Exploring the Impact of Leishmania Major on Mesenchymal Stem Cells: Evaluating Differentiation, and Immunomodulatory Function
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Abstract
Pathogen recognition receptors (PRRs), which play a crucial role in responding to pathogens, affect the function of mesenchymal stem cells (MSCs). One important group of PRRs is the toll-like receptors (TLRs). When PRRs are activated, they can alter the expression of specific surface markers, the ability of MSCs to differentiate, and the types of substances they secrete. These modifications in MSC function may have unexpected consequences for patients. In this study, we examined how Leishmania major (L. major) promastigotes affect the properties of MSCs.
MSCs were isolated from adipose tissue and categorized into two groups: one group left untreated and the other group exposed to L. major. Giemsa staining was employed to accurately quantify the number of parasites that entered the cells. After 72 hours, real-time polymerase chain reaction was utilized to assess the expression of TLRs. Additionally, the flow cytometry technique was used to evaluate the expression of surface markers on the MSCs.
Our results showed that MSCs can engulf parasites and increase the expression of TLR4 and TLR6. The pro-inflammatory cytokine increased, and the transforming growth factor-β decreased significantly. The parasite exposure increased reactive oxygen species production. Additionally, the percentage of cluster differentiation (CD) 73 decreased, and the mean fluorescent index of CD29 and CD73 was down-regulated by L. major.
Exposure to parasites diminishes the immunomodulatory capacity of MSCs. This discovery holds significance for the application of MSCs in addressing parasite infections and underscores the need for additional research to enhance their therapeutic effectiveness.
1. 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(4):423-40.
2. Ikebe C, Suzuki K. Mesenchymal stem cells for regenerative therapy: optimization of cell preparation protocols. BioMed research international. 2014;2014.
3. Wang S, Qu X, Zhao RC. Clinical applications of mesenchymal stem cells. Journal of hematology & oncology. 2012;5(1):1-9.
4. Cruz FF, Rocco PRM. The potential of mesenchymal stem cell therapy for chronic lung disease. Expert Review of Respiratory Medicine. 2020;14(1):31-9.
5. Golpanian S, Wolf A, Hatzistergos KE, Hare JM. Rebuilding the damaged heart: mesenchymal stem cells, cell-based therapy, and engineered heart tissue. Physiological reviews. 2016;96(3):1127-68.
6. Oryan A, Alemzadeh E, Alemzadeh E, Barghi M, Zarei M, Salehiniya H. Effectiveness of the adipose stem cells in burn wound healing: literature review. Cell and Tissue Banking. 2021:1-12.
7. 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 Sciences. 2022;310:120938.
8. 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 Sciences. 2023:121813.
9. Sharma A, Chakraborty A, Jaganathan BG. Review of the potential of mesenchymal stem cells for the treatment of infectious diseases. World Journal of Stem Cells. 2021;13(6):568.
10. Luz-Crawford P, Djouad F, Toupet K, Bony C, Franquesa M, Hoogduijn MJ, et al. Mesenchymal stem cell-derived interleukin 1 receptor antagonist promotes macrophage polarization and inhibits B cell differentiation. Stem Cells. 2016;34(2):483-92.
11. Liu W, Gao Y, Li H, Wang H, Ye M, Jiang G, et al. Intravenous transplantation of mesenchymal stromal cells has therapeutic effects in a sepsis mouse model through inhibition of septic natural killer cells. The International Journal of Biochemistry & Cell Biology. 2016;79:93-103.
12. Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee J-W, et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem cells. 2010;28(12):2229-38.
13. WHO. Leishmaniasis: World Health Organization; 2022 [updated 1.8.2022. Available from: www.who.int/news-room/fact-sheets/detail/leishmaniasis#:~:text=Cutaneous%20leishmaniasis%20(CL)%20is%20the,Middle%20East%20and%20Central%20Asia.
14. Ebrahimzadeh A, Karamian M, Abedi F, Hanafi-Bojd MY, Ghatee MA, Hemmati M, et al. Topically applied luteolin/quercetin-capped silver nanoparticle ointment as antileishmanial composite: Acceleration wound healing in BALB/c mice. Advances in Materials Science and Engineering. 2023;2023:1-11.
