Extracellular vesicles as biomarkers of pathology of the fetal central nervous system in placental dysfunction
Kan N.E., Leonova A.A., Gusar V.A., Tyutyunnik V.L.
An analysis of modern literature data on the study of extracellular vesicles in the context of biomarker molecules is presented. The article focuses on their key role in communication between mother and fetus. The possibility of obtaining extracellular vesicles from various types of nerve cells, their role in regulating nervous system plasticity, neurotransmission, brain development, as well as the pathogenesis of neurological disorders are discussed. This paper reviews the function of neuronal exosomes as important mediators of placenta-associated mechanisms of perinatal inflammation and fetal brain damage. New data on the study of the level of signaling molecules that are part of exosomes of neuronal origin are presented. These data support the possibility of using the molecules as biomarkers for liquid biopsy of the brain. This paper describes the successful use of technology for obtaining neuronal fetal exosomes from maternal blood, which can be used to assess adverse outcomes of fetal nervous system development resulting from ethanol exposure in the first trimester of pregnancy.
Conclusion: The technology of obtaining neuronal fetal exosomes from maternal blood presents a unique opportunity for non-invasive dynamic assessment of the brain and the degree of dysfunction of the fetal nervous system during pregnancy. This assessment is based on the study of biomarker molecules that compose neuronal exosomes. The improvement of the algorithm for pregnancy management using this technology can reduce the risk of neonatal brain damage and avoid the long-term consequences of neurological disorders in adulthood.
Authors’ contributions: Leonova A.A. – search for publications, processing and analyzing the material on the subject of the study, writing the text of the manuscript; Kan N.E., Gusar V.A., Tyutyunnik V.L. – developing the concept and design of the study, editing the article.
Conflicts of interest: Authors declare lack of the possible conflicts of interests.
Funding: The work was financially supported by the grant of the Russian Science Foundation №24-64-00006.
For citation: Kan N.E., Leonova A.A., Gusar V.A., Tyutyunnik V.L. Extracellular vesicles
as biomarkers of pathology of the fetal central nervous system in placental dysfunction.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2024; (9): 5-11 (in Russian)
https://dx.doi.org/10.18565/aig.2024.135
Keywords
References
- Di Renzo G.C. The great obstetrical syndromes. J. Matern. Fetal Neonatal. Med. 2009; 22(8): 633-5. https://dx.doi.org/10.1080/14767050902866804.
- Ахмадеев Н.Р., Фаткуллин И.Ф., Фаткуллина Л.С. Сердечно-сосудистые последствия больших акушерских синдромов. Акушерство и гинекология. 2023; 4: 5-11. [Akhmadeev N.R., Fatkullin I.F., Fatkullina L.S. Cardiovascular consequences of great obstetrical syndromes. Obstetrics and Gynecology. 2023; (4): 5-11. (in Russian)]. https://dx.doi.org/ 10.18565/aig.2022.287.
- Моргоева А.А., Цахилова С.Г., Сакварелидзе Н.Ю., Зыкова А.С., Олисаева И.В. Роль внеклеточных везикул в развитии эндотелиальной дисфункции при преэклампсии. Эффективная фармакотерапия. 2021; 17(32): 8-12. [Morgoyeva A.A., Tsakhilovа S.G., Sakvarelidze N.Yu., Zikova A.S., Olisayeva I.V. The role of extracellular vesicles in the development of endothelial dysfunction in preeclampsia. Effective Pharmacotherapy. 2021; 17(32): 8-12. (in Russian)]. https://dx.doi.org/10.33978/2307-3586-2021-17-32-8-12.
- Wan L., Luo K., Chen P. Mechanisms underlying neurologic injury in intrauterine growth restriction. J. Child Neurol. 2021; 36(9): 776-84. https://dx.doi.org/10.1177/0883073821999896.
- Mazarico E., Llurba E., Cabero L., Sánchez O., Valls A., Martín-Ancel A. et al. Associations between neural injury markers of intrauterine growth-restricted infants and neurodevelopment at 2 years of age. J. Matern. Fetal Neonatal. Med. 2019; 32(19): 3197-203. https://dx.doi.org/10.1080/14767058.2018.1460347.
- Sacchi C., Marino C., Nosarti C., Vieno A., Visentin S., Simonelli A. Association of intrauterine growth restriction and small for gestational age status with childhood cognitive outcomes: a systematic review and meta-analysis. JAMA Pediatr. 2020; 174(8): 772-81. https://dx.doi.org/10.1001/jamapediatrics.2020.1097.
