Journal of Pediatric Perspectives

Journal of Pediatric Perspectives

The Role of Exosomes in the Pathogenesis of Intrauterine Growth Restriction (IUGR): Future Perspective

Document Type : review article

Authors
Noushin Modaber 1
Roghayeh Amiri 1
Fatemeh Jayeravand 1
Seyed Amir Hossein Hosseini 2
Bahareh Shateri Amiri Shateri Amiri 3
Minoo Rostami 3
Ezzat Khodashenas 4
Bahareh Ghahrodizadehabyaneh 5
1 Shahid AkbarAbadi Clinical Research Development Unit (SHACRDU), School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
2 Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
3 Assistant Professor of Internal Medicine Department of Internal Medicine, School of Medicine Hazrat-e Rasool General Hospital Iran University of Medical Sciences.
4 Neonatal research center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
5 Resident of Obstetrics and Gynecology, Medical Faculty, Tehran University of Medical Sciences, Tehran, Iran.
10.22038/ijp.2023.72768.5284
Abstract
Background: Exosomes are among the factors whose importance has been shown in many diseases today. Recently, it has been shown that exosomes play an important role in the pathogenesis of Intrauterine Growth Restriction (IUGR); however, few studies have been conducted in this regard.
Methods: The articles in this review study were retrieved from some databases including PubMed, Google scholar, and Scopus. All the included articles were in English, and those in other languages were excluded. Search keywords included IUGR, exosome, pathogenesis, Mechanism, Cell Signaling, Oxidative Stress, Inflammation, and Endothelial Dysfunction.
Results and conclusion: Studies have shown that exosomes contain factors, molecules and gene activators that affect molecular pathways regulation. These molecules play an important role in regulating inflammatory reactions, oxidative stress, and production of Reactive Oxygen Species (ROS). The activation of these pathways can aggravate the clinical symptoms of IUGR. In addition, exosomes can impress induction or inhibition of endothelial dysfunction, which leads to the development of IUGR. Hence, identifying upstream and downstream pathways helps design therapeutic strategies to treat patients.
Keywords
Exosome,,
,،Intrauterine Growth Restriction,,
,،Pathogenesis,,
,،Mechanism
  1. Romo A, Carceller R, Tobajas J. Intrauterine growth retardation (IUGR): epidemiology and etiology. Pediatr Endocrinol Rev. 2009; 6 Suppl 3:332-6.
  2. Vandenbosche RC, Kirchner JT. Intrauterine growth retardation. Am Fam Physician. 1998; 58(6):1384-90, 93-4.
  3. Saleem T, Sajjad N, Fatima S, Habib N, Ali SR, Qadir M. Intrauterine growth retardation - small events, big consequences. Italian Journal of Pediatrics. 2011; 37(1):41.
  4. Kesavan K, Devaskar SU. Intrauterine Growth Restriction: Postnatal Monitoring and Outcomes. Pediatr Clin North Am. 2019; 66(2):403-23.
  5. Ergaz Z, Avgil M, Ornoy A. Intrauterine growth restriction-etiology and consequences: what do we know about the human situation and experimental animal models? Reprod Toxicol. 2005; 20(3):301-22.
  6. Bai K, Li X, Zhong J, Ng EHY, Yeung WSB, Lee CL, Chiu PCN. Placenta-Derived Exosomes as a Modulator in Maternal Immune Tolerance During Pregnancy. Front Immunol. 2021; 12:671093.
  7. Miranda J, Paules C, Nair S, Lai A, Palma C, Scholz-Romero K, Rice GE, Gratacos E, Crispi F, Salomon C. Placental exosomes profile in maternal and fetal circulation in intrauterine growth restriction - Liquid biopsies to monitoring fetal growth. Placenta. 2018; 64:34-43.