15. Khosrowpour Z, Hashemi SM, Mohammadi‐Yeganeh S, Soudi S. Pretreatment of Mesenchymal Stem Cells With Leishmania major Soluble Antigens Induce Anti‐Inflammatory Properties in Mouse Peritoneal Macrophages. Journal of Cellular Biochemistry. 2017;118(9):2764-79.
16. Bahrami S, Safari M, Jalali MHR, Ghorbanpoor M, Tabandeh MR, Rezaie A. The potential therapeutic effect of adipose-derived mesenchymal stem cells in the treatment of cutaneous leishmaniasis caused by L. major in BALB/c mice. Experimental Parasitology. 2021;222:108063.
17. Gomez-Salazar M, Gonzalez-Galofre ZN, Casamitjana J, Crisan M, James AW, Péault B. Five decades later, are mesenchymal stem cells still relevant? Frontiers in bioengineering and biotechnology. 2020:148.
18. Melief SM, Geutskens SB, Fibbe WE, Roelofs H. Multipotent stromal cells skew monocytes towards an anti-inflammatory function: the link with key immunoregulatory molecules. Haematologica. 2013;98(9):e121.
19. Li Y-P, Paczesny S, Lauret E, Poirault S, Bordigoni P, Mekhloufi F, et al. Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway. The Journal of Immunology. 2008;180(3):1598-608.
20. Lee DK, Song SU. Immunomodulatory mechanisms of mesenchymal stem cells and their therapeutic applications. Cellular immunology. 2018;326:68-76.
21. Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nature immunology. 2014;15(11):1009-16.
22. Xu C, Yu P, Han X, Du L, Gan J, Wang Y, et al. TGF-β promotes immune responses in the presence of mesenchymal stem cells. The Journal of Immunology. 2014;192(1):103-9.
23. Saparov A, Ogay V, Nurgozhin T, Jumabay M, Chen WC. Preconditioning of human mesenchymal stem cells to enhance their regulation of the immune response. Stem cells international. 2016;2016.
24. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PloS one. 2010;5(4):e10088.
25. Zhao X, Liu D, Gong W, Zhao G, Liu L, Yang L, et al. The toll-like receptor 3 ligand, poly (I: C), improves immunosuppressive function and therapeutic effect of mesenchymal stem cells on sepsis via inhibiting MiR-143. Stem cells. 2014;32(2):521-33.
26. Costela Ruiz VJ, Melguizo Rodríguez L, Illescas Montes R, García Recio E, Arias Santiago S, Ruiz C, et al. Human adipose tissue–derived mesenchymal stromal cells and their phagocytic capacity. Journal of Cellular and Molecular Medicine. 2022;26(1):178-85.
27. Lopes CS, Daifalla N, Das B, Dias da Silva V, Campos-Neto A. CD271+ mesenchymal stem cells as a possible infectious niche for leishmania infantum. PLoS One. 2016;11(9):e0162927.
28. Allahverdiyev AM, Bagirova M, Elcicek S, Koc RC, Baydar SY, Findikli N, et al. Adipose tissue-derived mesenchymal stem cells as a new host cell in latent leishmaniasis. The American journal of tropical medicine and hygiene. 2011;85(3):535.
29. Monguió-Tortajada M, Roura S, Gálvez-Montón C, Franquesa M, Bayes-Genis A, Borràs FE. Mesenchymal stem cells induce expression of CD73 in human monocytes in vitro and in a swine model of myocardial infarction in vivo. Frontiers in Immunology. 2017;8:1577.
30. Ode A, Kopf J, Kurtz A, Schmidt-Bleek K, Schrade P, Kolar P, et al. CD73 and CD29 concurrently mediate the mechanically induced decrease of migratory capacity of mesenchymal stromal cells. European Cells and Materials. 2011;22:26-42.
31. Pevsner-Fischer M, Morad V, Cohen-Sfady M, Rousso-Noori L, Zanin-Zhorov A, Cohen S, et al. Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood. 2007;109(4):1422-32.
32. Raicevic G, Rouas R, Najar M, Stordeur P, Boufker HI, Bron D, et al. Inflammation modifies the pattern and the function of Toll-like receptors expressed by human mesenchymal stromal cells. Human immunology. 2010;71(3):235-44.
