c-kit+ cells offer hopes in ameliorating asthmatic pathologies via regulation of miRNA-133 and -126

Document Type : Original Article

Authors

1 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

2 Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

3 Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

4 Solid Tumor Research Center, Research Institute for Cellular and Molecular Medicine, Urmia University of Medical Sciences, Urmia, Iran

5 Department of Physiology, Ardabil Branch, Islamic Azad University, Ardabil, Iran

6 Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

7 Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Science, Mashhad, Iran

8 Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran

9 Young Researchers and Elite Club, Tabriz Branch Islamic Azad university, Tabriz, Iran

Abstract

Objective(s): There are still challenges regarding c-kit+ cells’ therapeutic outcome in the clinical setting. Here, we examined the c-kit+ cell effect on the alleviation of asthma by modulating miRNAs expression.
Materials and Methods: To induce asthma, male rats were exposed to ovalbumin. Bone marrow-derived c-kit+ cells were enriched by MACS. Animals were classified into four groups (6 rats each). Control rats received PBS intratracheally; Ovalbumin-sensitized rats received PBS intratracheally; Ovalbumin-sensitized rats received PBS intratracheally containing 3×105 c-kit+ and c-kit- cells. Cells were stained with Dil fluorescent dye to track in vivo condition. Pathological changes were monitored in asthmatic rats after transplantation of c-kit+ and c-kit- cells. Serum levels of IL-4 and INF-γ were measured by ELISA. Transcription of miRNAs (-126 and 133) was assessed by real-time PCR analysis.
Results: Pathological examination and Th1 and Th2 associated cytokine fluctuation confirmed the occurrence of asthma in rats indicated by chronic changes and prominent inflammation compared with the control group (p <0.05). Both c-kit+ and c-kit- cells were verified in pulmonary niche. Administration of c-kit positive cells had the potential to change INF-γ/IL-4 ratio close to the normal values compared with matched-control asthmatic rats (p <0.05). We also found that c-kit+ cells regulated the expression of miRNA-126 and -133, indicated by an increase of miRNA-133 and decrease of miRNA-126 compared with cell-free sensitized groups (p <0.05).
Conclusion: c-kit- cells were unable to promote any therapeutic outcomes in the asthmatic milieu. c-kit+ cells had the potential to diminish asthma-related pathologies presumably by controlling the transcription of miRNA-126 and -133.

