Wharton's Jelly Mesenchymal Stem Cells-derived Exosomes and Imipenem in Combination Reduce Apoptosis and Inflammatory Responses in E.coli-infected HepG2 Cells
Abstract
Antibiotics are used to treat bacterial liver infections and the resulting inflammation. However, their use is limited due to their side effects, especially the development of antibiotic resistance.
Mesenchymal stem cells (MSCs) are recognized for their immunomodulatory properties. In this study, we investigated the immunomodulatory effect of Wharton's jelly MSC-derived exosomes in combination with imipenem on HepG2 cells infected with Escherichia col
i.MSC-derived exosomes were separated from MSCs, which were isolated by flow cytometry. Scanning electron microscopy and dynamic light scanning were used to confirm the presence of exosomes. Quantitative real-time PCR, ELISA, and nitric oxide assay were used to assess the inflammatory response in the infected cells. Annexin-PI was used to measure the extent of apoptosis.
The results showed that the combination of imipenem and MSC-derived exosomes were more effective than imipenem or exosomes alone in reducing the production and secretion of inflammatory cytokines, nitric oxide, and apoptotic rate in E Coli-infected HepG2 cells.
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2. Kimura T, Flynn CT, Whitton JL. Hepatocytes engulf and rapidly silence coxsackievirus, protecting the host against systemic viral pathology. Am Assoc Immnol; 2020.
3. Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology 2012;143:1158-72.
4. Zhou Z, Xu M-J, Gao B. Hepatocytes: a key cell type for innate immunity. Cellular & molecular immunology 2016;13:301-15.
5. Mabuchi A, Mullaney I, Sheard PW, Hessian PA, Mallard BL, Tawadrous MN, et al. Role of hepatic stellate cell/hepatocyte interaction and activation of hepatic stellate cells in the early phase of liver regeneration in the rat. Journal of hepatology 2004;40:910-6.
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7. 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;55:423-40.
8. Li Y, Mölter A, White A, Welfare W, Palin V, Belmonte M, et al. Relationship between prescribing of antibiotics
and other medicines in primary care: a cross-sectional
study. British Journal of General Practice 2019;69:e42-e51.
9. Piraghaj MG, Soudi S, Ghanbarian H, Bolandi Z, Namaki S, Hashemi SM. Effect of efferocytosis of apoptotic mesenchymal stem cells (MSCs) on C57BL/6 peritoneal macrophages function. Life sciences 2018;212:203-12.
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11. Xu S-j, Ye L-p, Wang W, Chen Y-h, Dong J, Mao X-l, et al. Role of the Microenvironment in Mesenchymal Stem Cell-Based Strategies for Treating Human Liver Diseases. Stem Cells International 2021;2021.
12. Turturici G, Tinnirello R, Sconzo G, Geraci F. Extracellular membrane vesicles as a mechanism of cell-to-cell communication: advantages and disadvantages. American Journal of Physiology-Cell Physiology 2014;306:C621-C33.
13. Hazrati A, Soudi S, Malekpour K, Mahmoudi M, Rahimi A, Hashemi SM, et al. Immune cells-derived exosomes function as a double-edged sword: role in disease progression and their therapeutic applications. Biomarker Research 2022;10:1-25.
14. Lai CP-K, Breakefield XO. Role of exosomes/ microvesicles in the nervous system and use in emerging therapies. Frontiers in physiology 2012;3:228.
15. Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cellular and Molecular Life Sciences 2018;75:193-208.
16. Khan I, Zhang L, Mohammed M, Archer FE, Abukharmah J, Yuan Z, et al. Effects of Wharton’s jelly-derived mesenchymal stem cells on neonatal neutrophils. Journal of Inflammation Research 2015;8:1.
17. Sperandio V, Nguyen Y. Enterohemorrhagic E. coli (EHEC) pathogenesis. Frontiers in cellular and infection microbiology 2012;2:90.
18. Deng M, Scott MJ, Loughran P, Gibson G, Sodhi C, Watkins S, et al. Lipopolysaccharide clearance, bacterial clearance, and systemic inflammatory responses are regulated by cell type–specific functions of TLR4 during Sepsis. The Journal of Immunology 2013;190:5152-60.