  8. Hakemi MS, Nassiri AA, Nobakht A, Mardani M, Darazam IA, Parsa M, Miri MM, Shahrami R, Ahmadi Koomleh A, Entezarmahdi K, Karimi A. Benefit of hemoadsorption therapy in patients suffering sepsis-associated acute kidney injury: a case series. Blood Purification. 2022; 51(10):823-30.
  9. Shalom-Paz E, Weill S, Ginzberg Y, Khatib N, Anabusi S, Klorin G, Sabo E, Beloosesky R. IUGR induced by maternal chronic inflammation: long-term effect on offspring's ovaries in rat model-a preliminary report. J Endocrinol Invest. 2017; 40(10):1125-31.
  10. Ding H, Dai Y, Lei Y, Wang Z, Liu D, Li R, Shen L, Gu N, Zheng M, Zhu X, Zhao G, Hu Y. Upregulation of CD81 in trophoblasts induces an imbalance of Treg/Th17 cells by promoting IL-6 expression in preeclampsia. Cell Mol Immunol. 2019; 16(1):302-12.
  11. Li Y, Yan C, Fan J, Hou Z, Han Y. MiR-221-3p targets Hif-1α to inhibit angiogenesis in heart failure. Laboratory Investigation. 2021; 101(1):104-15.
  12. Li L, Ma X, Zhao YF, Zhang C. MiR-1-3p facilitates Th17 differentiation associating with multiple sclerosis via targeting ETS1. Eur Rev Med Pharmacol Sci. 2020; 24(12):6881-92.
  13. Song KS, Yoon JH, Kim KS, Ahn DW. c-Ets1 inhibits the interaction of NF-κB and CREB, and downregulates IL-1β-induced MUC5AC overproduction during airway inflammation. Mucosal Immunol. 2012; 5(2):207-15.
  14. Ariyakumar G, Morris JM, McKelvey KJ, Ashton AW, McCracken SA. NF-κB regulation in maternal immunity during normal and IUGR pregnancies. Sci Rep. 2021; 11(1):20971.
  15. Wang R, Zhao Z, Zheng L, Xing X, Ba W, Zhang J, Huang M, Zhu W, Liu B, Meng X, Bai J, Li C, Li H. MicroRNA-520a suppresses the proliferation and mitosis of HaCaT cells by inactivating protein kinase B. Exp Ther Med. 2017;14(6):6207-12.
  16. Liang X, Xu Z, Yuan M, Zhang Y, Zhao B, Wang J, Zhang A, Li G. MicroRNA-16 suppresses the activation of inflammatory macrophages in atherosclerosis by targeting PDCD4. Int J Mol Med. 2016; 37(4):967-75.

17. Sánchez-López E, Rayego S, Rodrigues-Díez R, Rodriguez JS, Rodrigues-Díez R, Rodríguez-Vita J, Carvajal G, Aroeira LS, Selgas R, Mezzano SA, Ortiz A, Egido J, Ruiz-Ortega M. CTGF promotes inflammatory 

cell infiltration of the renal interstitium by activating NF-kappaB. J Am Soc Nephrol. 2009; 20(7):1513-26.

  1. Luo P, Jiang C, Ji P, Wang M, Xu J. Exosomes of stem cells from human exfoliated deciduous teeth as an anti-inflammatory agent in temporomandibular joint chondrocytes via miR-100-5p/mTOR. Stem Cell Res Ther. 2019; 10(1):216.
  2. Jara D, Carvajal P, Castro I, Barrera MJ, Aguilera S, González S, Molina C, Hermoso M, González MJ. Type I Interferon Dependent hsa-miR-145-5p Downregulation Modulates MUC1 and TLR4 Overexpression in Salivary Glands From Sjögren's Syndrome Patients. Front Immunol. 2021; 12:685837.
  3. Paik JH, Jang JY, Jeon YK, Kim WY, Kim TM, Heo DS, Kim TM, Heo DS, Kim CW. MicroRNA-146a downregulates NFκB activity via targeting TRAF6 and functions as a tumor suppressor having strong prognostic implications in NK/T cell lymphoma. Clin Cancer Res. 2011; 17(14):4761-71.