Keywords

References

1. To T, Stanojevic S, Moores G, Gershon AS, Bateman ED, Cruz AA, et al. Global asthma prevalence in adults: Findings from the cross-sectional world health survey. BMC Public Health 2012;12:204-211.
2. Ahmadi M, Rahbarghazi R, Shahbazfar A-A, Baghban H, Keyhanmanesh R. Bone marrow mesenchymal stem cells modified pathological changes and immunological responses in ovalbumin-induced asthmatic rats possibly by the modulation of miRNA155 and miRNA133. Gen Physiol and Biophys 2018;37:263-274.
3. Dong F, Wang C, Duan J, Zhang W, Xiang D, Li M. Puerarin attenuates ovalbumin-induced lung inflammation and hemostatic unbalance in rat asthma model. Evid Based Complement Alternat Med 2014;2014.
4. Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 2008;8:183-192.
5. Fan X-L, Zhang Z, Ma CY, Fu Q-L. Mesenchymal stem cells for inflammatory airway disorders: promises and challenges. Biosci Rep 2019;39: BSR20182160.
6. 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.
7. Dixit P, Katare R. Challenges in identifying the best source of stem cells for cardiac regeneration therapy. Stem Cell Res Ther 2015;6:1-12.
8. Ramachandran S, Suguihara C, Drummond S, Chatzistergos K, Klim J, Torres E, et al. Bone marrow-derived c-kit+ cells attenuate neonatal hyperoxia-induced lung injury. Cell Transplant 2015;24:85-95.
9. Rahbarghazi R, Keyhanmanesh R, Aslani MR, Hassanpour M, Ahmadi M. Bone marrow mesenchymal stem cells and condition media diminish inflammatory adhesion molecules of pulmonary endothelial cells in an ovalbumin-induced asthmatic rat model. Microvasc Res 2019;121:63-70.
10. Fazel S, Cimini M, Chen L, Li S, Angoulvant D, Fedak P, et al. Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J Clin Invest 2006;116:1865-1877.
11. Loffredo FS, Steinhauser ML, Gannon J, Lee RT. Bone marrow-derived cell therapy stimulates endogenous cardiomyocyte progenitors and promotes cardiac repair. Cell Stem Cell 2011;8:389-398.
12. Xu H, Sun Q, Lu L, Luo F, Zhou L, Liu J, et al. MicroRNA-218 acts by repressing TNFR1-mediated activation of NF-κB, which is involved in MUC5AC hyper-production and inflammation in smoking-induced bronchiolitis of COPD. Toxicol Lett 2017;280:171-180.
13. Yang G, Yang L, Wang W, Wang J, Wang J, Xu Z. Discovery and validation of extracellular/circulating microRNAs during idiopathic pulmonary fibrosis disease progression. Gene 2015;562:138-144.
14. Ahmadi M, Rahbarghazi R, Shahbazfar A-A. Monitoring IL-13 expression in relation to miRNA-155 and miRNA-133 changes following intra-tracheal administration of mesenchymal stem cells and conditioned media in ovalbuminsensitized rats. Thai J Vet Med 2018;48:347-355.
15. Li JJ, Tay HL, Maltby S, Xiang Y, Eyers F, Hatchwell L, et al. MicroRNA-9 regulates steroid-resistant airway hyperresponsiveness by reducing protein phosphatase 2A activity. J Allergy Clin Immunol 2015;136:462-473.
16. Kai W, Xu Q, Wu ZQ. MicroRNAs and asthma regulation. Iran J Allergy, Asthma and Immunol 2015;14:120-125.
17. Ahmadi M, Rahbarghazi R, Aslani MR, Shahbazfar AA, Kazemi M, Keyhanmanesh R. Bone marrow mesenchymal stem cells and their conditioned media could potentially ameliorate ovalbumin-induced asthmatic changes. Biomed Pharmacother 2017;85:28-40.
18. Khaksar M, Sayyari M, Rezaie J, Pouyafar A, Montazersaheb S, Rahbarghazi R. High glucose condition limited the angiogenic/cardiogenic capacity of murine cardiac progenitor cells in in vitro and in vivo milieu. Cell biochem Funct 2018;36:346-356.
19. Guo H-W, Yun C-X, Hou G-H, Du J, Huang X, Lu Y, et al. Mangiferin attenuates Th1/Th2 cytokine imbalance in an ovalbumin-induced asthmatic mouse model. PloS One 2014; 9:e100394.
20. Fernandez-Blanco J, Arike L, Ermund A, Fakih D, Rodriguez A, Abad B, et al. COPD lungs show an attached stratified mucus layer resembling the protective colonic mucus. BioRxiv. 2017:205948.
21. Chien KR, Frisén J, Fritsche-Danielson R, Melton DA, Murry CE, Weissman IL. Regenerating the field of cardiovascular cell therapy. Nat Biotechnol 2019;37:232-237.
22. Fransioli J, Bailey B, Gude NA, Cottage CT, Muraski JA, Emmanuel G, et al. Evolution of the c-kit-positive cell response to pathological challenge in the myocardium. Stem Cells 2008;26:1315-1324.
23. Vajravelu BN, Hong KU, Al-Maqtari T, Cao P, Keith MC, Wysoczynski M, et al. C-Kit promotes growth and migration of human cardiac progenitor cells via the PI3K-AKT and MEK-ERK pathways. PloS one 2015;10:e0140798.
24. Li C, Matsushita S, Li Z, Guan J, Amano A. C-kit positive cardiac outgrowth cells demonstrate better ability for cardiac recovery against ischemic myopathy. Stem Cell Res Ther 2017;7:402-417.
25. Czarna A, Sanada F, Matsuda A, Kim J, Signore S, Pereira JD, et al. Single-cell analysis of the fate of c-kit-positive bone marrow cells. NPJ Regen med 2017;2:27.
26. Spaziano G, Cappetta D, Urbanek K, Piegari E, Esposito G, Tartaglione G, et al. New role of adult lung c-kit+ cells in a mouse model of airway hyperresponsiveness.Mediators Inflamm 2016;3917471.
27. Keyhanmanesh R, Rahbarghazi R, Ahmadi M. Systemic transplantation of mesenchymal stem cells modulates endothelial cell adhesion molecules induced by ovalbumin in rat model of asthma. Inflammation 2018;41:2236-2245.
28. Agrawal DK, Shao Z. Pathogenesis of allergic airway inflammation. Curr Allergy Asthma Rep 2010;10:39-48.
29. Lee JK, Choi IS, Oh TI, Lee E. Cell-surface engineering for advanced cell therapy. Chemistry 2018;24:15725-15743.
30. Collison A, Herbert C, Siegle JS, Mattes J, Foster PS, Kumar RK. Altered expression of microRNA in the airway wall in chronic asthma: miR-126 as a potential therapeutic target. BMC Pulm Med 2011;11:29-39.
31. Chiba Y, Misawa M. MicroRNAs and their therapeutic potential for human diseases: MiR-133a and bronchial smooth muscle hyperresponsiveness in asthma. Pharmacol Sci 2010;114:264-268.
Iranian Journal of Basic Medical Sciences
Volume 24, Issue 3
March 2021
Pages 369-376

Files

Share

How to cite

Statistics