Secretome of adipose derived-mesenchymal stem cells reduces the Vibrio cholerae attachment to Caco-2 cells and subsequent inflammatory responses
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Abstract
Background and Objectives: Mesenchymal Stem Cells (MSCs) can repair gastrointestinal tract damage. The Secretome of MSCs has a high capacity to inhibit bacterial colonization and the subsequent inflammatory responses of Vibrio cholerae.
Materials and Methods: The Caco-2 cells were treated with adipose-derived MSCs (AD-MSCs) secretome and then infected with V. cholerae. Subsequently, the bacterial attachment and invasion, cholera toxin gene expression, PGE2 and IL-6 secretion, TNF-α, IL-1β, and IL-8 expression, and apoptosis of Caco-2 cells were evaluated.
Results: The secretome of AD-MSCs significantly reduced the V. cholerae attachment and internalization on Caco-2 epithelial cells (P<0.0001). The cholera toxin (Ctx-B) gene expression (FR=4.56 ± 0.66) and PGE2 production (P=0.0007) were also significantly reduced. The production of NO and TNF-α, IL-1β, and IL-8 pro-inflammatory cytokines were significantly (P<0.05) reduced in exposure to the secretome of AD-MSCs. Secretome also improved a significant 81.33% increase in IL-6 production (128.1 ± 37.6 pg/mL) and showed a 12.36% significant decrease in epithelial cell apoptosis (P< 0.0001) after exposure to V. cholerae.
Conclusion: The secretome of AD-MSCs can play a critical role in inhibiting bacterial colonization, and subsequent inflammatory responses, and maintaining the integrity of the epithelial barrier. The secretome may be effective in the prevention of hypovolemic shock.
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8. Moulazadeh A, Soudi S, Bakhshi B. Immunomodulatory effects of adipose-derived mesenchymal stem cells on epithelial cells function in response to Vibrio cholera in a co-culture model. Iran J Allergy Asthma Immunol 2021; 20: 550-562.
9. Lozito TP, Jackson WM, Nesti LJ, Tuan RS. Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs. Matrix Biol 2014; 34: 132-143.
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13. Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal stem cells for regenerative medicine. Cells 2019; 8: 886.
14. Liu H, Li R, Liu T, Yang L, Yin G, Xie Q. Immunomodulatory effects of mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles in rheumatoid arthritis. Front Immunol 2020; 11: 1912.
15. Casado-Díaz A, Quesada-Gómez JM, Dorado G. Extracellular vesicles derived from mesenchymal stem cells (MSC) in regenerative medicine: applications in skin wound healing. Front Bioeng Biotechnol 2020; 8: 146.
16. Hazrati A, Soudi S, Hashemi SM. Wharton's Jelly mesenchymal stem cells-derived exosomes and imipenem in combination reduce apoptosis and inflammatory Responses in E. coli-infected HepG2 cells. Iran J Allergy Asthma Immunol 2022; 21: 273-286.
17. Chenari A, Hazrati A, Hosseini AZ, Motiee M, Soudi S. The effect of mesenchymal stem cell-derived supernatant nasal administration on lung inflammation and immune response in BCG-vaccinated BALB/c mice. Life Sci 2023; 317: 121465.
18. Rezazadeh A, Soleimanjahi H, Soudi S, Habibian A. Comparison of the effect of adipose mesenchymal stem cells-derived secretome with and without reovirus in CT26 cells. Arch Razi Inst 2022; 77: 615-622.
19. Shirjang S, Mansoori B, Solali S, Hagh MF, Shamsasenjan K. Toll-like receptors as a key regulator of mesenchymal stem cell function: An up-to-date review. Cell Immunol 2017; 315: 1-10.
20. Khosrojerdi A, Soudi S, Hosseini AZ, Eshghi F, Shafiee A, Hashemi SM. Immunomodulatory and therapeutic effects of mesenchymal stem cells on organ dysfunction in sepsis. Shock 2021; 55: 423-440.
21. Bahroudi M, Bakhshi B, Soudi S, Najar-Peerayeh S. Antibacterial and antibiofilm activity of bone marrow-derived human mesenchymal stem cells secretome against Vibrio cholerae. Microb Pathog 2020; 139: 103867.
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23. Alamdary SZ, Bakhshi B. Lactobacillus acidophilus attenuates toxin production by Vibrio cholerae and shigella dysenteriae following intestinal epithelial cells infection. Microb Pathog 2020; 149: 104543.