33. Faria MS, Reis FC, Azevedo-Pereira RL, Morrison LS, Mottram JC, Lima APC. Leishmania inhibitor of serine peptidase 2 prevents TLR4 activation by neutrophil elastase promoting parasite survival in murine macrophages. The Journal of Immunology. 2011;186(1):411-22.
34. Karmakar S, Bhaumik SK, Paul J, De T. TLR4 and NKT cell synergy in immunotherapy against visceral leishmaniasis. PLoS pathogens. 2012;8(4):e1002646.
35. Faria MS, Calegari-Silva TC, de Carvalho Vivarini A, Mottram JC, Lopes UG, Lima APC. Role of protein kinase R in the killing of Leishmania major by macrophages in response to neutrophil elastase and TLR4 via TNFα and IFNβ. The FASEB Journal. 2014;28(7):3050.
36. Pandey SP, Chandel HS, Srivastava S, Selvaraj S, Jha MK, Shukla D, et al. Pegylated bisacycloxypropylcysteine, a diacylated lipopeptide ligand of TLR6, plays a host-protective role against experimental Leishmania major infection. The Journal of Immunology. 2014;193(7):3632-43.
37. Soni B, Saha B, Singh S. Systems cues governing IL6 signaling in leishmaniasis. Cytokine. 2018;106:169-75.
38. Zanganeh E, Soudi S, Zavaran Hosseini A. Intralesional Injection of Mouse Mesenchymal Stem Cells Reduces IL-10 Production and Parasite Burden in L. major Infected BALB/c Mice. Cell J. 2020;22(Suppl 1):11-8.
39. Hamoon Navard S, Rezvan H, Feiz Haddad MH, Baghaban Eslaminejad M, Azami S. Expression of cytokine genes in Leishmania major-infected BALB/c mice treated with mesenchymal stem cells. Journal of Medical Microbiology and Infectious Diseases. 2020;8(1):7-13.
40. Reverte M, Snäkä T, Fasel N. The dangerous liaisons in the oxidative stress response to leishmania infection. Pathogens. 2022;11(4):409.
41. Formaglio P, Alabdullah M, Siokis A, Handschuh J, Sauerland I, Fu Y, et al. Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells. Immunity. 2021;54(12):2724-39. e10.
42. Thakur RS, Tousif S, Awasthi V, Sanyal A, Atul P, Punia P, et al. Mesenchymal stem cells play an important role in host protective immune responses against malaria by modulating regulatory T cells. European journal of immunology. 2013;43(8):2070-7.
43. Li W, Ren G, Huang Y, Su J, Han Y, Li J, et al. Mesenchymal stem cells: a double-edged sword in regulating immune responses. Cell Death & Differentiation. 2012;19(9):1505-13.
2. Ikebe C, Suzuki K. Mesenchymal stem cells for regenerative therapy: optimization of cell preparation protocols. BioMed research international. 2014;2014.
3. Wang S, Qu X, Zhao RC. Clinical applications of mesenchymal stem cells. Journal of hematology & oncology. 2012;5(1):1-9.
4. Cruz FF, Rocco PRM. The potential of mesenchymal stem cell therapy for chronic lung disease. Expert Review of Respiratory Medicine. 2020;14(1):31-9.
5. Golpanian S, Wolf A, Hatzistergos KE, Hare JM. Rebuilding the damaged heart: mesenchymal stem cells, cell-based therapy, and engineered heart tissue. Physiological reviews. 2016;96(3):1127-68.
6. Oryan A, Alemzadeh E, Alemzadeh E, Barghi M, Zarei M, Salehiniya H. Effectiveness of the adipose stem cells in burn wound healing: literature review. Cell and Tissue Banking. 2021:1-12.
7. 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 Sciences. 2022;310:120938.
8. 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 Sciences. 2023:121813.
9. Sharma A, Chakraborty A, Jaganathan BG. Review of the potential of mesenchymal stem cells for the treatment of infectious diseases. World Journal of Stem Cells. 2021;13(6):568.
10. Luz-Crawford P, Djouad F, Toupet K, Bony C, Franquesa M, Hoogduijn MJ, et al. Mesenchymal stem cell-derived interleukin 1 receptor antagonist promotes macrophage polarization and inhibits B cell differentiation. Stem Cells. 2016;34(2):483-92.