- Goetzl L., Darbinian N., Goetzl E.J. Novel window on early human neurodevelopment via fetal exosomes in maternal blood. Ann. Clin. Transl. Neurol. 2016; 3(5): 381-5. https://dx.doi.org/10.1002/acn3.296.
- Buca D., Bologna G., D'Amico A., Cugini S., Musca F., Febbo M. et al. Extracellular vesicles in feto-maternal crosstalk and pregnancy disorders. Int J Mol. Sci. 2020; 21(6): 2120. https://dx.doi.org/10.3390/ijms21062120.
- Adam S., Elfeky O., Kinhal V., Dutta S., Lai A., Jayabalan N. et al. Review: Fetal-maternal communication via extracellular vesicles – Implications for complications of pregnancies. Placenta. 2017; 54: 83-8. https://dx.doi.org/10.1016/j.placenta.2016.12.001.
- Menon R., Shahin H. Extracellular vesicles in spontaneous preterm birth. Am. J. Reprod. Immunol. 2021; 85(2): e13353. https://dx.doi.org/10.1111/aji.13353.
- Yang C., Song G., Lim W. Effects of extracellular vesicles on placentation and pregnancy disorders. Reproduction. 2019; 158(5): R189-R196. https://dx.doi.org/10.1530/REP-19-0147.
- Salomon C., Rice G.E. Role of exosomes in placental homeostasis and pregnancy disorders. Prog. Mol. Biol. Transl. Sci. 2017; 145: 163-79. https://dx.doi.org/10.1016/bs.pmbts.2016.12.006.
- Afzal A., Khan M., Gul Z., Asif R., Shahzaman S., Parveen A. et al. Extracellular vesicles: the next frontier in pregnancy research. Reprod. Sci. 2024; 31(5): 1204-14. https://dx.doi.org/10.1007/s43032-023-01434-2.
- Morelli A.E., Sadovsky Y. Extracellular vesicles and immune response during pregnancy: A balancing act. Immunol. Rev. 2022; 308(1): 105-22. https://dx.doi.org/10.1111/imr.13074.
- Wang Z., Yang R., Zhang J., Wang P., Wang Z., Gao J. et al. Role of extracellular vesicles in placental inflammation and local immune balance. Mediators Inflamm. 2021; 2021: 5558048. https://dx.doi.org/10.1155/2021/5558048.
- Fudono A., Imai C., Takimoto H., Tarui I., Aoyama T., Yago S. et al. Trimester-specific associations between extracellular vesicle microRNAs and fetal growth. J. Matern. Fetal Neonatal. Med. 2022; 35(25): 8728-34. https://dx.doi.org/10.1080/14767058.2021.2000598.
- Gebara N., Correia Y., Wang K., Bussolati B. Angiogenic properties of placenta-derived extracellular vesicles in normal pregnancy and in preeclampsia. Int. J. Mol. Sci. 2021; 22(10): 5402. https://dx.doi.org/10.3390/ijms22105402.
- Taglauer E.S., Fernandez-Gonzalez A., Willis G.R., Reis M., Yeung V., Liu X. et al. Mesenchymal stromal cell-derived extracellular vesicle therapy prevents preeclamptic physiology through intrauterine immunomodulation. Biol. Reprod. 2021; 104(2): 457-67. https://dx.doi.org/10.1093/biolre/ioaa198.
- Ortega M.A., Fraile-Martínez O., García-Montero C., Paradela A., Asunción Sánchez-Gil M., Rodriguez-Martin S. et al. Unfolding the role of placental-derived extracellular vesicles in pregnancy: from homeostasis to pathophysiology. Front. Cell. Dev. Biol. 2022; 10: 1060850. https://dx.doi.org/10.3389/fcell.2022.1060850.
- van Niel G., D'Angelo G., Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell. Biol. 2018; 19(4): 213-28. https://dx.doi.org/10.1038/nrm.2017.125.
- Ghafourian M., Mahdavi R., Akbari Jonoush Z., Sadeghi M., Ghadiri N., Farzaneh M. et al. The implications of exosomes in pregnancy: emerging as new diagnostic markers and therapeutics targets. Cell. Commun. Signal. 2022; 20(1): 51. https://dx.doi.org/10.1186/s12964-022-00853-z.
- Yang W., Pan X., Ma A. The potential of exosomal RNAs in atherosclerosis diagnosis and therapy. Front. Neurol. 2021; 11: 572226. https://dx.doi.org/10.3389/fneur.2020.572226.