24. Hsiao A, Zhu J. Pathogenicity and virulence regulation of Vibrio cholerae at the interface of host-gut microbiome interactions. Virulence 2020; 11: 1582-1599.
25. Ghasemi M, Bakhshi B, Khashei R, Soudi S. Modulatory effect of Vibrio cholerae toxin co-regulated pilus on mucins, toll-like receptors and NOD genes expression in co-culture model of Caco-2 and peripheral blood mononuclear cells (PBMC). Microb Pathog 2020; 149: 104566.
26. Nuidate T, Tansila N, Chomchuen P, Phattaranit P, Eangchuan S, Vuddhakul V. Characterization of tryptophanase from Vibrio cholerae. Appl Biochem Biotechnol 2015; 175: 243-252.
27. Mueller RS, Beyhan S, Saini SG, Yildiz FH, Bartlett DH. Indole acts as an extracellular cue regulating gene expression in Vibrio cholerae. J Bacteriol 2009; 191: 3504-3516.
28. Lozito TP, Tuan RS. Mesenchymal stem cells inhibit both endogenous and exogenous MMPs via secreted TIMPs. J Cell Physiol 2011; 226: 385-396.
29. Benitez JA, Silva AJ. Vibrio cholerae hemagglutinin(HA)/protease: An extracellular metalloprotease with multiple pathogenic activities. Toxicon 2016; 115: 55-62.
30. Miyoshi S. Extracellular proteolytic enzymes produced by human pathogenic vibrio species. Front Microbiol 2013; 4: 339.
31. Lee JW, Krasnodembskaya A, McKenna DH, Song Y, Abbott J, Matthay MA. Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. Am J Respir Crit Care Med 2013; 187: 751-760.
32. Yuan Y, Lin S, Guo N, Zhao C, Shen S, Bu X, et al. Marrow mesenchymal stromal cells reduce methicillin-resistant Staphylococcus aureus infection in rat models. Cytotherapy 2014; 16: 56-63.
33. Eshghi F, Tahmasebi S, Alimohammadi M, Soudi S, Khaligh SG, Khosrojerdi A, et al. Study of immunomodulatory effects of mesenchymal stem cell-derived exosomes in a mouse model of LPS induced systemic inflammation. Life Sci 2022; 310: 120938.
34. Khosrojerdi A, Soudi S, Hosseini AZ, Khaligh SG, Hashemi SM. The combination of mesenchymal stem cell- and hepatocyte-derived exosomes, along with imipenem, ameliorates inflammatory responses and liver damage in a sepsis mouse model. Life Sci 2023; 326: 121813.
35. Moulazadeh A, Farjadfar A, Ghanbariasad A. The unspecific primers of nuclear factor-kappa B (NF-κB) signaling mediators. Iran J Allergy Asthma Immunol 2022; 21: 228-231.
36. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 2013; 13: 392-402.
37. Kuhn KA, Schulz HM, Regner EH, Severs EL, Hendrickson JD, Mehta G, et al. Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity. Mucosal Immunol 2018; 11: 357-368.
38. Kuhn KA, Manieri NA, Liu T-C, Stappenbeck TS. IL-6 stimulates intestinal epithelial proliferation and repair after injury. PLoS One 2014; 9(12): e114195.
39. Castells M, Milhas D, Gandy C, Thibault B, Rafii A, Delord JP, et al. Microenvironment mesenchymal cells protect ovarian cancer cell lines from apoptosis by inhibiting XIAP inactivation. Cell Death Dis 2013; 4(10): e887.
40. Watanabe S, Arimura Y, Nagaishi K, Isshiki H, Onodera K, Nasuno M, et al. Conditioned mesenchymal stem cells produce pleiotropic gut trophic factors. J Gastroenterol 2014; 49: 270-282.
2. Weil AA, Becker RL, Harris JB. Vibrio cholerae at the intersection of immunity and the microbiome. mSphere 2019; 4(6): e00597-19.
3. Yang JS, Jeon JH, Jang MS, Kang SS, Ahn KB, Song M, et al. Vibrio cholerae OmpU induces IL-8 expression in human intestinal epithelial cells. Mol Immunol 2018; 93: 47-54.
4. Al-Sadi R, Ye D, Boivin M, Guo S, Hashimi M, Ereifej L, et al. Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene. PLoS One 2014; 9(3): e85345.