19. Yu J, Zhu C, Wang X, Kim K, Bartolome A, Dongiovanni P, et al. Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis. Science Translational Medicine 2021;13.
20. Yang X, Meng Y, Han Z, Ye F, Wei L, Zong C. Mesenchymal stem cell therapy for liver disease: full of chances and challenges. Cell & Bioscience 2020;10:1-18.
21. Yan J, Li S, Li S. The role of the liver in sepsis. International reviews of immunology 2014;33:498-510.
22. Woźnica EA, Inglot M, Woźnica RK, Łysenko L. Liver dysfunction in sepsis. Advances in clinical and experimental medicine: official organ Wroclaw Medical University 2018;27:547-51.
23. Parvez MK, Niyazi S. Bacterial Infection of Liver: A Bird’s Eye View. Journal of Gastroenterology and Hepatology Research 2016;5:2112-4.
24. Slayton RB, Toth D, Lee BY, Tanner W, Bartsch SM, Khader K, et al. Vital signs: estimated effects of a coordinated approach for action to reduce antibiotic-resistant infections in health care facilities—United States. MMWR Morbidity and mortality weekly report 2015;64:826.
25. Hauser WE, Remington JS. Effect of antibiotics on the immune response. The Journal of Urology 1982;128:1414.
26. Gillissen G. Side effects of antibiotics on immune response parameters and their possible implications in antimicrobial chemotherapy. Zentralblatt für Bakteriologie, Mikrobiologie und Hygiene Series A: Medical Microbiology, Infectious Diseases, Virology, Parasitology 1988;270:171-99.
27. Lee SM, Lee SD, Wang SZ, Sarkar D, Lee HM, Khan A, et al. Effect of mesenchymal stem cell in liver regeneration and clinical applications. Hepatoma Research 2021;7:53.
28. Petrenko Y, Vackova I, Kekulova K, Chudickova M, Koci Z, Turnovcova K, et al. A comparative analysis of multipotent mesenchymal stromal cells derived from different sources, with a focus on neuroregenerative potential. Scientific reports 2020;10:1-15.
29. Deuse T, Stubbendorff M, Tang-Quan K, Phillips N, Kay MA, Eiermann T, et al. Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell transplantation 2011;20:655-67.
30. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell stem cell 2008;2:141-50.
31. Kode JA, Mukherjee S, Joglekar MV, Hardikar AA. Mesenchymal stem cells: immunobiology and role in immunomodulation and tissue regeneration. Cytotherapy 2009;11:377-91.
32. Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T, et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 2007;109:228-34.
33. Wang J, Cen P, Chen J, Fan L, Li J, Cao H, et al. Role of mesenchymal stem cells, their derived factors, and extracellular vesicles in liver failure. Stem cell research & therapy 2017;8:1-6.
34. Kaspi H, Semo J, Abramov N, Dekel C, Lindborg S, Kern R, et al. MSC-NTF (NurOwn®) exosomes: a novel therapeutic modality in the mouse LPS-induced ARDS model. Stem Cell Research & Therapy 2021;12:1-10.
35. Khatri M, Richardson LA, Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model. Stem cell research & therapy 2018;9:1-13.
36. Kawaratani H, Tsujimoto T, Douhara A, Takaya H, Moriya K, Namisaki T, et al. The effect of inflammatory cytokines in alcoholic liver disease. Mediators of inflammation 2013;2013.
37. Gao F, Chiu S, Motan D, Zhang Z, Chen L, Ji H, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell death & disease 2016;7:e2062.
38. Gotoh T, Mori M. Nitric oxide and endoplasmic reticulum stress. Arteriosclerosis, thrombosis, and vascular biology 2006;26:1439-46.
39. Bruckdorfer R. The basics about nitric oxide. Molecular aspects of medicine 2005;26:3-31.
40. Burgner D, Rockett K, Kwiatkowski D. Nitric oxide and infectious diseases. Archives of disease in childhood 1999;81:185-8.
