LinkedIn

 آمار

تعداد نشریات20
تعداد شماره‌ها1,174
تعداد مقالات10,723
تعداد مشاهده مقاله67,059,254
تعداد دریافت فایل اصل مقاله12,407,463
Moayedfard, Zahra, Lankarani, Kamran, Alizadeh, Ali Akbar, Nekooeian, Ali Akbar, Dara, Mahintaj, Koohpeyma, Farhad, Parsa, Shima, Nikeghbalian, Saman, Hosseinpouri, Arghavan, Azarpira, Negar. (1403). The Ameliorative Effect of Adipose-Derived Mesenchymal Stem Cells and Their Exosomes in Non-alcoholic Steatohepatitis by Simultaneously Enhancing Autophagic Flux and Suppressing Endoplasmic Reticulum Stress. سامانه مدیریت نشریات علمی, (), -. doi: 10.30476/ijms.2024.103376.3660
Zahra Moayedfard; Kamran Bagheri Lankarani; Ali Akbar Alizadeh; Ali Akbar Nekooeian; Mahintaj Dara; Farhad Koohpeyma; Shima Parsa; Saman Nikeghbalian; Arghavan Hosseinpouri; Negar Azarpira. "The Ameliorative Effect of Adipose-Derived Mesenchymal Stem Cells and Their Exosomes in Non-alcoholic Steatohepatitis by Simultaneously Enhancing Autophagic Flux and Suppressing Endoplasmic Reticulum Stress". سامانه مدیریت نشریات علمی, , , 1403, -. doi: 10.30476/ijms.2024.103376.3660
Moayedfard, Zahra, Lankarani, Kamran, Alizadeh, Ali Akbar, Nekooeian, Ali Akbar, Dara, Mahintaj, Koohpeyma, Farhad, Parsa, Shima, Nikeghbalian, Saman, Hosseinpouri, Arghavan, Azarpira, Negar. (1403). 'The Ameliorative Effect of Adipose-Derived Mesenchymal Stem Cells and Their Exosomes in Non-alcoholic Steatohepatitis by Simultaneously Enhancing Autophagic Flux and Suppressing Endoplasmic Reticulum Stress', سامانه مدیریت نشریات علمی, (), pp. -. doi: 10.30476/ijms.2024.103376.3660
Moayedfard, Zahra, Lankarani, Kamran, Alizadeh, Ali Akbar, Nekooeian, Ali Akbar, Dara, Mahintaj, Koohpeyma, Farhad, Parsa, Shima, Nikeghbalian, Saman, Hosseinpouri, Arghavan, Azarpira, Negar. The Ameliorative Effect of Adipose-Derived Mesenchymal Stem Cells and Their Exosomes in Non-alcoholic Steatohepatitis by Simultaneously Enhancing Autophagic Flux and Suppressing Endoplasmic Reticulum Stress. سامانه مدیریت نشریات علمی, 1403; (): -. doi: 10.30476/ijms.2024.103376.3660

The Ameliorative Effect of Adipose-Derived Mesenchymal Stem Cells and Their Exosomes in Non-alcoholic Steatohepatitis by Simultaneously Enhancing Autophagic Flux and Suppressing Endoplasmic Reticulum Stress

Iranian Journal of Medical Sciences
مقالات آماده انتشار، اصلاح شده برای چاپ، انتشار آنلاین از تاریخ 19 اسفند 1403    اصل مقاله (3.83 M)
نوع مقاله: Original Article(s)
شناسه دیجیتال (DOI): 10.30476/ijms.2024.103376.3660
نویسندگان
Zahra Moayedfard1، 2؛ Kamran Bagheri Lankarani3؛ Ali Akbar Alizadeh2؛ Ali Akbar Nekooeian4؛ Mahintaj Dara5؛ Farhad Koohpeyma1، 6؛ Shima Parsa7؛ Saman Nikeghbalian8؛ Arghavan Hosseinpouri1، 2؛ Negar Azarpira* 7
1Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
2Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
3Health Policy Research Center (HPRC), Shiraz University of Medical Sciences, Shiraz, Iran.
4Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
5Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
6Endocrine and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
7Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
8Abu Ali Sina Hospital for Medicine and Organ Transplant, Shiraz University of Medical Sciences, Shiraz, Iran
چکیده
Background: Due to the scarcity of treatment options, managing the progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to cirrhosis necessitates innovative approaches. This study focused on endoplasmic reticulum (ER) stress, apoptosis, and autophagy as key mechanisms in NAFLD pathogenesis. It also highlighted the potential of adipose-derived mesenchymal stem cells (AD-MSCs) and their exosomes as promising therapeutic options.
Methods: The study was conducted at the Department of Regenerative Medicine, Shiraz University of Medical Sciences, (Shiraz, Iran) from November 2021 to December 2023. The mice (n=32) were divided into four groups: control, high-fat diet (HFD) without treatment, HFD with AD-MSCs treatment, and HFD with AD-MSCs-derived exosomes groups. The mice were fed HFD for 8 weeks. They received MSC and exosomes for the last 3 weeks. One week after the final injection, mice were tested for serum testing, stereological analysis, and real-time polymerase chain reaction (RT-PCR). The data were analyzed using the Graph-Pad Prism software by one-way analysis of variance (ANOVA) with Tukey analysis as a post hoc comparison between groups. P<0.05 indicated a significant difference. 
Results: AD-MSCs-exosomes significantly reduced ER stress indicators (IRE1α [P=0.0001], PERK [P=0.0006], ATF6 [P=0.0001], and GRP78 [P=0.0001]), apoptosis markers (Bax [P=0.005] and Cas3 [P=0.001]), and autophagic flux markers (P62 [P=0.0001] and LC3B/A [P=0.003]). 
Conclusion: In this investigation, AD-MSCs-exosomes significantly restored autophagy and suppressed unfolded protein response (UPR) pathways in the early stages of NAFLD.
کلیدواژه‌ها
Non-alcoholic fatty liver disease؛ Mesenchymal stem cells؛ Exosome؛ Autophagy؛ Endoplasmic reticulum stress
مراجع
  1. Rinaldi L, Pafundi PC, Galiero R, Caturano A, Morone MV, Silvestri C, et al. Mechanisms of Non-Alcoholic Fatty Liver Disease in the Metabolic Syndrome. A Narrative Review. Antioxidants (Basel). 2021;10. doi: 10.3390/antiox10020270. PubMed PMID: 33578702; PubMed Central PMCID: PMCPMC7916383.
  2. Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet. 2014;383:1749-61. doi: 10.1016/S0140-6736(14)60121-5. PubMed PMID: 24480518.
  3. Lebeaupin C, Vallee D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018;69:927-47. doi: 10.1016/j.jhep.2018.06.008. PubMed PMID: 29940269.
  4. Wu WKK, Zhang L, Chan MTV. Autophagy, NAFLD and NAFLD-Related HCC. Adv Exp Med Biol. 2018;1061:127-38. doi: 10.1007/978-981-10-8684-7_10. PubMed PMID: 29956211.
  5. Chen X, Shi C, He M, Xiong S, Xia X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct Target Ther. 2023;8:352. doi: 10.1038/s41392-023-01570-w. PubMed PMID: 37709773; PubMed Central PMCID: PMCPMC10502142.
  6. Moncan M, Mnich K, Blomme A, Almanza A, Samali A, Gorman AM. Regulation of lipid metabolism by the unfolded protein response. J Cell Mol Med. 2021;25:1359-70. doi: 10.1111/jcmm.16255. PubMed PMID: 33398919; PubMed Central PMCID: PMCPMC7875919.
  7. Mostafa RG, El-Aleem Hassan Abd El-Aleem A, Mahmoud Fouda EA, Ahmed Taha FR, Amin Elzorkany KM. A pilot study on gene expression of endoplasmic reticulum unfolded protein response in chronic kidney disease. Biochem Biophys Rep. 2020;24:100829. doi: 10.1016/j.bbrep.2020.100829. PubMed PMID: 33134564; PubMed Central PMCID: PMCPMC7588702.
