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http://dx.doi.org/10.14348/molcells.2021.0101

Mesenchymal Stem Cells Suppress Severe Asthma by Directly Regulating Th2 Cells and Type 2 Innate Lymphoid Cells  

Shin, Jae Woo (Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine)
Ryu, Seungwon (Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine)
Ham, Jongho (Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine)
Jung, Keehoon (Department of Anatomy and Cell Biology, Seoul National University College of Medicine)
Lee, Sangho (Department of Biological Sciences, Sungkyunkwan University)
Chung, Doo Hyun (Department of Pathology, Seoul National University College of Medicine)
Kang, Hye-Ryun (Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center)
Kim, Hye Young (Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine)
Abstract
Patients with severe asthma have unmet clinical needs for effective and safe therapies. One possibility may be mesenchymal stem cell (MSC) therapy, which can improve asthma in murine models. However, it remains unclear how MSCs exert their beneficial effects in asthma. Here, we examined the effect of human umbilical cord blood-derived MSCs (hUC-MSC) on two mouse models of severe asthma, namely, Alternaria alternata-induced and house dust mite (HDM)/diesel exhaust particle (DEP)-induced asthma. hUC-MSC treatment attenuated lung type 2 (Th2 and type 2 innate lymphoid cell) inflammation in both models. However, these effects were only observed with particular treatment routes and timings. In vitro co-culture showed that hUC-MSC directly downregulated the interleukin (IL)-5 and IL-13 production of differentiated mouse Th2 cells and peripheral blood mononuclear cells from asthma patients. Thus, these results showed that hUC-MSC treatment can ameliorate asthma by suppressing the asthmogenic cytokine production of effector cells. However, the successful clinical application of MSCs in the future is likely to require careful optimization of the route, dosage, and timing.
Keywords
cell therapy; innate lymphoid cells; mesenchymal stem cells; severe asthma; Th2 cells;
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1 Zhang, L.B. and He, M. (2019). Effect of mesenchymal stromal (stem) cell (MSC) transplantation in asthmatic animal models: a systematic review and meta-analysis. Pulm. Pharmacol. Ther. 54, 39-52.   DOI
2 Backman, H., Jansson, S.A., Stridsman, C., Eriksson, B., Hedman, L., Eklund, B.M., Sandstrom, T., Lindberg, A., Lundback, B., and Ronmark, E. (2018). Severe asthma among adults: prevalence and clinical characteristics. Eur. Respir. J. 52(Suppl 62), PA3918.
3 Boldrini-Leite, L.M., Michelotto, P.V., Jr., de Moura, S.A.B., Capriglione, L.G.A., Barussi, F.C.M., Fragoso, F.Y.I., Senegaglia, A.C., and Brofman, P.R.S. (2020). Lung tissue damage associated with allergic asthma in BALB/c mice could be controlled with a single injection of mesenchymal stem cells from human bone marrow up to 14 d after transplantation. Cell Transplant. 29, 963689720913254.
4 Ministry of Food and Drug Safety (2014a). Considerations in Immunotoxicity Assessment of Allogenic Stem Cell Therapy Product (Cheongju: Ministry of Food and Drug Safety).
5 Ministry of Food and Drug Safety (2014b). Guideline in Quality, Non-clinical and Clinical Assessment of Stem Cell Therapy Product (Cheongju: Ministry of Food and Drug Safety).
6 Mirershadi, F., Ahmadi, M., Rezabakhsh, A., Rajabi, H., Rahbarghazi, R., and Keyhanmanesh, R. (2020). Unraveling the therapeutic effects of mesenchymal stem cells in asthma. Stem Cell Res. Ther. 11, 400.   DOI
7 Moll, G., Ankrum, J.A., Kamhieh-Milz, J., Bieback, K., Ringden, O., Volk, H.D., Geissler, S., and Reinke, P. (2019). Intravascular mesenchymal stromal/stem cell therapy product diversification: time for new clinical guidelines. Trends Mol. Med. 25, 149-163.   DOI
8 Munir, H. and McGettrick, H.M. (2015). Mesenchymal stem cell therapy for autoimmune disease: risks and rewards. Stem Cells Dev. 24, 2091-2100.   DOI
9 Acciani, T.H., Brandt, E.B., Khurana Hershey, G.K., and Le Cras, T.D. (2013). Diesel exhaust particle exposure increases severity of allergic asthma in young mice. Clin. Exp. Allergy 43, 1406-1418.   DOI