41. Phinney DG, Pittenger MF. Concise review: MSC‐derived exosomes for cell‐free therapy. Stem cells 2017;35:851-8.
2. Kimura T, Flynn CT, Whitton JL. Hepatocytes engulf and rapidly silence coxsackievirus, protecting the host against systemic viral pathology. Am Assoc Immnol; 2020.
3. Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology 2012;143:1158-72.
4. Zhou Z, Xu M-J, Gao B. Hepatocytes: a key cell type for innate immunity. Cellular & molecular immunology 2016;13:301-15.
5. Mabuchi A, Mullaney I, Sheard PW, Hessian PA, Mallard BL, Tawadrous MN, et al. Role of hepatic stellate cell/hepatocyte interaction and activation of hepatic stellate cells in the early phase of liver regeneration in the rat. Journal of hepatology 2004;40:910-6.
6. Hazrati A, Malekpour K, Soudi S, Hashemi SM. Mesenchymal Stromal/Stem Cells and Their Extracellular Vesicles Application in Acute and Chronic Inflammatory Liver Diseases: Emphasizing on the Anti-Fibrotic and Immunomodulatory Mechanisms. Frontiers in Immunology 2022;13:865888.
7. 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;55:423-40.
8. Li Y, Mölter A, White A, Welfare W, Palin V, Belmonte M, et al. Relationship between prescribing of antibiotics
and other medicines in primary care: a cross-sectional
study. British Journal of General Practice 2019;69:e42-e51.
9. Piraghaj MG, Soudi S, Ghanbarian H, Bolandi Z, Namaki S, Hashemi SM. Effect of efferocytosis of apoptotic mesenchymal stem cells (MSCs) on C57BL/6 peritoneal macrophages function. Life sciences 2018;212:203-12.
10. Lee C, Kim M, Han J, Yoon M, Jung Y. Mesenchymal Stem Cells Influence Activation of Hepatic Stellate Cells, and Constitute a Promising Therapy for Liver Fibrosis. Biomedicines 2021;9:1598.
11. Xu S-j, Ye L-p, Wang W, Chen Y-h, Dong J, Mao X-l, et al. Role of the Microenvironment in Mesenchymal Stem Cell-Based Strategies for Treating Human Liver Diseases. Stem Cells International 2021;2021.
12. Turturici G, Tinnirello R, Sconzo G, Geraci F. Extracellular membrane vesicles as a mechanism of cell-to-cell communication: advantages and disadvantages. American Journal of Physiology-Cell Physiology 2014;306:C621-C33.
13. Hazrati A, Soudi S, Malekpour K, Mahmoudi M, Rahimi A, Hashemi SM, et al. Immune cells-derived exosomes function as a double-edged sword: role in disease progression and their therapeutic applications. Biomarker Research 2022;10:1-25.
14. Lai CP-K, Breakefield XO. Role of exosomes/ microvesicles in the nervous system and use in emerging therapies. Frontiers in physiology 2012;3:228.
15. Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cellular and Molecular Life Sciences 2018;75:193-208.
16. Khan I, Zhang L, Mohammed M, Archer FE, Abukharmah J, Yuan Z, et al. Effects of Wharton’s jelly-derived mesenchymal stem cells on neonatal neutrophils. Journal of Inflammation Research 2015;8:1.
17. Sperandio V, Nguyen Y. Enterohemorrhagic E. coli (EHEC) pathogenesis. Frontiers in cellular and infection microbiology 2012;2:90.
18. Deng M, Scott MJ, Loughran P, Gibson G, Sodhi C, Watkins S, et al. Lipopolysaccharide clearance, bacterial clearance, and systemic inflammatory responses are regulated by cell type–specific functions of TLR4 during Sepsis. The Journal of Immunology 2013;190:5152-60.
19. Yu J, Zhu C, Wang X, Kim K, Bartolome A, Dongiovanni P, et al. Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis. Science Translational Medicine 2021;13.
20. Yang X, Meng Y, Han Z, Ye F, Wei L, Zong C. Mesenchymal stem cell therapy for liver disease: full of chances and challenges. Cell & Bioscience 2020;10:1-18.