  4. Rasheed Z, Rasheed N, Abdulmonem WA, Khan MI. Author Correction: MicroRNA-125b-5p regulates IL-1β induced inflammatory genes via targeting TRAF6-mediated MAPKs and NF-κB signaling in human osteoarthritic chondrocytes. Sci Rep. 2019; 9(1):14729.
  5. Liu J, Wei E, Wei J, Zhou W, Webster KA, Zhang B, Li D, Zhang G, Wei Y, Long Y, Qi X, Zhang Q, Xu D. MiR-126-HMGB1-HIF-1 Axis Regulates Endothelial Cell Inflammation during Exposure to Hypoxia-Acidosis. Dis Markers. 2021; 2021:4933194.
  6. Scalavino V, Piccinno E, Bianco G, Schena N, Armentano R, Giannelli G, Serino G. The Increase of miR-195-5p Reduces Intestinal Permeability in Ulcerative Colitis, Modulating Tight Junctions' Expression. Int J Mol Sci. 2022; 23(10).
  7. Wang Y, Luo J, Wang X, Yang B, Cui L. MicroRNA-199a-5p Induced Autophagy and Inhibits the Pathogenesis of Ankylosing Spondylitis by Modulating the mTOR Signaling via Directly Targeting Ras Homolog Enriched in Brain (Rheb). Cell Physiol Biochem. 2017; 42(6):2481-91.
  8. Zaccagnini G, Greco S, Longo M, Maimone B, Voellenkle C, Fuschi P, Carrara M, Creo P, Maselli D, Tirone M, Mazzone M, Gaetano C, Spinetti G, Martelli F. Hypoxia-induced miR-210 modulates the inflammatory response and fibrosis upon acute ischemia. Cell Death Dis. 2021; 12(5):435.
  9. Zhang D, Cao X, Li J, Zhao G. MiR-210 inhibits NF-κB signaling pathway by targeting DR6 in osteoarthritis. Sci Rep. 2015; 5:12775.
  10. Yang H, Zhang L, Wang Q. MicroRNA-221-3p alleviates cell apoptosis and inflammatory response by targeting cyclin dependent kinase inhibitor 1B in chronic obstructive pulmonary disease. Bioengineered. 2021; 12(1):5705-15.
  11. Zhang S, Liu L, Lv Z, Li Q, Gong W, Wu H. MicroRNA-342-3p Inhibits the Proliferation, Migration, and Invasion of Osteosarcoma Cells by Targeting Astrocyte-Elevated Gene-1 (AEG-1). Oncol Res. 2017; 25(9):1505-15.
  12. Konwar C, Manokhina I, Terry J, Inkster AM, Robinson WP. Altered levels of placental miR-338-3p and miR-518b are associated with acute chorioamnionitis and IL6 genotype. Placenta. 2019; 82:42-5.
  13. Eshraghi N, Jamal A, Eshraghi N, Kashanian M, Sheikhansari N. Cerebroplacental ratio (CPR) and reduced fetal movement: predicting neonatal outcomes. The Journal of Maternal-Fetal & Neonatal Medicine. 2022; 35(10):1923-8.
  14. Rudov A, Balduini W, Carloni S, Perrone S, Buonocore G, Albertini MC. Involvement of miRNAs in placental alterations mediated by oxidative stress. Oxid Med Cell Longev. 2014; 2014:103068.
  15. Ye LL, Cheng ZG, Cheng XE, Huang YL. Propofol regulates miR-1-3p/IGF1 axis to inhibit the proliferation and accelerates apoptosis of colorectal cancer cells. Toxicol Res (Camb). 2021; 10(4):696-705.