5. Thiagarajah JR, Donowitz M, Verkman AS. Secretory diarrhoea: mechanisms and emerging therapies. Nat Rev Gastroenterol Hepatol 2015; 12: 446-457.
6. Shen Y, Zhou M, Yan J, Gong Z, Xiao Y, Zhang C, et al. miR-200b inhibits TNF-α-induced IL-8 secretion and tight junction disruption of intestinal epithelial cells in vitro. Am J Physiol Gastrointest Liver Physiol 2017; 312: G123-G132.
7. Kim C-K, Yang VW, Bialkowska AB. The role of intestinal stem cells in epithelial regeneration following radiation-induced gut injury. Curr Stem Cell Rep 2017; 3: 320-332.
8. Moulazadeh A, Soudi S, Bakhshi B. Immunomodulatory effects of adipose-derived mesenchymal stem cells on epithelial cells function in response to Vibrio cholera in a co-culture model. Iran J Allergy Asthma Immunol 2021; 20: 550-562.
9. Lozito TP, Jackson WM, Nesti LJ, Tuan RS. Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs. Matrix Biol 2014; 34: 132-143.
10. Dameshghi S, Zavaran-Hosseini A, Soudi S, Shirazi FJ, Nojehdehi S, Hashemi SM. Mesenchymal stem cells alter macrophage immune responses to Leishmania major infection in both susceptible and resistance mice. Immunol Lett 2016; 170: 15-26.
11. Jiang F, Bi R, Deng L, Kang H, Gu B, Ma P. Virulence-associated genes and molecular characteristics of non-O1/non-O139 Vibrio cholerae isolated from hepatitis B cirrhosis patients in China. Int J Infect Dis 2018; 74: 117-122.
12. Alamdary SZ, Bakhshi B, Soudi S. The anti-apoptotic and anti-inflammatory effect of Lactobacillus acidophilus on Shigella sonnei and Vibrio cholerae interaction with intestinal epithelial cells: A comparison between invasive and non-invasive bacteria. PLoS One 2018; 13(6): e0196941.
13. Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal stem cells for regenerative medicine. Cells 2019; 8: 886.
14. Liu H, Li R, Liu T, Yang L, Yin G, Xie Q. Immunomodulatory effects of mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles in rheumatoid arthritis. Front Immunol 2020; 11: 1912.
15. Casado-Díaz A, Quesada-Gómez JM, Dorado G. Extracellular vesicles derived from mesenchymal stem cells (MSC) in regenerative medicine: applications in skin wound healing. Front Bioeng Biotechnol 2020; 8: 146.
16. Hazrati A, Soudi S, Hashemi SM. Wharton's Jelly mesenchymal stem cells-derived exosomes and imipenem in combination reduce apoptosis and inflammatory Responses in E. coli-infected HepG2 cells. Iran J Allergy Asthma Immunol 2022; 21: 273-286.
17. Chenari A, Hazrati A, Hosseini AZ, Motiee M, Soudi S. The effect of mesenchymal stem cell-derived supernatant nasal administration on lung inflammation and immune response in BCG-vaccinated BALB/c mice. Life Sci 2023; 317: 121465.
18. Rezazadeh A, Soleimanjahi H, Soudi S, Habibian A. Comparison of the effect of adipose mesenchymal stem cells-derived secretome with and without reovirus in CT26 cells. Arch Razi Inst 2022; 77: 615-622.
19. Shirjang S, Mansoori B, Solali S, Hagh MF, Shamsasenjan K. Toll-like receptors as a key regulator of mesenchymal stem cell function: An up-to-date review. Cell Immunol 2017; 315: 1-10.
20. Khosrojerdi A, Soudi S, Hosseini AZ, Eshghi F, Shafiee A, Hashemi SM. Immunomodulatory and therapeutic effects of mesenchymal stem cells on organ dysfunction in sepsis. Shock 2021; 55: 423-440.
21. Bahroudi M, Bakhshi B, Soudi S, Najar-Peerayeh S. Antibacterial and antibiofilm activity of bone marrow-derived human mesenchymal stem cells secretome against Vibrio cholerae. Microb Pathog 2020; 139: 103867.
22. Bahroudi M, Bakhshi B, Soudi S, Najar-Peerayeh S. Immunomodulatory effects of mesenchymal stem cell-conditioned media on lipopolysaccharide of Vibrio cholerae as a vaccine candidate. Stem Cell Res Ther 2021; 12: 564.