- Gurung S., Perocheau D., Touramanidou L., Baruteau J. The exosome journey: from biogenesis to uptake and intracellular signalling. Cell. Commun. Signal. 2021; 19(1): 47. https://dx.doi.org/10.1186/s12964-021-00730-1.
- Colombo M., Raposo G., Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell. Dev. Biol. 2014; 30: 255-89. https://dx.doi.org/10.1146/annurev-cellbio-101512-122326.
- Minciacchi V.R., Freeman M.R., Di Vizio D. Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin. Cell. Dev. Biol. 2015; 40: 41-51. https://dx.doi.org/10.1016/j.semcdb.2015.02.010.
- Zhang Y., Liu Y., Liu H., Tang W.H. Exosomes: biogenesis, biologic function and clinical potential. Cell. Biosci. 2019; 9: 19. https://dx.doi.org/10.1186/s13578-019-0282-2.
- Abels E.R., Breakefield X.O. Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell. Mol. Neurobiol. 2016; 36(3): 301-12. https://dx.doi.org/10.1007/s10571-016-0366-z.
- Villarroya-Beltri C., Gutiérrez-Vázquez C., Sánchez-Cabo F., Pérez-Hernández D., Vázquez J., Martin-Cofreces N. et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 2013; 4: 2980. https://dx.doi.org/10.1038/ncomms3980.
- Qin J., Xu Q. Functions and application of exosomes. Acta Pol. Pharm. 2014; 71(4): 537-43.
- Morishita M., Takahashi Y., Nishikawa M., Takakura Y. Pharmacokinetics of exosomes-an important factor for elucidating the biological roles of exosomes and for the development of exosome-based therapeutics. J. Pharm. Sci. 2017; 106(9): 2265-9. https://dx.doi.org/10.1016/j.xphs.2017.02.030.
- Zhang J., Shi W., Qu D., Yu T., Qi C., Fu H. Extracellular vesicle therapy for traumatic central nervous system disorders. Stem. Cell. Res. Ther. 2022; 13(1): 442. https://dx.doi.org/10.1186/s13287-022-03106-5.
- Graham E.M., Burd I., Everett A.D., Northington F.J. Blood biomarkers for evaluation of perinatal encephalopathy. Front. Pharmacol. 2016; 7: 196. https://dx.doi.org/10.3389/fphar.2016.00196.
- Приходько А.М., Киртбая А.Р., Романов А.Ю., Баев О.Р. Биомаркеры повреждения головного мозга у новорожденных. Неонатология: новости, мнения, обучение. 2018; 7(1): 70-6. [Prikhod’ko A.M., Kirtbaya A.R., Romanov A.Yu., Baev O.R. Biomarkers of brain damage in newborns. Neonatology: News, Opinions, Training. 2018; 7(1): 70-6. (in Russian)]. https://dx.doi.org/10.24411/2308-2402-2018-00009.
- Griffiths P.D., Bradburn M., Campbell M.J., Cooper C.L., Embleton N., Graham R. et al. MRI in the diagnosis of fetal developmental brain abnormalities: the MERIDIAN diagnostic accuracy study. Health Technol. Assess. 2019; 23(49): 1-144. https://dx.doi.org/10.3310/hta23490.
- Huo L., Du X., Li X., Liu S., Xu Y. The emerging role of neural cellderived exosomes in intercellular communication in health and neurodegenerative diseases. Front. Neurosci. 2021; 15: 738442. https://dx.doi.org/10.3389/fnins.2021.738442.
- Silachev D.N., Goryunov K.V., Shpilyuk M.A., Beznoschenko O.S., Morozova N.Y., Kraevaya E.E. et al. Effect of MSCs and MSC-derived extracellular vesicles on human blood coagulation. Cells. 2019; 8(3): 258. https://dx.doi.org/10.3390/cells8030258.
- Wang L., Zhang L. Circulating exosomal miRNA as diagnostic biomarkers of neurodegenerative diseases. Front. Mol. Neurosci. 2020; 13: 53. https://dx.doi.org/10.3389/fnmol.2020.00053.
- Morton M.C., Neckles V.N., Seluzicki C.M., Holmberg J.C., Feliciano D.M. Neonatal subventricular zone neural stem cells release extracellular vesicles that act as a microglial morphogen. Cell. Rep. 2018; 23(1): 78-89. https://dx.doi.org/10.1016/j.celrep.2018.03.037.