21. Yan J, Li S, Li S. The role of the liver in sepsis. International reviews of immunology 2014;33:498-510.
22. Woźnica EA, Inglot M, Woźnica RK, Łysenko L. Liver dysfunction in sepsis. Advances in clinical and experimental medicine: official organ Wroclaw Medical University 2018;27:547-51.
23. Parvez MK, Niyazi S. Bacterial Infection of Liver: A Bird’s Eye View. Journal of Gastroenterology and Hepatology Research 2016;5:2112-4.
24. Slayton RB, Toth D, Lee BY, Tanner W, Bartsch SM, Khader K, et al. Vital signs: estimated effects of a coordinated approach for action to reduce antibiotic-resistant infections in health care facilities—United States. MMWR Morbidity and mortality weekly report 2015;64:826.
25. Hauser WE, Remington JS. Effect of antibiotics on the immune response. The Journal of Urology 1982;128:1414.
26. Gillissen G. Side effects of antibiotics on immune response parameters and their possible implications in antimicrobial chemotherapy. Zentralblatt für Bakteriologie, Mikrobiologie und Hygiene Series A: Medical Microbiology, Infectious Diseases, Virology, Parasitology 1988;270:171-99.
27. Lee SM, Lee SD, Wang SZ, Sarkar D, Lee HM, Khan A, et al. Effect of mesenchymal stem cell in liver regeneration and clinical applications. Hepatoma Research 2021;7:53.
28. Petrenko Y, Vackova I, Kekulova K, Chudickova M, Koci Z, Turnovcova K, et al. A comparative analysis of multipotent mesenchymal stromal cells derived from different sources, with a focus on neuroregenerative potential. Scientific reports 2020;10:1-15.
29. Deuse T, Stubbendorff M, Tang-Quan K, Phillips N, Kay MA, Eiermann T, et al. Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell transplantation 2011;20:655-67.
30. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell stem cell 2008;2:141-50.
31. Kode JA, Mukherjee S, Joglekar MV, Hardikar AA. Mesenchymal stem cells: immunobiology and role in immunomodulation and tissue regeneration. Cytotherapy 2009;11:377-91.
32. Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T, et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 2007;109:228-34.
33. Wang J, Cen P, Chen J, Fan L, Li J, Cao H, et al. Role of mesenchymal stem cells, their derived factors, and extracellular vesicles in liver failure. Stem cell research & therapy 2017;8:1-6.
34. Kaspi H, Semo J, Abramov N, Dekel C, Lindborg S, Kern R, et al. MSC-NTF (NurOwn®) exosomes: a novel therapeutic modality in the mouse LPS-induced ARDS model. Stem Cell Research & Therapy 2021;12:1-10.
35. Khatri M, Richardson LA, Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model. Stem cell research & therapy 2018;9:1-13.
36. Kawaratani H, Tsujimoto T, Douhara A, Takaya H, Moriya K, Namisaki T, et al. The effect of inflammatory cytokines in alcoholic liver disease. Mediators of inflammation 2013;2013.
37. Gao F, Chiu S, Motan D, Zhang Z, Chen L, Ji H, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell death & disease 2016;7:e2062.
38. Gotoh T, Mori M. Nitric oxide and endoplasmic reticulum stress. Arteriosclerosis, thrombosis, and vascular biology 2006;26:1439-46.
39. Bruckdorfer R. The basics about nitric oxide. Molecular aspects of medicine 2005;26:3-31.
40. Burgner D, Rockett K, Kwiatkowski D. Nitric oxide and infectious diseases. Archives of disease in childhood 1999;81:185-8.
41. Phinney DG, Pittenger MF. Concise review: MSC‐derived exosomes for cell‐free therapy. Stem cells 2017;35:851-8.
| Files | ||
| Issue | Vol 21 No 3 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i3.9801 | |
| Keywords | ||
| Escherichia coli Exosomes Immunomodulation InflammationInflammation Mesenchymal stem cells | ||
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How to Cite
1.
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(3):273-286.