  16. Kashanian M, Eshraghi N, Sheikhansari N, Eshraghi N. Comparing the efficacy of dilapan with extra-amniotic saline infusion and oral misoprostol for cervical ripening in term pregnancies. The Journal of Maternal-Fetal & Neonatal Medicine. 2022; 35(25):5616-20.
  17. Wen X, Yin Y, Li X, He T, Wang P, Song M, Gao J. Effect of miR-26a-5p targeting ADAM17 gene on apoptosis, inflammatory factors and oxidative stress response of myocardial cells in hypoxic model. J Bioenerg Biomembr. 2020; 52(2):83-92.
  18. Li X, Wang Y, Cai Z, Zhou Q, Li L, Fu P. Exosomes from human umbilical cord mesenchymal stem cells inhibit ROS production and cell apoptosis in human articular chondrocytes via the miR-100-5p/NOX4 axis. Cell Biol Int. 2021; 45(10):2096-106.
  19. Barutta F, Bellini S, Guarrera S, Matullo G, Schalkwijk C, Stehouwer CD, Chaturvedi N, Soedamah-Muthu SS, Durazzo M, Gruden G. Association of serum MicroRNA-145-5p levels with microvascular complications of type 1 Diabetes: The EURODIAB prospective complications study. Diabetes Res Clin Pract. 2022; 190:109987.
  20. Ye Y, Liu Q, Li C, He P. miR-125a-5p Regulates Osteogenic Differentiation of Human Adipose-Derived Mesenchymal Stem Cells under Oxidative Stress. Biomed Res Int. 2021; 2021:6684709.
  21. Li J, Yang C, Wang Y. miR‑126 overexpression attenuates oxygen‑glucose deprivation/reperfusion injury by inhibiting oxidative stress and inflammatory response via the activation of SIRT1/Nrf2 signaling pathway in human umbilical vein endothelial cells. Mol Med Rep. 2021; 23(2).
  22. Gong C, Xu Q, Zhang X, Mao G, Pei Z, Meng W, Cen JF, He XW, Lu Y, Xu QQ, Xiao K. HMSCs exosome-derived miR-199a-5p attenuates sulfur mustard-associated oxidative stress via the CAV1/NRF2 signaling pathway. Research Square; 2022.
  23. Diao H, Liu B, Shi Y, Song C, Guo Z, Liu N, Song X, Lu Y, Lin X, Li Z. MicroRNA-210 alleviates oxidative stress-associated cardiomyocyte apoptosis by regulating BNIP3. Biosci Biotechnol Biochem. 2017; 81(9):1712-20.
  24. Wang Y, Song X, Li Z, Liu N, Yan Y, Li T, Li T, Sun W, Guan Y, Li M, Yang Y, Yang X, Liu B. MicroRNA-103 Protects Coronary Artery Endothelial Cells against H(2)O(2)-Induced Oxidative Stress via BNIP3-Mediated End-Stage Autophagy and Antipyroptosis Pathways. Oxid Med Cell Longev. 2020; 2020:8351342.
  25. Sheikh M, Ostadrahimi P, Salarzaei M, Parooie F. Cardiac complications in pregnancy: a systematic review and meta-analysis of diagnostic accuracy of BNP and N-terminal pro-BNP. Cardiology and Therapy. 2021; 10:501-14.
  26. Fu M, Zhu Y, Zhang J, Wu W, Sun Y, Zhang X, Tao J, Li Z. MicroRNA-221-3p Suppresses the Microglia Activation and Seizures by Inhibiting of HIF-1α in Valproic Acid-Resistant Epilepsy. Frontiers in Pharmacology. 2021; 12.
  27. Yang C, Yan Z, Hu F, Wei W, Sun Z, Xu W. Silencing of microRNA-517a induces oxidative stress injury in melanoma cells via inactivation of the JNK signaling pathway by upregulating CDKN1C. Cancer Cell International. 2020; 20(1):32.
  28. Garziera M, Scarabel L, Toffoli G. Hypoxic Modulation of HLA-G Expression through the Metabolic Sensor HIF-1 in Human Cancer Cells. J Immunol Res. 2017; 2017:4587520.