10 Fan, X.L., Zhang, Y., Li, X., and Fu, Q.L. (2020). Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell. Mol. Life Sci. 77, 2771-2794.   DOI
11 Jeong, E.M., Shin, J.W., Lim, J., Kim, J.H., Kang, H., Yin, Y., Kim, H.M., Kim, Y., Kim, S.G., Kang, H.S., et al. (2019). Monitoring glutathione dynamics and heterogeneity in living stem cells. Int. J. Stem Cells 12, 367-379.   DOI
12 GBD 2016 Disease and Injury Incidence and Prevalence Collaborators (2017). Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390, 1211-1259.   DOI
13 Goodwin, M., Sueblinvong, V., Eisenhauer, P., Ziats, N.P., LeClair, L., Poynter, M.E., Steele, C., Rincon, M., and Weiss, D.J. (2011). Bone marrowderived mesenchymal stromal cells inhibit Th2-mediated allergic airways inflammation in mice. Stem Cells 29, 1137-1148.   DOI
14 Hong, G.H., Kwon, H.S., Lee, K.Y., Ha, E.H., Moon, K.A., Kim, S.W., Oh, W., Kim, T.B., Moon, H.B., and Cho, Y.S. (2017). hMSCs suppress neutrophil-dominant airway inflammation in a murine model of asthma. Exp. Mol. Med. 49, e288.   DOI
15 Kavanagh, H. and Mahon, B.P. (2011). Allogeneic mesenchymal stem cells prevent allergic airway inflammation by inducing murine regulatory T cells. Allergy 66, 523-531.   DOI
16 Cruz, F.F., Borg, Z.D., Goodwin, M., Sokocevic, D., Wagner, D.E., Coffey, A., Antunes, M., Robinson, K.L., Mitsialis, S.A., Kourembanas, S., et al. (2015). Systemic administration of human bone marrow-derived mesenchymal stromal cell extracellular vesicles ameliorates Aspergillus hyphal extract-induced allergic airway inflammation in immunocompetent mice. Stem Cells Transl. Med. 4, 1302-1316.   DOI
17 Levy, O., Kuai, R., Siren, E.M.J., Bhere, D., Milton, Y., Nissar, N., De Biasio, M., Heinelt, M., Reeve, B., Abdi, R., et al. (2020). Shattering barriers toward clinically meaningful MSC therapies. Sci. Adv. 6, eaba6884.   DOI
18 Inamdar, A.C. and Inamdar, A.A. (2013). Mesenchymal stem cell therapy in lung disorders: pathogenesis of lung diseases and mechanism of action of mesenchymal stem cell. Exp. Lung Res. 39, 315-327.   DOI
19 Ryu, Y.J., Cho, T.J., Lee, D.S., Choi, J.Y., and Cho, J. (2013). Phenotypic characterization and in vivo localization of human adipose-derived mesenchymal stem cells. Mol. Cells 35, 557-564.   DOI
20 Castro, L.L., Kitoko, J.Z., Xisto, D.G., Olsen, P.C., Guedes, H.L.M., Morales, M.M., Lopes-Pacheco, M., Cruz, F.F., and Rocco, P.R.M. (2020). Multiple doses of adipose tissue-derived mesenchymal stromal cells induce immunosuppression in experimental asthma. Stem Cells Transl. Med. 9, 250-260.   DOI
21 Brandt, E.B., Biagini Myers, J.M., Acciani, T.H., Ryan, P.H., Sivaprasad, U., Ruff, B., LeMasters, G.K., Bernstein, D.I., Lockey, J.E., LeCras, T.D., et al. (2015). Exposure to allergen and diesel exhaust particles potentiates secondary allergen-specific memory responses, promoting asthma susceptibility. J. Allergy Clin. Immunol. 136, 295-303.e7.   DOI
22 Braza, F., Dirou, S., Forest, V., Sauzeau, V., Hassoun, D., Chesne, J., Cheminant-Muller, M.A., Sagan, C., Magnan, A., and Lemarchand, P. (2016). Mesenchymal stem cells induce suppressive macrophages through phagocytosis in a mouse model of asthma. Stem Cells 34, 1836-1845.   DOI
23 Cahill, E.F., Tobin, L.M., Carty, F., Mahon, B.P., and English, K. (2015). Jagged-1 is required for the expansion of CD4+ CD25+ FoxP3+ regulatory T cells and tolerogenic dendritic cells by murine mesenchymal stromal cells. Stem Cell Res. Ther. 6, 19.   DOI
24 Fallon, P.G. and Schwartz, C. (2020). The high and lows of type 2 asthma and mouse models. J. Allergy Clin. Immunol. 145, 496-498.   DOI
25 Chae, D., Han, S., Lee, M., and Kim, S. (2021). Genome edited Sirt1-overexpressing human mesenchymal stem cells exhibit therapeutic effects in treating collagen-induced arthritis. Mol. Cells 44, 245-253.   DOI
26 Court, A.C., Le-Gatt, A., Luz-Crawford, P., Parra, E., Aliaga-Tobar, V., Batiz, L.F., Contreras, R.A., Ortuzar, M.I., Kurte, M., Elizondo-Vega, R., et al. (2020). Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response. EMBO Rep. 21, e48052.