  8. Iurlaro R, Munoz-Pinedo C. Cell death induced by endoplasmic reticulum stress. FEBS J. 2016;283:2640-52. doi: 10.1111/febs.13598. PubMed PMID: 26587781.
  9. Gomez-Virgilio L, Silva-Lucero MD, Flores-Morelos DS, Gallardo-Nieto J, Lopez-Toledo G, Abarca-Fernandez AM, et al. Autophagy: A Key Regulator of Homeostasis and Disease: An Overview of Molecular Mechanisms and Modulators. Cells. 2022;11. doi: 10.3390/cells11152262. PubMed PMID: 35892559; PubMed Central PMCID: PMCPMC9329718.
  10. Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer. Mol Cancer. 2020;19:12. doi: 10.1186/s12943-020-1138-4. PubMed PMID: 31969156; PubMed Central PMCID: PMCPMC6975070.
  11. Xie Y, Li J, Kang R, Tang D. Interplay Between Lipid Metabolism and Autophagy. Front Cell Dev Biol. 2020;8:431. doi: 10.3389/fcell.2020.00431. PubMed PMID: 32582708; PubMed Central PMCID: PMCPMC7283384.
  12. Zhang Y, Li K, Kong A, Zhou Y, Chen D, Gu J, et al. Dysregulation of autophagy acts as a pathogenic mechanism of non-alcoholic fatty liver disease (NAFLD) induced by common environmental pollutants. Ecotoxicol Environ Saf. 2021;217:112256. doi: 10.1016/j.ecoenv.2021.112256. PubMed PMID: 33901779.
  13. Lee S, Kim S, Hwang S, Cherrington NJ, Ryu DY. Dysregulated expression of proteins associated with ER stress, autophagy and apoptosis in tissues from nonalcoholic fatty liver disease. Oncotarget. 2017;8:63370-81. doi: 10.18632/oncotarget.18812. PubMed PMID: 28968997; PubMed Central PMCID: PMCPMC5609929.
  14. Cao Y, Ji C, Lu L. Mesenchymal stem cell therapy for liver fibrosis/cirrhosis. Ann Transl Med. 2020;8:562. doi: 10.21037/atm.2020.02.119. PubMed PMID: 32775363; PubMed Central PMCID: PMCPMC7347778.
  15. Volarevic V, Nurkovic J, Arsenijevic N, Stojkovic M. Concise review: Therapeutic potential of mesenchymal stem cells for the treatment of acute liver failure and cirrhosis. Stem Cells. 2014;32:2818-23. doi: 10.1002/stem.1818. PubMed PMID: 25154380.
  16. Pan Y, Tan WF, Yang MQ, Li JY, Geller DA. The therapeutic potential of exosomes derived from different cell sources in liver diseases. Am J Physiol Gastrointest Liver Physiol. 2022;322:G397-G404. doi: 10.1152/ajpgi.00054.2021. PubMed PMID: 35107032; PubMed Central PMCID: PMCPMC8917924.
  17. Kumar MA, Baba SK, Sadida HQ, Marzooqi SA, Jerobin J, Altemani FH, et al. Extracellular vesicles as tools and targets in therapy for diseases. Signal Transduct Target Ther. 2024;9:27. doi: 10.1038/s41392-024-01735-1. PubMed PMID: 38311623; PubMed Central PMCID: PMCPMC10838959.
  18. Ohara M, Ohnishi S, Hosono H, Yamamoto K, Yuyama K, Nakamura H, et al. Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats. Stem Cells Int. 2018;2018:3212643. doi: 10.1155/2018/3212643. PubMed PMID: 30675167; PubMed Central PMCID: PMCPMC6323530.