- Xia X., Wang Y., Zheng J.C. Extracellular vesicles, from the pathogenesis to the therapy of neurodegenerative diseases. Transl. Neurodegener. 2022; 74(2): 101558. https://dx.doi.org/10.1186/s40035-022-00330-0.
- Frühbeis C., Fröhlich D., Kuo W.P., Amphornrat J., Thilemann S., Saab A.S. et al. Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol. 2013; 11(7): e1001604. https://dx.doi.org/10.1371/journal.pbio.1001604.
- Яковлев А.А. Нейрональные экзосомы как новые системы сигналинга. Биохимия. 2023; 88(4): 457-65. [Yakovlev A.A. Neuronal exosomes as a new signaling system. Biochemistry (Moscow). 2023; 88(4): 457-65. (in Russian)]. https://dx.doi.org/10.31857/S0320972523040024.
- Турчинец А.М., Яковлев А.А. Структурные детерминанты малых внеклеточных везикул (экзосом) и их роль в осуществлении биологических функций. Нейрохимия. 2023; 40(4): 353-66. [Tourchinets A.M., Yakovlev A.A. Structural determinants of small extracellular vesicles (exosomes) and their role in biological functions. Neurochemistry. 2023; 40(4): 353-66. (in Russian)]. https://dx.doi.org/10.31857/S1027813323040222.
- Gamage T.K.J.B., Fraser M. The role of extracellular vesicles in the developing brain: current perspective and promising source of biomarkers and therapy for perinatal brain injury. Front. Neurosci. 2021; 15: 744840. https://dx.doi.org/10.3389/fnins.2021.744840.
- Lachenal G., Pernet-Gallay K., Chivet M., Hemming F.J., Belly A., Bodon G. et al. Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity. Mol. Cell. Neurosci. 2011; 46(2): 409-18. https://dx.doi.org/10.1016/j.mcn.2010.11.004.
- Chen C.C., Liu L., Ma F., Wong C.W., Guo X.E., Chacko J.V. et al. Elucidation of exosome migration across the blood-brain barrier model in vitro. Cell. Mol. Bioeng. 2016; 9(4): 509-29. https://dx.doi.org/10.1007/s12195-016-0458-3.
- Potolicchio I., Carven G.J., Xu X., Stipp C., Riese R.J., Stern L.J. et al. Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J. Immunol. 2005; 175(4): 2237-43. https://dx.doi.org/10.4049/jimmunol.175.4.2237.
- Goetzl E.J., Mustapic M., Kapogiannis D., Eitan E., Lobach I.V., Goetzl L. et al. Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease. FASEB J. 2016; 30(11): 3853-9. https://dx.doi.org/10.1096/fj.201600756R.
- Reiter C.R., Bongarzone E.R. The role of vesicle trafficking and release in oligodendrocyte biology. Neurochem. Res. 2020; 45(3): 620-9. https://dx.doi.org/10.1007/s11064-019-02913-2.
- Krämer-Albers E.M., Bretz N., Tenzer S., Winterstein C., Möbius W., Berger H. et al. Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: Trophic support for axons? Proteomics Clin. Appl. 2007; 1(11): 1446-61. https://dx.doi.org/10.1002/prca.200700522.
- Gall A.R., Amoah S., Kitase Y., Jantzie L.L. Placental mediated mechanisms of perinatal brain injury: evolving inflammation and exosomes. Exp. Neurol. 2022; 347: 113914. https://dx.doi.org/10.1016/j.expneurol.2021.113914.
- Monsivais L.A., Sheller-Miller S., Russell W., Saade G.R., Dixon C.L., Urrabaz-Garza R. et al. Fetal membrane extracellular vesicle profiling reveals distinct pathways induced by infection and inflammation in vitro. Am. J. Reprod. Immunol. 2020; 84(3): e13282. https://dx.doi.org/10.1111/aji.13282.
- Gupta A., Pulliam L. Exosomes as mediators of neuroinflammation. J. Neuroinflammation. 2014; 11: 68. https://dx.doi.org/10.1186/1742-2094-11-68.
- Tsilioni I., Theoharides T.C. Extracellular vesicles are increased in the serum of children with autism spectrum disorder, contain mitochondrial DNA, and stimulate human microglia to secrete IL-1β. J. Neuroinflammation. 2018; 15(1): 239. https://dx.doi.org/10.1186/s12974-018-1275-5.
- Prada I., Gabrielli M., Turola E., Iorio A., D'Arrigo G., Parolisi R. et al. Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations. Acta Neuropathol. 2018; 135(4): 529-50. https://dx.doi.org/10.1007/s00401-017-1803-x.
