Conditioned medium from the bone marrow mesenchymal stem cells modulates immune response via signal transduction and activator of transcription 6 signaling pathway in an allergic rhinitis mouse model

Main Article Content

Wentao Zou
Pei Zou
Jiaxiong Zhang
Xiaojing Cai
Xueying Mao
Guangpeng Liu

Keywords

allergic rhinitis, bone marrow mesenchymal stem cells, conditioned medium, immune regulation, signal transduction and activator of transcription 6

Abstract

Background: Allergic rhinitis (AR) is a common immune disease of the nasal mucosa characterized with immunoglobulin E (IgE)-mediated allergic inflammation after exposure to allergens in susceptible population. Previous reports have demonstrated that the bone marrow mesenchymal stem cells (BMSCs) could reduce allergic inflammation. However, there is little knowledge about whether the culture supernatant of BMSCs (conditioned medium, CM) has similar anti- inflammatory potential in treating AR.


Objective: The study aimed to evaluate the immunoregulatory effects of conditioned medium derived from BMSCs (BMSC-CM) on allergic inflammation in an AR mouse model.


Material and Methods: The AR murine model was induced by repeated sensitization and challenges with ovalbumin (OVA). Subsequently the allergic symptoms of AR mice, cytokine levels, the histopathological features of the nasal mucosa and T helper 1 (Th1) : T helper 2 (Th2) cells ratio were evaluated.


Results: Treatment with BMSC-CM was found as effective as BMSCs in reducing allergic symptoms and inhibiting eosinophilic infiltration in the nasal mucosa. After BMSC-CM or BMSCs administration, the OVA-specific IgE and interleukin 4 levels in serum decreased and interferon gamma level increased compared with AR mice treated with uncultured fresh medium. Flow cytometry analysis revealed a decrease in Th1:Th2 cells ratio after OVA-sensitization and the ratio was reversed by BMSC-CM and BMSCs treatments. Furthermore, the data revealed that BMSC-CM suppressed the production of signal transduction and activator of transcription 6 (STAT6) at messenger RNA and protein levels in the nasal mucosa.


Conclusion: BMSC-CM could ameliorate allergic inflammation and regulate the balance of Th cells, and the underlying mechanism was closely related to STAT6 signaling pathway. The immunoregulatory effects of BMSCs could be achieved through paracrine function, and nasal dripping of BMSC-CM might be a novel approach for the treatment of AR.

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References

1. Wheatley LM, Togias A. Clinical practice. Allergic rhinitis. N Engl J Med. 2015;372(5):456–63. 10.1056/nejmcp044141

2. Kuperman DA, Schleimer RP. Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma. Curr Mol Med. 2016;8(5):384–92. 10.2174/156652408785161032

3. Kim SH, Hong JH, Lee JE, Lee YC. 18β-Glycyrrhetinic acid, the major bioactive component of glycyrrhizae radix, attenuates airway inflammation by modulating Th2 cytokines, GATA-3, STAT6, and Foxp3 transcription factors in an asthmatic mouse model. Environ Toxicol Pharmacol. 2017;52:99–113. 10.1016/j.etap.2017.03.011

4. Seumois G, Zapardiel-Gonzalo J, White B, Singh D, Schulten V, Vijayanand P, et al. Transcriptional profiling of Th2 cells identifies pathogenic features associated with asthma. J Immunol. 2016;197(2):655–64. 10.4049/jimmunol.1600397

5. Li Y, Rui X, Ma B, Jiang F, Chen J. Early-life environmental factors, IFN-γ methylation patterns, and childhood allergic rhinitis. Int Arch Allergy Immunol. 2019;178(4):323–32. 10.1159/000495304

6. Hng CH, Camp E, Anderson P, Breen J, Zannettino A, Gronthos S. HOPX regulates bone marrow-derived mesenchymal stromal cell fate determination via suppression of adipogenic gene pathways. Sci Rep. 2020;10(1):11345. 10.1038/s41598-020-68261-2

7. Luby AO, Ranganathan K, Lynn JV, Buchman SR, Donneys A, Buchman SR. Stem cells for bone regeneration: Current state and future directions. J Craniofac Surg. 2019;30(3):730–5. 10.1097/SCS.0000000000005250