  19. He Y, Yang W, Gan L, Liu S, Ni Q, Bi Y, et al. Silencing HIF-1alpha aggravates non-alcoholic fatty liver disease in vitro through inhibiting PPAR-alpha/ANGPTL4 singling pathway. Gastroenterol Hepatol. 2021;44:355-65. doi: 10.1016/j.gastrohep.2020.09.014. PubMed PMID: 33272734.
  20. Sani F, Soufi Zomorrod M, Azarpira N, Soleimani M. The Effect of Mesenchymal Stem Cell-Derived Exosomes and miR17-5p Inhibitor on Multicellular Liver Fibrosis Microtissues. Stem Cells Int. 2023;2023:8836452. doi: 10.1155/2023/8836452. PubMed PMID: 37576406; PubMed Central PMCID: PMCPMC10421706.
  21. Care IoLARCo, Animals UoL. Guide for the care and use of laboratory animals. US Department of Health and Human Services: Public Health Service, National Institutes of Health; 1986.
  22. Bordbar H, Soleymani F, Nadimi E, Yahyavi SS, Fazelian-Dehkordi K. A Quantitative Study on the Protective Effects of Resveratrol against Bisphenol A-induced Hepatotoxicity in Rats: A Stereological Study. Iran J Med Sci. 2021;46:218-27. doi: 10.30476/ijms.2020.83308.1233. PubMed PMID: 34083854; PubMed Central PMCID: PMCPMC8163701
  23. Liao Z, Luo R, Li G, Song Y, Zhan S, Zhao K, et al. Exosomes from mesenchymal stem cells modulate endoplasmic reticulum stress to protect against nucleus pulposus cell death and ameliorate intervertebral disc degeneration in vivo. Theranostics. 2019;9:4084-100. doi: 10.7150/thno.33638. PubMed PMID: 31281533; PubMed Central PMCID: PMCPMC6592170.
  24. Lee EJ, Cardenes N, Alvarez D, Sellares J, Sembrat J, Aranda P, et al. Mesenchymal stem cells reduce ER stress via PERK-Nrf2 pathway in an aged mouse model. Respirology. 2020;25:417-26. doi: 10.1111/resp.13646. PubMed PMID: 31364255.
  25. Ulum B, Teker HT, Sarikaya A, Balta G, Kuskonmaz B, Uckan-Cetinkaya D, et al. Bone marrow mesenchymal stem cell donors with a high body mass index display elevated endoplasmic reticulum stress and are functionally impaired. J Cell Physiol. 2018;233:8429-36. doi: 10.1002/jcp.26804. PubMed PMID: 29797574.
  26. Kim SH, Kim JY, Park SY, Jeong WT, Kim JM, Bae SH, et al. Activation of the EGFR-PI3K-CaM pathway by PRL-1-overexpressing placenta-derived mesenchymal stem cells ameliorates liver cirrhosis via ER stress-dependent calcium. Stem Cell Res Ther. 2021;12:551. doi: 10.1186/s13287-021-02616-y. PubMed PMID: 34689832; PubMed Central PMCID: PMCPMC8543968.
  27. Psaraki A, Ntari L, Karakostas C, Korrou-Karava D, Roubelakis MG. Extracellular vesicles derived from mesenchymal stem/stromal cells: The regenerative impact in liver diseases. Hepatology. 2022;75:1590-603. doi: 10.1002/hep.32129. PubMed PMID: 34449901.
  28. Du X, Li H, Han X, Ma W. Mesenchymal stem cells-derived exosomal miR-24-3p ameliorates non-alcohol fatty liver disease by targeting Keap-1. Biochem Biophys Res Commun. 2022;637:331-40. doi: 10.1016/j.bbrc.2022.11.012. PubMed PMID: 36423379.
  29. Rong X, Liu J, Yao X, Jiang T, Wang Y, Xie F. Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/beta-catenin pathway. Stem Cell Res Ther. 2019;10:98. doi: 10.1186/s13287-019-1204-2. PubMed PMID: 30885249; PubMed Central PMCID: PMCPMC6421647.