- Kitase Y., Chin E.M., Ramachandra S., Burkhardt C., Madurai N.K., Lenz C. et al. Sustained peripheral immune hyper-reactivity (SPIHR): an enduring biomarker of altered inflammatory responses in adult rats after perinatal brain injury. J. Neuroinflammation. 2021; 18(1): 242. https://dx.doi.org/10.1186/s12974-021-02291-z.
- Mustapić M., Eitan E., Werner J.K., Berkowitz S.T., Lazaropoulos M.P., Tran J. et al. Plasma extracellular vesicles enriched for neuronal origin: a potential window into brain pathologic processes. Front. Neurosci. 2017; 11: 278. https://dx.doi.org/10.3389/fnins.2017.00278.
- Athauda D., Gulyani S., Karnati H.K., Li Y., Tweedie D., Mustapic M. et al. Utility of neuronal-derived exo utility of neuronal-derived exosomes to examine molecular mechanisms that affect motor function in patients with parkinson disease: a secondary analysis of the Exenatide-PD trial. JAMA Neurol. 2019; 76(4): 420-9. https://dx.doi.org/10.1001/jamaneurol.2018.4304.
- Pulliam L., Sun B., Mustapic M., Chawla S., Kapogiannis D. Plasma neuronal exosomes serve as biomarkers of cognitive impairment in HIV infection and Alzheimer's disease. J. Neurovirol. 2019; 25(5): 702-9. https://dx.doi.org/10.1007/s13365-018-0695-4.
- Goetzl E.J., Boxer A., Schwartz J.B., Abner E.L., Petersen R.C., Miller B.L. et al. Low neural exosomal levels of cellular survival factors in Alzheimer's disease. Ann. Clin. Transl. Neurol. 2015; 2(7): 769-73. https://dx.doi.org/10.1002/acn3.211.
- Goetzl E.J., Kapogiannis D., Schwartz J.B., Lobach I.V., Goetzl L., Abner E.L. et al. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease. FASEB J. 2016; 30(12): 4141-8. https://dx.doi.org/10.1096/fj.201600816R.
- Goetzl L., Darbinian N., Merabova N. Noninvasive assessment of fetal central nervous system insult: Potential application to prenatal diagnosis. Prenat. Diagn. 2019; 39(8): 609-15. https://dx.doi.org/10.1002/pd.5474.
- Goetzl L., Thompson-Felix T., Darbinian N., Merabova N., Merali S., Merali C. et al. Novel biomarkers to assess in utero effects of maternal opioid use: First steps toward understanding short- and long-term neurodevelopmental sequelae. Genes Brain Behav. 2019; 18(6): e12583. https://dx.doi.org/10.1111/gbb.12583.
- Sheller-Miller S., Lei J., Saade G., Salomon C., Burd I., Menon R. Feto-maternal trafficking of exosomes in murine pregnancy models. Front. Pharmacol. 2016; 7: 432. https://dx.doi.org/10.3389/fphar.2016.00432.
- Cho K.H.T., Xu B., Blenkiron C., Fraser M. Emerging roles of miRNAs in brain development and perinatal brain injury. Front. Physiol. 2019; 10: 227. https://dx.doi.org/10.3389/fphys.2019.00227.
Received 06.09.2024
Accepted 03.07.2024
About the Authors
Natalia E. Kan, Professor, Dr. Med. Sci., Deputy Director of Science, Honored Scientist of the Russian Federation, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, kan-med@mail.ru, Researcher ID: B-2370-2015, SPIN-code: 5378-8437, Authors ID: 624900, Scopus Author ID: 57008835600, https://orcid.org/0000-0001-5087-5946Anastasia A. Leonova, PhD student, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, nastena27-03@mail.ru, https://orcid.org/0000-0001-6707-3464
Vladislava А. Gusar, PhD, Senior Researcher at the Laboratory of Transcriptomic, Department of Systems Biology in Reproduction, Academician V.I. Kulakov National
Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, v_gusar@oparina4.ru,
https://orcid.org/0000-0003-3990-6224
Victor L. Tyutyunnik, Professor, Dr. Med. Sci., Leading Researcher of the Center for Scientific and Clinical Research, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, tioutiounnik@mail.ru,
Researcher ID: B-2364-2015, SPIN-code: 1963-1359, Authors ID: 213217, Scopus Author ID: 56190621500, https://orcid.org/0000-0002-5830-5099