The Role of Extracellular Vesicles in the Developing Brain: Current Perspective and Promising Source of Biomarkers and Therapy for Perinatal Brain Injury

Overview

Journal Front Neurosci

Date 2021 Oct 11

PMID 34630028

Citations 7

Authors

Teena K J B Gamage

Mhoyra Fraser

Affiliations

Soon will be listed here.

Abstract

This comprehensive review focuses on our current understanding of the proposed physiological and pathological functions of extracellular vesicles (EVs) in the developing brain. Furthermore, since EVs have attracted great interest as potential novel cell-free therapeutics, we discuss advances in the knowledge of stem cell- and astrocyte-derived EVs in relation to their potential for protection and repair following perinatal brain injury. This review identified 13 peer-reviewed studies evaluating the efficacy of EVs in animal models of perinatal brain injury; 12/13 utilized mesenchymal stem cell-derived EVs (MSC-EVs) and 1/13 utilized astrocyte-derived EVs. Animal model, method of EV isolation and size, route, timing, and dose administered varied between studies. Notwithstanding, EV treatment either improved and/or preserved perinatal brain structures both macroscopically and microscopically. Additionally, EV treatment modulated inflammatory responses and improved brain function. Collectively this suggests EVs can ameliorate, or repair damage associated with perinatal brain injury. These findings warrant further investigation to identify the optimal cell numbers, source, and dosage regimens of EVs, including long-term effects on functional outcomes.

Citing Articles

Extracellular vesicles and preterm infant diseases.

Chen W, Kongsomros S, Thorman A, Esfandiari L, Morrow A, Chutipongtanate S Front Pediatr. 2025; 13:1550115.

PMID: 40034714 PMC: 11873092. DOI: 10.3389/fped.2025.1550115.

Congenital Zika Syndrome: Insights from Integrated Proteomic and Metabolomic Analysis.

Gomes-de-Pontes L, Barreiros L, Gomes L, Salgado R, da Silva Napoleao S, Soeiro-Pereira P Biomolecules. 2025; 15(1).

PMID: 39858427 PMC: 11762526. DOI: 10.3390/biom15010032.

Unraveling the Emerging Niche Role of Extracellular Vesicles (EVs) in Traumatic Brain Injury (TBI).

Ashique S, Pal R, Sharma H, Mishra N, Garg A CNS Neurol Disord Drug Targets. 2024; 23(11):1357-1370.

PMID: 38351688 DOI: 10.2174/0118715273288155240201065041.

Circulating exosomes decrease in size and increase in number between birth and age 7: relations to fetal growth and liver fat.

Diaz M, Casano P, Quesada T, Lopez-Bermejo A, de Zegher F, Villarroya F Front Endocrinol (Lausanne). 2023; 14:1257768.

PMID: 38027180 PMC: 10653443. DOI: 10.3389/fendo.2023.1257768.

Anti-inflammatory effects of antenatal administration of stem cell derived extracellular vesicles in the brain of rat fetuses with congenital diaphragmatic hernia.

Blundell M, Doktor F, Figueira R, Khalaj K, Biouss G, Antounians L Pediatr Surg Int. 2023; 39(1):291.

PMID: 37955723 DOI: 10.1007/s00383-023-05578-9.

References

Bassler D, Stoll B, Schmidt B, Asztalos E, Roberts R, Robertson C . Using a count of neonatal morbidities to predict poor outcome in extremely low birth weight infants: added role of neonatal infection. Pediatrics. 2009; 123(1):313-8. PMC: 2829863. DOI: 10.1542/peds.2008-0377. View

Thomi G, Surbek D, Haesler V, Joerger-Messerli M, Schoeberlein A . Exosomes derived from umbilical cord mesenchymal stem cells reduce microglia-mediated neuroinflammation in perinatal brain injury. Stem Cell Res Ther. 2019; 10(1):105. PMC: 6429800. DOI: 10.1186/s13287-019-1207-z. View

Danzer K, Kranich L, Ruf W, Cagsal-Getkin O, Winslow A, Zhu L . Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener. 2012; 7:42. PMC: 3483256. DOI: 10.1186/1750-1326-7-42. View

de Almeida P, Ransohoff J, Nahid A, Wu J . Immunogenicity of pluripotent stem cells and their derivatives. Circ Res. 2013; 112(3):549-61. PMC: 3638957. DOI: 10.1161/CIRCRESAHA.111.249243. View