  30. Mardpour S, Hassani SN, Mardpour S, Sayahpour F, Vosough M, Ai J, et al. Extracellular vesicles derived from human embryonic stem cell-MSCs ameliorate cirrhosis in thioacetamide-induced chronic liver injury. J Cell Physiol. 2018;233:9330-44. doi: 10.1002/jcp.26413. PubMed PMID: 29266258.
  31. Chen YX, Zeng ZC, Sun J, Zeng HY, Huang Y, Zhang ZY. Mesenchymal stem cell-conditioned medium prevents radiation-induced liver injury by inhibiting inflammation and protecting sinusoidal endothelial cells. J Radiat Res. 2015;56:700-8. doi: 10.1093/jrr/rrv026. PubMed PMID: 26070321; PubMed Central PMCID: PMCPMC4497399.
  32. Gonzalez-Rodriguez A, Mayoral R, Agra N, Valdecantos MP, Pardo V, Miquilena-Colina ME, et al. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis. 2014;5:e1179. doi: 10.1038/cddis.2014.162. PubMed PMID: 24743734; PubMed Central PMCID: PMCPMC4001315.
  33. Lin D, Chen H, Xiong J, Zhang J, Hu Z, Gao J, et al. Mesenchymal stem cells exosomal let-7a-5p improve autophagic flux and alleviate liver injury in acute-on-chronic liver failure by promoting nuclear expression of TFEB. Cell Death Dis. 2022;13:865. doi: 10.1038/s41419-022-05303-9. PubMed PMID: 36224178; PubMed Central PMCID: PMCPMC9556718.
  34. Yang B, Yang X. Mesenchymal stem cell-derived exosomes are beneficial to suppressing inflammation and promoting autophagy in intervertebral disc degeneration. Folia Morphol (Warsz). 2024;83:102-12. doi: 10.5603/FM.a2023.0021. PubMed PMID: 36967623.
  35. Park M, Kim YH, Woo SY, Lee HJ, Yu Y, Kim HS, et al. Tonsil-derived mesenchymal stem cells ameliorate CCl4-induced liver fibrosis in mice via autophagy activation. Sci Rep. 2015;5:8616. doi: 10.1038/srep08616. PubMed PMID: 25722117; PubMed Central PMCID: PMCPMC4342568.
  36. Hua D, Ju Z, Gan X, Wang Q, Luo C, Gu J, et al. Human amniotic mesenchymal stromal cells alleviate acute liver injury by inhibiting the pro-inflammatory response of liver resident macrophage through autophagy. Ann Transl Med. 2019;7:392. doi: 10.21037/atm.2019.08.83. PubMed PMID: 31555706; PubMed Central PMCID: PMCPMC6736825.
  37. Wang Y, Wang JL, Ma HC, Tang ZT, Ding HR, Shi XL. Mesenchymal stem cells increase heme oxygenase 1-activated autophagy in treatment of acute liver failure. Biochem Biophys Res Commun. 2019;508:682-9. doi: 10.1016/j.bbrc.2018.11.146. PubMed PMID: 30528392.
  38. Hu C, Zhao L, Zhang L, Bao Q, Li L. Mesenchymal stem cell-based cell-free strategies: safe and effective treatments for liver injury. Stem Cell Res Ther. 2020;11:377. doi: 10.1186/s13287-020-01895-1. PubMed PMID: 32883343; PubMed Central PMCID: PMCPMC7469278.
  39. Watanabe T, Tsuchiya A, Takeuchi S, Nojiri S, Yoshida T, Ogawa M, et al. Development of a non-alcoholic steatohepatitis model with rapid accumulation of fibrosis, and its treatment using mesenchymal stem cells and their small extracellular vesicles. Regen Ther. 2020;14:252-61. doi: 10.1016/j.reth.2020.03.012. PubMed PMID: 32455155; PubMed Central PMCID: PMCPMC7232114.
آمار
تعداد مشاهده مقاله: 45
تعداد دریافت فایل اصل مقاله: 37


سامانه مدیریت نشریات علمی. قدرت گرفته از سیناوب