10753-014-9954-6
- Abdelaziz MH, Abdelwahab SF, Wan J, Cai W, Huixuan W, Jianjun C, Kumar KD, Vasudevan A, Sadek A, Su Z, et al. Alternatively activated macrophages; a double-edged sword in allergic asthma. J Transl Med 2020;18:58.
- Yang J, Zhang L, Yu C, Yang XF, Wang H. Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res 2014;2:1.
- Misharin AV, Cuda CM, Saber R, Turner JD, Gierut AK, Haines GK 3rd, Berdnikovs S, Filer A, Clark AR, Buckley CD, et al. Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice. Cell Reports 2014;9:591-604. https://doi.org/10.1016/j.celrep.2014.09.032
- Clements M, Gershenovich M, Chaber C, Campos-Rivera J, Du P, Zhang M, Ledbetter S, Zuk A. Differential Ly6c expression after renal ischemia-reperfusion identifies unique macrophage populations. J Am Soc Nephrol 2016;27:159-170. https://doi.org/10.1681/ASN.2014111138
- Melino M, Gadd VL, Alexander KA, Beattie L, Lineburg KE, Martinez M, Teal B, Le Texier L, Irvine KM, Miller GC, et al. Spatiotemporal characterization of the cellular and molecular contributors to liver fibrosis in a murine hepatotoxic-injury model. Am J Pathol 2016;186:524-538. https://doi.org/10.1016/j.ajpath.2015.10.029
- Puchner A, Saferding V, Bonelli M, Mikami Y, Hofmann M, Brunner JS, Caldera M, Goncalves-Alves E, Binder NB, Fischer A, et al. Non-classical monocytes as mediators of tissue destruction in arthritis. Ann Rheum Dis 2018;77:1490-1497. https://doi.org/10.1136/annrheumdis-2018-213250
- Ko JH, Lee HJ, Jeong HJ, Kim MK, Wee WR, Yoon SO, Choi H, Prockop DJ, Oh JY. Mesenchymal stem/ stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye. Proc Natl Acad Sci U S A 2016;113:158-163. https://doi.org/10.1073/pnas.1522905113
- Zaslona Z, Przybranowski S, Wilke C, van Rooijen N, Teitz-Tennenbaum S, Osterholzer JJ, Wilkinson JE, Moore BB, Peters-Golden M. Resident alveolar macrophages suppress, whereas recruited monocytes promote, allergic lung inflammation in murine models of asthma. J Immunol 2014;193:4245-4253. https://doi.org/10.4049/jimmunol.1400580
- Yu X, Yu L, Guo B, Chen R, Qiu C. A narrative review of research advances in mesenchymal stem cell therapy for asthma. Ann Transl Med 2020;8:1461.
- Kim RL, Bang JY, Kim J, Mo Y, Kim Y, Lee CG, Elias JA, Kim HY, Kang HR. Mesenchymal stem cells exert their anti-asthmatic effects through macrophage modulation in a murine chronic asthma model. Sci Rep 2022;12:9811.
- 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;113:6576-6583. https://doi.org/10.1182/blood-2009-02-203943
- Habibian R, Delirezh N, Farshid AA. The effects of bone marrow-derived mesenchymal stem cells on ovalbumin-induced allergic asthma and cytokine responses in mice. Iran J Basic Med Sci 2018;21:483-488.
- Najar M, Merimi M, Faour WH, Lombard CA, Moussa Agha D, Ouhaddi Y, Sokal EM, Lagneaux L, Fahmi H. In vitro cellular and molecular interplay between human foreskin-derived mesenchymal stromal/stem cells and the Th17 cell pathway. Pharmaceutics 2021;13:1736.
- Obermajer N, Popp FC, Soeder Y, Haarer J, Geissler EK, Schlitt HJ, Dahlke MH. Conversion of Th17 into IL-17A(neg) regulatory T cells: a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell-supported minimized immunosuppressive therapy. J Immunol 2014;193:4988-4999. https://doi.org/10.4049/jimmunol.1401776
- Fang SB, Zhang HY, Wang C, He BX, Liu XQ, Meng XC, Peng YQ, Xu ZB, Fan XL, Wu ZJ, et al. Small extracellular vesicles derived from human mesenchymal stromal cells prevent group 2 innate lymphoid celldominant allergic airway inflammation through delivery of miR-146a-5p. J Extracell Vesicles 2020;9:1723260.
- van Hoeven V, Munneke JM, Cornelissen AS, Omar SZ, Spruit MJ, Kleijer M, Bernink JH, Blom B, Voermans C, Hazenberg MD. Mesenchymal stromal cells stimulate the proliferation and il-22 production of group 3 innate lymphoid cells. J Immunol 2018;201:1165-1173. https://doi.org/10.4049/jimmunol.1700901
- Negi N, Griffin MD. Effects of mesenchymal stromal cells on regulatory T cells: Current understanding and clinical relevance. Stem Cells 2020;38:596-605. https://doi.org/10.1002/stem.3151
- Hayashi T, Beck L, Rossetto C, Gong X, Takikawa O, Takabayashi K, Broide DH, Carson DA, Raz E. Inhibition of experimental asthma by indoleamine 2,3-dioxygenase. J Clin Invest 2004;114:270-279. https://doi.org/10.1172/JCI21275
- Hartert TV, Dworski RT, Mellen BG, Oates JA, Murray JJ, Sheller JR. Prostaglandin E(2) decreases allergenstimulated release of prostaglandin D(2) in airways of subjects with asthma. Am J Respir Crit Care Med 2000;162:637-640. https://doi.org/10.1164/ajrccm.162.2.9904038
- Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol 2014;32:252-260. https://doi.org/10.1038/nbt.2816
- Kavanagh H, Mahon BP. Allogeneic mesenchymal stem cells prevent allergic airway inflammation by inducing murine regulatory T cells. Allergy 2011;66:523-531. https://doi.org/10.1111/j.1398-9995.2010.02509.x