Inder T, Anderson N, Spencer C, Wells S, Volpe J . White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term. AJNR Am J Neuroradiol. 2003; 24(5):805-9. PMC: 7975772. View

Reddy K, Mallard C, Guan J, Marks K, Bennet L, Gunning M . Maturational change in the cortical response to hypoperfusion injury in the fetal sheep. Pediatr Res. 1998; 43(5):674-82. DOI: 10.1203/00006450-199805000-00017. View

Izadpanah R, Kaushal D, Kriedt C, Tsien F, Patel B, Dufour J . Long-term in vitro expansion alters the biology of adult mesenchymal stem cells. Cancer Res. 2008; 68(11):4229-38. PMC: 2713721. DOI: 10.1158/0008-5472.CAN-07-5272. View

El Andaloussi S, Mager I, Breakefield X, Wood M . Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013; 12(5):347-57. DOI: 10.1038/nrd3978. View

Ranasinghe H, Williams C, Christophidis L, Mitchell M, Fraser M, Scheepens A . Proteolytic activity during cortical development is distinct from that involved in hypoxic ischemic injury. Neuroscience. 2008; 158(2):732-44. DOI: 10.1016/j.neuroscience.2008.07.069. View

10.

Cook D, Tymianski M . Translating promising preclinical neuroprotective therapies to human stroke trials. Expert Rev Cardiovasc Ther. 2011; 9(4):433-49. DOI: 10.1586/erc.11.34. View

11.

van Velthoven C, Kavelaars A, van Bel F, Heijnen C . Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun. 2009; 24(3):387-93. DOI: 10.1016/j.bbi.2009.10.017. View

12.

Donders R, Bogie J, Ravanidis S, Gervois P, Vanheusden M, Maree R . Human Wharton's Jelly-Derived Stem Cells Display a Distinct Immunomodulatory and Proregenerative Transcriptional Signature Compared to Bone Marrow-Derived Stem Cells. Stem Cells Dev. 2017; 27(2):65-84. DOI: 10.1089/scd.2017.0029. View

13.

Hagberg H, Mallard C, Ferriero D, Vannucci S, Levison S, Vexler Z . The role of inflammation in perinatal brain injury. Nat Rev Neurol. 2015; 11(4):192-208. PMC: 4664161. DOI: 10.1038/nrneurol.2015.13. View

14.

de Paula S, Greggio S, DaCosta J . Use of stem cells in perinatal asphyxia: from bench to bedside. J Pediatr (Rio J). 2010; 86(6):451-64. DOI: 10.2223/JPED.2035. View

15.

de Haan T, Bijleveld Y, van der Lee J, Groenendaal F, van den Broek M, Rademaker C . Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study. BMC Pediatr. 2012; 12:45. PMC: 3358232. DOI: 10.1186/1471-2431-12-45. View

16.

Hagberg H, Gilland E, Bona E, Hanson L, Blennow M, Holst M . Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats. Pediatr Res. 1996; 40(4):603-9. DOI: 10.1203/00006450-199610000-00015. View

17.

Irmady K, Jackman K, Padow V, Shahani N, Martin L, Cerchietti L . Mir-592 regulates the induction and cell death-promoting activity of p75NTR in neuronal ischemic injury. J Neurosci. 2014; 34(9):3419-28. PMC: 3935094. DOI: 10.1523/JNEUROSCI.1982-13.2014. View

18.

Liu W, Wang Y, Gong F, Rong Y, Luo Y, Tang P . Exosomes Derived from Bone Mesenchymal Stem Cells Repair Traumatic Spinal Cord Injury by Suppressing the Activation of A1 Neurotoxic Reactive Astrocytes. J Neurotrauma. 2018; 36(3):469-484. DOI: 10.1089/neu.2018.5835. View

19.

Ratajczak M, Kucia M, Jadczyk T, Greco N, Wojakowski W, Tendera M . Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: can we translate stem cell-secreted paracrine factors and microvesicles into better therapeutic strategies?. Leukemia. 2011; 26(6):1166-73. DOI: 10.1038/leu.2011.389. View

20.

Lutz I, Allegaert K, de Hoon J, Marynissen H . Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review. BMJ Paediatr Open. 2020; 4(1):e000685. PMC: 7299043. DOI: 10.1136/bmjpo-2020-000685. View