8. Dai YY, Ni SY, Ma K, Ma YS, Wang ZS, Zhao XL. Stem cells from human exfoliated deciduous teeth correct the immune imbalance of allergic rhinitis via Treg cells in vivo and in vitro. Stem Cell Res Ther. 2019;10(1):39. 10.1186/s13287-019-1134-z

9. Cho KS, Park HK, Park HY, Roh HJ, Jung JS, Roh HJ, et al. IFATS collection: Immunomodulatory effects of adipose tissue-derived stem cells in an allergic rhinitis mouse model. Stem Cells. 2009;27(1):259–65. 10.1634/stemcells.2008-0283

10. Ebrahim N, Mandour Y, Farid AS, Nafie E, Mohamed AZ, Refae A, et al. Adipose tissue-derived mesenchymal stem cell modulates the immune response of allergic rhinitis in a rat model. Int J Mol Sci. 2019;20(4):873. 10.3390/ijms20040873

11. Zhao N, Liu Y, Liang H, Jiang X. Bone marrow-derived mesenchymal stem cells reduce immune reaction in a mouse model of allergic rhinitis. Am J Transl Res. 2016;8(12):5628–36. eCollection 2016

12. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: Immune evasive, not immune privileged. Nat Biotechnol. 2014;32(3):252–60. 10.1038/nbt.2816

13. Abreu SC, Weiss DJ, Rocco PR. Extracellular vesicles derived from mesenchymal stromal cells: A therapeutic option in respiratory diseases? Stem Cell Res Ther. 2016;7(1):53. 10.1186/s13287-016-0317-0

14. Heo JS, Choi Y, Kim HS, Kim HO. Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue. Int J Mol Med. 2016;37(1):115–25. 10.3892/ijmm.2015.2413

15. Gesundheit B, Ashwood P, Keating A, Naor D, Melamed M, Rosenzweig JP. Therapeutic properties of mesenchymal stem cells for autism spectrum disorders. Med Hypotheses. 2015;84(3):169–77. 10.1016/j.mehy.2014.12.016

16. Basu J, Ludlow JW. Exosomes for repair, regeneration and rejuvenation. Expert Opin Biol Ther. 2016;16(4):489–506. 10.1517/14712598.2016.1131976

17. Goolaerts A, Pellan-Randrianarison N, Larghero J, Vanneaux V, Uzunhan Y, Clerici C, et al. Conditioned media from mesenchymal stromal cells restore sodium transport and preserve epithelial permeability in an in vitro model of acute alveolar injury. Am J Physiol Lung Cell Mol Physiol. 2014;306(11):975–85. 10.1152/ajplung.00242.2013

18. Park IS, Kim JH, Bae JS, Kim DK, Mo JH. The supernatant of tonsil-derived mesenchymal stem cell has antiallergic effects in allergic rhinitis mouse model. Mediators Inflamm. 2020;2020:6982438. 10.1155/2020/6982438

19. Nagata M, Iwasaki K, Akazawa K, Komaki M, Yokoyama N, Morita I, et al. Conditioned medium from periodontal ligament stem cells enhances periodontal regeneration. Tissue Eng A. 2017;23(9–10):367–77. 10.1089/ten.tea.2016.0274

20. Menicanin D, Bartold PM, Zannettino AC, Gronthos S. Identification of a common gene expression signature associated with immature clonal mesenchymal cell populations derived from bone marrow and dental tissues. Stem Cells Dev. 2010;19(10):1501–10. 10.1089/scd.2009.0492

21. Yu HS, Park MK, Kang SA, Cho KS, Mun SJ, Roh HJ. Culture supernatant of adipose stem cells can ameliorate allergic airway inflammation via recruitment of CD4(+) CD25(+) Foxp3 T cells. Stem Cell Res Ther. 2017;8(1):8. 10.1186/s13287-016-0462-5

22. Hellings PW, Hessel EM, Van Den Oord JJ, Kasran A, Van Hecke P, Ceuppens JL. Eosinophilic rhinitis accompanies the development of lower airway inflammation and hyper-reactivity in sensitized mice exposed to aerosolized allergen. Clin Exp Allergy. 2001;31:782–90. 10.1046/j.1365-2222.2001.01081.x