  29. Zhou X, Zhang GY, Wang J, Lu SL, Cao J, Sun LZ. A novel bridge between oxidative stress and immunity: the interaction between hydrogen peroxide and human leukocyte antigen G in placental trophoblasts during preeclampsia. Am J Obstet Gynecol. 2012; 206(5):447.e7-16.
  30. Yinon Y, Kingdom JC, Odutayo A, Moineddin R, Drewlo S, Lai V, Lai V, Cherney DZI, Hladunewich MA. Vascular dysfunction in women with a history of preeclampsia and intrauterine growth restriction: insights into future vascular risk. Circulation. 2010; 122(18):1846-53.
  31. Zhang W, Dong X, Wang T, Kong Y. Exosomes derived from platelet-rich plasma mediate hyperglycemia-induced retinal endothelial injury via targeting the TLR4 signaling pathway. Experimental eye research. 2019; 189:107813.
  32. Sheikh M, Mahabadi BS, Ostadrahimi P. Infective endocarditis in Iranian children: A systematic review and meta-analysis in three age groups. Int J Adv Res Biol Sci. 2019; 6(5):110-7.
  33. Zadeh FJ, Ghasemi Y, Bagheri S, Maleknia M, Davari N, Rezaeeyan H. Do exosomes play a role in cardiovascular disease development in hematological malignancy? Molecular Biology Reports. 2020; 47:5487-93.
  34. Deng L, Blanco FJ, Stevens H, Lu R, Caudrillier A, McBride M, McClure JD, Grant J, Thomas M, Frid M, Stenmark K, White K, Seto AG, Morrell NW, Bradshaw AC, MacLean MR, Baker AH. MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension. Circulation research. 2015; 117(10):870-83.
  35. Mehrpisheh S, Mosayebi Z, Memarian A, Kadivar M, Nariman S, Ostadrahimi P, Dalili H. Evaluation of specificity and sensitivity of gastric aspirate shake test to predict surfactant deficiency in Iranian premature infants. Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health. 2015; 5(2):182-6.
  36. Liu X, Shao Y, Tu J, Sun J, Li L, Tao J, Chen J. Trimethylamine-n-oxide-stimulated hepatocyte-derived exosomes promote inflammation and endothelial dysfunction through nuclear factor-kappa b signaling. Annals of Translational Medicine. 2021; 9(22).
  37. Xiong Y, Chen L, Yan C, Zhou W, Endo Y, Liu J, Hu L, Hu Y, Mi B, Liu G. Circulating exosomal miR‐20b‐5p inhibition restores Wnt9b signaling and reverses diabetes‐associated impaired wound healing. Small. 2020; 16(3):1904044.
  38. Shahramian I, Tabrizian K, Ostadrahimi P, Afshari M, Soleymanifar M, Bazi A. Therapeutic effects of ursodeoxycholic acid in neonatal indirect hyperbilirubinemia: a randomized double-blind clinical trial. Archives of Anesthesiology and Critical Care. 2019; 5(3):99-103.
  39. Migneault F, Dieudé M, Turgeon J, Beillevaire D, Hardy M-P, Brodeur A, Thibodeau N, Perreault C, Hébert MJ. Apoptotic exosome-like vesicles regulate endothelial gene expression, inflammatory signaling, and function through the NF-κB signaling pathway. Scientific reports. 2020; 10(1):1-15.
  40. Zadeh FJ, Akbari T, Zayeri ZD, Samimi A, Davari N, Rezaeeyan H. The role of molecular mechanism of Ten-

    Eleven Translocation2 (TET2) family proteins in pathogenesis of cardiovascular diseases (CVDs). Molecular Biology Reports. 2020; 47(7):5503-9.