23. Alamdary SZ, Bakhshi B. Lactobacillus acidophilus attenuates toxin production by Vibrio cholerae and shigella dysenteriae following intestinal epithelial cells infection. Microb Pathog 2020; 149: 104543.
24. Hsiao A, Zhu J. Pathogenicity and virulence regulation of Vibrio cholerae at the interface of host-gut microbiome interactions. Virulence 2020; 11: 1582-1599.
25. Ghasemi M, Bakhshi B, Khashei R, Soudi S. Modulatory effect of Vibrio cholerae toxin co-regulated pilus on mucins, toll-like receptors and NOD genes expression in co-culture model of Caco-2 and peripheral blood mononuclear cells (PBMC). Microb Pathog 2020; 149: 104566.
26. Nuidate T, Tansila N, Chomchuen P, Phattaranit P, Eangchuan S, Vuddhakul V. Characterization of tryptophanase from Vibrio cholerae. Appl Biochem Biotechnol 2015; 175: 243-252.
27. Mueller RS, Beyhan S, Saini SG, Yildiz FH, Bartlett DH. Indole acts as an extracellular cue regulating gene expression in Vibrio cholerae. J Bacteriol 2009; 191: 3504-3516.
28. Lozito TP, Tuan RS. Mesenchymal stem cells inhibit both endogenous and exogenous MMPs via secreted TIMPs. J Cell Physiol 2011; 226: 385-396.
29. Benitez JA, Silva AJ. Vibrio cholerae hemagglutinin(HA)/protease: An extracellular metalloprotease with multiple pathogenic activities. Toxicon 2016; 115: 55-62.
30. Miyoshi S. Extracellular proteolytic enzymes produced by human pathogenic vibrio species. Front Microbiol 2013; 4: 339.
31. Lee JW, Krasnodembskaya A, McKenna DH, Song Y, Abbott J, Matthay MA. Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. Am J Respir Crit Care Med 2013; 187: 751-760.
32. Yuan Y, Lin S, Guo N, Zhao C, Shen S, Bu X, et al. Marrow mesenchymal stromal cells reduce methicillin-resistant Staphylococcus aureus infection in rat models. Cytotherapy 2014; 16: 56-63.
33. Eshghi F, Tahmasebi S, Alimohammadi M, Soudi S, Khaligh SG, Khosrojerdi A, et al. Study of immunomodulatory effects of mesenchymal stem cell-derived exosomes in a mouse model of LPS induced systemic inflammation. Life Sci 2022; 310: 120938.
34. Khosrojerdi A, Soudi S, Hosseini AZ, Khaligh SG, Hashemi SM. The combination of mesenchymal stem cell- and hepatocyte-derived exosomes, along with imipenem, ameliorates inflammatory responses and liver damage in a sepsis mouse model. Life Sci 2023; 326: 121813.
35. Moulazadeh A, Farjadfar A, Ghanbariasad A. The unspecific primers of nuclear factor-kappa B (NF-κB) signaling mediators. Iran J Allergy Asthma Immunol 2022; 21: 228-231.
36. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 2013; 13: 392-402.
37. Kuhn KA, Schulz HM, Regner EH, Severs EL, Hendrickson JD, Mehta G, et al. Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity. Mucosal Immunol 2018; 11: 357-368.
38. Kuhn KA, Manieri NA, Liu T-C, Stappenbeck TS. IL-6 stimulates intestinal epithelial proliferation and repair after injury. PLoS One 2014; 9(12): e114195.
39. Castells M, Milhas D, Gandy C, Thibault B, Rafii A, Delord JP, et al. Microenvironment mesenchymal cells protect ovarian cancer cell lines from apoptosis by inhibiting XIAP inactivation. Cell Death Dis 2013; 4(10): e887.
40. Watanabe S, Arimura Y, Nagaishi K, Isshiki H, Onodera K, Nasuno M, et al. Conditioned mesenchymal stem cells produce pleiotropic gut trophic factors. J Gastroenterol 2014; 49: 270-282.
| Files | ||
| Issue | Vol 16 No 1 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijm.v16i1.14875 | |
| Keywords | ||
| Inflammation; Apoptosis; Epithelium; Mesenchymal stem cell; Vibrio cholerae | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Moulazade A, Soudi S, Bakhshi B. Secretome of adipose derived-mesenchymal stem cells reduces the Vibrio cholerae attachment to Caco-2 cells and subsequent inflammatory responses. Iran J Microbiol. 2024;16(1):79-89.