23. Isik S, Karaman M, Adan A, Kiray M, Bagriyanik H, Uzuner N, et al. Intraperitoneal mesenchymal stem cell administration ameliorates allergic rhinitis in the murine model. Eur Arch Otorhinolaryngol. 2017;274(1):197–207. 10.1007/s00405-016-4166-3

24. Sobkowiak P, Narozna B, Wojsyk-Banaszak I, Breborowicz A, Szczepankiewicz A. Expression of proteins associated with airway fibrosis differs between children with allergic asthma and allergic rhinitis. Int J Immunopathol Pharmacol. 2021;35: 2058738421990493. 10.1177/2058738421990493

25. Zhao C, Yu S, Li J, Ge R, Xu W, Ge R. Changes in IL-4 and IL-13 expression in allergic-rhinitis treated with hydrogen-rich saline in guinea-pig model. Allergol Immunopathol (Madr). 2017;45(4):350–5. 10.1016/j.aller.2016.10.007

26. Cheng L, Chen J, Fu Q, He S, Li H, Liu Z, et al. Chinese society of allergy guidelines for diagnosis and treatment of allergic rhinitis. Allergy Asthma Immunol Res. 2018;10(4):300–53. 10.4168/aair.2018.10.4.300

27. Marinas-Pardo L, Mirones I, Amor-Carro O, Fraga-Iriso R, Lema-Costa B, Ramos-Barbon D, et al. Mesenchymal stem cells regulate airway contractile tissue remodeling in murine experimental asthma. Allergy. 2014;69(6):730–40. 10.1111/all.12392

28. Li C, Fu Y, Wang Y, Kong Y, Li M, Wang Y, et al. Mesenchymal stromal cells ameliorate acute allergic rhinitis in rat. Cell Biochem Funct. 2017;35(7):420–5. 10.1002/cbf.3291

29. Borg ZD, Goodwin M, Sokocevic D, Wagner DE, Weiss DJ, et al. 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. 2015;4(11):1302–16. 10.5966/sctm.2014-0280

30. Small P, Keith PK, Kim H. Allergic rhinitis. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):51. 10.1186/s13223-018-0280-7

31. Michaud B, Gouvis-Echraghi R, Candon S, Couderc R, Jais JP, Just J, et al. Quantification of circulating house dust mite-specific IL-4-and IL-13-secreting T cells correlates with rhinitis severity in asthmatic children and varies with the seasons. Clin Exp Allergy. 2014;44(2):222–30. 10.1111/cea.12222

32. Folci M, Ramponi G, Arcari I, Zumbo A, Brunetta E. Eosinophils as major player in type 2 inflammation: Autoimmunity and beyond. Adv Exp Med Biol. 2021;1347:197–219 10.1007/5584_2021_640

33. McCormick SM, Heller NM. Commentary: IL-4 and IL-13 receptors and signaling. Cytokine. 2015;75(1):38–50. 10.1016/j.cyto.2015.05.023

34. Howell MD, Fitzsimons C, Smith PA. JAK/STAT inhibitors and other small molecule cytokine antagonists for the treatment of allergic disease. Ann Allergy Asthma Immunol. 2018;120(4):367–75. 10.1016/j.anai.2018.02.012

35. Antczak A, Domańska-Senderowska D, Górski P, Pastuszak-Lewandoska D, Nielepkowicz-Gozdzinska A, Brzezianska-Lasota E, et al. Analysis of changes in expression of IL-4/IL-13/STAT6 pathway and correlation with the selected clinical parameters in patients with atopic asthma. Int J Immunopathol Pharmacol. 2016;29(2):195–204. 10.1177/0394632015623794

36. Börger V, Bremer M, Ferrer-Tur R, Gockeln L, Stambouli O, Giebel B, et al. Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents. Int J Mol Sci. 2017;18(7):1450. 10.3390/ijms18071450

37. Haddad R, Saldanha-Araujo F. Mechanisms of T-cell immuno-suppression by mesenchymal stromal cells: What do we know so far? Biomed Res Int. 2014;(2):216806. 10.1155/2014/216806

38. Yu QN, Guo YB, Li X, Li CL, Tan WP, Fu QL, et al. ILC2 frequency and activity are inhibited by glucocorticoid treatment via STAT pathway in patients with asthma. Allergy. 2018;73(9):1860–70. 10.1111/all.13438