27 de Castro, L.L., Xisto, D.G., Kitoko, J.Z., Cruz, F.F., Olsen, P.C., Redondo, P.A.G., Ferreira, T.P.T., Weiss, D.J., Martins, M.A., Morales, M.M., et al. (2017). Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma. Stem Cell Res. Ther. 8, 151.   DOI
28 Nemeth, K., Keane-Myers, A., Brown, J.M., Metcalfe, D.D., Gorham, J.D., Bundoc, V.G., Hodges, M.G., Jelinek, I., Madala, S., Karpati, S., et al. (2010). Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma. Proc. Natl. Acad. Sci. U. S. A. 107, 5652-5657.   DOI
29 Partridge, M.R. (2007). Examining the unmet need in adults with severe asthma. Eur. Respir. Rev. 16, 67-72.   DOI
30 Regmi, S., Pathak, S., Kim, J.O., Yong, C.S., and Jeong, J.H. (2019). Mesenchymal stem cell therapy for the treatment of inflammatory diseases: challenges, opportunities, and future perspectives. Eur. J. Cell Biol. 98, 151041.   DOI
31 Ren, G., Zhao, X., Zhang, L., Zhang, J., L'Huillier, A., Ling, W., Roberts, A.I., Le, A.D., Shi, S., Shao, C., et al. (2010). Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J. Immunol. 184, 2321-2328.   DOI
32 Snelgrove, R.J., Gregory, L.G., Peiro, T., Akthar, S., Campbell, G.A., Walker, S.A., and Lloyd, C.M. (2014). Alternaria-derived serine protease activity drives IL-33-mediated asthma exacerbations. J. Allergy Clin. Immunol. 134, 583-592.e6.   DOI
33 Song, X., Xie, S., Lu, K., and Wang, C. (2015). Mesenchymal stem cells alleviate experimental asthma by inducing polarization of alveolar macrophages. Inflammation 38, 485-492.   DOI
34 Srour, N. and Thebaud, B. (2014). Stem cells in animal asthma models: a systematic review. Cytotherapy 16, 1629-1642.   DOI
35 Wang, G., Zhang, S., Wang, F., Li, G., Zhang, L., and Luan, X. (2013). Expression and biological function of programmed death ligands in human placenta mesenchymal stem cells. Cell Biol. Int. 37, 137-148.   DOI
36 Sun, Y.Q., Deng, M.X., He, J., Zeng, Q.X., Wen, W., Wong, D.S., Tse, H.F., Xu, G., Lian, Q., Shi, J., et al. (2012). Human pluripotent stem cell-derived mesenchymal stem cells prevent allergic airway inflammation in mice. Stem Cells 30, 2692-2699.   DOI
37 Zeng, S.L., Wang, L.H., Li, P., Wang, W., and Yang, J. (2015). Mesenchymal stem cells abrogate experimental asthma by altering dendritic cell function. Mol. Med. Rep. 12, 2511-2520.   DOI
38 Bonfield, T.L., Koloze, M., Lennon, D.P., Zuchowski, B., Yang, S.E., and Caplan, A.I. (2010). Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model. Am. J. Physiol. Lung Cell. Mol. Physiol. 299, L760-L770.   DOI
39 Lee, S.H., Jang, A.S., Kwon, J.H., Park, S.K., Won, J.H., and Park, C.S. (2011). Mesenchymal stem cell transfer suppresses airway remodeling in a toluene diisocyanate-induced murine asthma model. Allergy Asthma Immunol. Res. 3, 205-211.   DOI
40 Keating, A. (2012). Mesenchymal stromal cells: new directions. Cell Stem Cell 10, 709-716.   DOI
41 Kim, J., Ryu, S., and Kim, H.Y. (2021). Innate lymphoid cells in tissue homeostasis and disease pathogenesis. Mol. Cells 44, 301-309.   DOI
42 Khurana, S., Bush, A., and Holguin, F. (2020). Management of severe asthma: summary of the European Respiratory Society/American Thoracic Society task force report. Breathe (Sheff.) 16, 200058.   DOI
43 Kim, H.Y., DeKruyff, R.H., and Umetsu, D.T. (2010). The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat. Immunol. 11, 577-584.   DOI
44 Kim, H.Y., Umetsu, D.T., and Dekruyff, R.H. (2016). Innate lymphoid cells in asthma: will they take your breath away? Eur. J. Immunol. 46, 795-806.   DOI
45 Kim, Y.S., Kokturk, N., Kim, J.Y., Lee, S.W., Lim, J., Choi, S.J., Oh, W., and Oh, Y.M. (2016). Gene profiles in a smoke-induced COPD mouse lung model following treatment with mesenchymal stem cells. Mol. Cells 39, 728-733.   DOI
46 Kurtz, A. (2008). Mesenchymal stem cell delivery routes and fate. Int. J. Stem Cells 1, 1-7.   DOI
47 Lundback, B., Backman, H., Lotvall, J., and Ronmark, E. (2016). Is asthma prevalence still increasing? Expert Rev. Respir. Med. 10, 39-51.   DOI
48 Luz-Crawford, P., Hernandez, J., Djouad, F., Luque-Campos, N., Caicedo, A., Carrere-Kremer, S., Brondello, J.M., Vignais, M.L., Pene, J., and Jorgensen, C. (2019). Mesenchymal stem cell repression of Th17 cells is triggered by mitochondrial transfer. Stem Cell Res. Ther. 10, 232.   DOI
49 McCracken, J.L., Veeranki, S.P., Ameredes, B.T., and Calhoun, W.J. (2017). Diagnosis and management of asthma in adults: a review. JAMA 318, 279-290.   DOI