    1. Ibrahim AA, Wahby AA, Ashmawy I, Saleh RM, Soliman H. Association of exosomal miR-34a with markers of dyslipidemia and endothelial dysfunction in children and adolescents with T1DM. Journal of Clinical Research in Pediatric Endocrinology. 2020; 12(4):401.
    2. Liu H, Wang J, Chen Y, Chen Y, Ma X, Bihl JC, Yang Y. NPC-EXs alleviate endothelial oxidative stress and dysfunction through the miR-210 downstream Nox2 and VEGFR2 pathways. Oxidative Medicine and Cellular Longevity. 2017; 2017.
    3. Wang Z, Jiao P, Zhong Y, Ji H, Zhang Y, Song H, Du H, Ding X, Wu H. The Endoplasmic Reticulum-Stressed Head and Neck Squamous Cell Carcinoma Cells Induced Exosomal miR-424-5p Inhibits Angiogenesis and Migration of Humanumbilical Vein Endothelial Cells Through LAMC1-Mediated Wnt/β-Catenin Signaling Pathway. Cell Transplantation. 2022; 31:09636897221083549.
    4. Akhavan S, Tutunchi S, Malmir A, Ajorlou P, Jalili A, Panahi G. Molecular study of the proliferation process of beta cells derived from pluripotent stem cells. Molecular Biology Reports. 2022:1-8.
    5. Ge X, Tang P, Rong Y, Jiang D, Lu X, Ji C, Wang J, Huang C, Duan A, Liu Y, Chen X, Chen X, Xu Z, Wang F, Wang Z, Li X, Zhao W, Fan J, Liu W, Yin G, Cai W. Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-κB signaling pathway in vascular endothelial cells after traumatic spinal cord injury. Redox biology. 2021; 41:101932.
    6. Luo J, Fan Y, Shen L, Niu L, Zhao Y, Jiang D, Zhu L, Jiang A, Tang Q, Ma J, Jin L, Wang J, Li X, Zhang S, Zhu L. The Pro-angiogenesis Of Exosomes Derived from Umbilical Cord Blood of Intrauterine Growth Restriction Pigs Was Repressed Associated with MiRNAs. Int J Biol Sci. 2018; 14(11):1426-36.
    7. Luo X, Hang C, Zhang Z, Le K, Ying Y, Lv Y, Lv Y, Yan L, Huang Y, Ye L, Xu X, Zhong Y, Du L. PVECs‐Derived Exosomal microRNAs Regulate PASMCs via FoxM1 Signaling in IUGR‐induced Pulmonary Hypertension. Journal of the American Heart Association. 2022; 11(24):e027177.
    8. Hu T-X, Wang G, Guo X-J, Sun Q-Q, He P, Gu H, Huang Y, Gao L, Ni X. MiR 20a,-20b and-200c are involved in hydrogen sulfide stimulation of VEGF production in human placental trophoblasts. Placenta. 2016; 39:101-10.
    9. Ranjan P, Kumari R, Goswami SK, Li J, Pal H, Suleiman Z, Cheng Z, Krishnamurthy P, Kishore R, Verma SK. Myofibroblast-derived exosome induces cardiac endothelial cell dysfunction. Frontiers in Cardiovascular Medicine. 2021; 8:676267.
    10. Hu T-X, Wang G, Guo X-J, Sun Q-Q, He P, Gu H, Huang Y, Gao L, Ni X. MiR 20a,-20b and -200c are involved in hydrogen sulfide stimulation of VEGF production in human placental trophoblasts. Placenta. 2016; 39:101-10.
    11. Zhang L, Song Y, Chen L, Li D, Feng H, Lu Z, Fan T, Chen Z, Livingston MJ, Geng Q. MiR‐20a‐containing exosomes from umbilical cord mesenchymal stem cells alleviates liver ischemia/reperfusion injury. Journal of Cellular Physiology. 2020; 235(4):3698-710.
Journal of Pediatric Perspectives
Volume 11, Issue 6
June 2023
Pages 17979-17989