11. Liu W, Gao Y, Li H, Wang H, Ye M, Jiang G, et al. Intravenous transplantation of mesenchymal stromal cells has therapeutic effects in a sepsis mouse model through inhibition of septic natural killer cells. The International Journal of Biochemistry & Cell Biology. 2016;79:93-103.
12. Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee J-W, et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem cells. 2010;28(12):2229-38.
13. WHO. Leishmaniasis: World Health Organization; 2022 [updated 1.8.2022. Available from: www.who.int/news-room/fact-sheets/detail/leishmaniasis#:~:text=Cutaneous%20leishmaniasis%20(CL)%20is%20the,Middle%20East%20and%20Central%20Asia.
14. Ebrahimzadeh A, Karamian M, Abedi F, Hanafi-Bojd MY, Ghatee MA, Hemmati M, et al. Topically applied luteolin/quercetin-capped silver nanoparticle ointment as antileishmanial composite: Acceleration wound healing in BALB/c mice. Advances in Materials Science and Engineering. 2023;2023:1-11.
15. Khosrowpour Z, Hashemi SM, Mohammadi‐Yeganeh S, Soudi S. Pretreatment of Mesenchymal Stem Cells With Leishmania major Soluble Antigens Induce Anti‐Inflammatory Properties in Mouse Peritoneal Macrophages. Journal of Cellular Biochemistry. 2017;118(9):2764-79.
16. Bahrami S, Safari M, Jalali MHR, Ghorbanpoor M, Tabandeh MR, Rezaie A. The potential therapeutic effect of adipose-derived mesenchymal stem cells in the treatment of cutaneous leishmaniasis caused by L. major in BALB/c mice. Experimental Parasitology. 2021;222:108063.
17. Gomez-Salazar M, Gonzalez-Galofre ZN, Casamitjana J, Crisan M, James AW, Péault B. Five decades later, are mesenchymal stem cells still relevant? Frontiers in bioengineering and biotechnology. 2020:148.
18. Melief SM, Geutskens SB, Fibbe WE, Roelofs H. Multipotent stromal cells skew monocytes towards an anti-inflammatory function: the link with key immunoregulatory molecules. Haematologica. 2013;98(9):e121.
19. Li Y-P, Paczesny S, Lauret E, Poirault S, Bordigoni P, Mekhloufi F, et al. Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway. The Journal of Immunology. 2008;180(3):1598-608.
20. Lee DK, Song SU. Immunomodulatory mechanisms of mesenchymal stem cells and their therapeutic applications. Cellular immunology. 2018;326:68-76.
21. Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nature immunology. 2014;15(11):1009-16.
22. Xu C, Yu P, Han X, Du L, Gan J, Wang Y, et al. TGF-β promotes immune responses in the presence of mesenchymal stem cells. The Journal of Immunology. 2014;192(1):103-9.
23. Saparov A, Ogay V, Nurgozhin T, Jumabay M, Chen WC. Preconditioning of human mesenchymal stem cells to enhance their regulation of the immune response. Stem cells international. 2016;2016.
24. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PloS one. 2010;5(4):e10088.
25. Zhao X, Liu D, Gong W, Zhao G, Liu L, Yang L, et al. The toll-like receptor 3 ligand, poly (I: C), improves immunosuppressive function and therapeutic effect of mesenchymal stem cells on sepsis via inhibiting MiR-143. Stem cells. 2014;32(2):521-33.
26. Costela Ruiz VJ, Melguizo Rodríguez L, Illescas Montes R, García Recio E, Arias Santiago S, Ruiz C, et al. Human adipose tissue–derived mesenchymal stromal cells and their phagocytic capacity. Journal of Cellular and Molecular Medicine. 2022;26(1):178-85.
27. Lopes CS, Daifalla N, Das B, Dias da Silva V, Campos-Neto A. CD271+ mesenchymal stem cells as a possible infectious niche for leishmania infantum. PLoS One. 2016;11(9):e0162927.
28. Allahverdiyev AM, Bagirova M, Elcicek S, Koc RC, Baydar SY, Findikli N, et al. Adipose tissue-derived mesenchymal stem cells as a new host cell in latent leishmaniasis. The American journal of tropical medicine and hygiene. 2011;85(3):535.
29. Monguió-Tortajada M, Roura S, Gálvez-Montón C, Franquesa M, Bayes-Genis A, Borràs FE. Mesenchymal stem cells induce expression of CD73 in human monocytes in vitro and in a swine model of myocardial infarction in vivo. Frontiers in Immunology. 2017;8:1577.
30. Ode A, Kopf J, Kurtz A, Schmidt-Bleek K, Schrade P, Kolar P, et al. CD73 and CD29 concurrently mediate the mechanically induced decrease of migratory capacity of mesenchymal stromal cells. European Cells and Materials. 2011;22:26-42.
31. Pevsner-Fischer M, Morad V, Cohen-Sfady M, Rousso-Noori L, Zanin-Zhorov A, Cohen S, et al. Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood. 2007;109(4):1422-32.
32. Raicevic G, Rouas R, Najar M, Stordeur P, Boufker HI, Bron D, et al. Inflammation modifies the pattern and the function of Toll-like receptors expressed by human mesenchymal stromal cells. Human immunology. 2010;71(3):235-44.
33. Faria MS, Reis FC, Azevedo-Pereira RL, Morrison LS, Mottram JC, Lima APC. Leishmania inhibitor of serine peptidase 2 prevents TLR4 activation by neutrophil elastase promoting parasite survival in murine macrophages. The Journal of Immunology. 2011;186(1):411-22.
34. Karmakar S, Bhaumik SK, Paul J, De T. TLR4 and NKT cell synergy in immunotherapy against visceral leishmaniasis. PLoS pathogens. 2012;8(4):e1002646.
35. Faria MS, Calegari-Silva TC, de Carvalho Vivarini A, Mottram JC, Lopes UG, Lima APC. Role of protein kinase R in the killing of Leishmania major by macrophages in response to neutrophil elastase and TLR4 via TNFα and IFNβ. The FASEB Journal. 2014;28(7):3050.
36. Pandey SP, Chandel HS, Srivastava S, Selvaraj S, Jha MK, Shukla D, et al. Pegylated bisacycloxypropylcysteine, a diacylated lipopeptide ligand of TLR6, plays a host-protective role against experimental Leishmania major infection. The Journal of Immunology. 2014;193(7):3632-43.
37. Soni B, Saha B, Singh S. Systems cues governing IL6 signaling in leishmaniasis. Cytokine. 2018;106:169-75.
38. Zanganeh E, Soudi S, Zavaran Hosseini A. Intralesional Injection of Mouse Mesenchymal Stem Cells Reduces IL-10 Production and Parasite Burden in L. major Infected BALB/c Mice. Cell J. 2020;22(Suppl 1):11-8.
39. Hamoon Navard S, Rezvan H, Feiz Haddad MH, Baghaban Eslaminejad M, Azami S. Expression of cytokine genes in Leishmania major-infected BALB/c mice treated with mesenchymal stem cells. Journal of Medical Microbiology and Infectious Diseases. 2020;8(1):7-13.
40. Reverte M, Snäkä T, Fasel N. The dangerous liaisons in the oxidative stress response to leishmania infection. Pathogens. 2022;11(4):409.
41. Formaglio P, Alabdullah M, Siokis A, Handschuh J, Sauerland I, Fu Y, et al. Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells. Immunity. 2021;54(12):2724-39. e10.
42. Thakur RS, Tousif S, Awasthi V, Sanyal A, Atul P, Punia P, et al. Mesenchymal stem cells play an important role in host protective immune responses against malaria by modulating regulatory T cells. European journal of immunology. 2013;43(8):2070-7.
43. Li W, Ren G, Huang Y, Su J, Han Y, Li J, et al. Mesenchymal stem cells: a double-edged sword in regulating immune responses. Cell Death & Differentiation. 2012;19(9):1505-13.
| Files | ||
| Issue | Vol 22 No 6 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v22i6.14647 | |
| Keywords | ||
| Cytokine Leishmania major Mesenchymal stem cells Oxidative stress | ||
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How to Cite
1.
Mashayekh E, Khosrojerdi A, Zavaran Hosseini A, Soudi S. Exploring the Impact of Leishmania Major on Mesenchymal Stem Cells: Evaluating Differentiation, and Immunomodulatory Function. Iran J Allergy Asthma Immunol. 2023;22(6):588-599.
