Extracellular Vesicles as a Potential Therapy for Neonatal Conditions: State of the Art and Challenges in Clinical Translation
Abstract
:1. Introduction
2. Methods
3. Hypoxic Ischemic Encephalopathy
4. Retinopathy of Prematurity
5. Spina Bifida
6. Bronchopulmonary Dysplasia
7. Necrotizing Enterocolitis
8. Summary of Neonatal Conditions with EV Based Therapy Reported in the Literature
9. Considerations and Challenges in the Therapeutic Application of EVs: Identity, Potency, Purity, Safety, and Quality
10. Final Remarks
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Study | EV Source | EV Isolation Technique | EV Administration Route | Model | Biological Effect |
---|---|---|---|---|---|
Hypoxic Ischemic Encephalopathy (HIE) | |||||
Ophelders et al. 2016 [32] | Human BM-MSCs | PEG + NaCl, low-speed centrifugation | In utero intravenous | In vivo: HIE ovine model | Reduced number and duration of seizures, restored myelination, restored baroreflex sensitivity |
Joerger-Messerli et al. 2018 [37] | Human WJ-MSCs | Serial centrifugation | Addition into culture media | In vitro: mouse neuroblastoma cell line neuro2a | Protected against hypoxic ischemic-induced apoptosis in neuronal cells |
Sisa et al. 2019 [26] | Human BM-MSCs | UC | Intranasal | In vivo: HIE mouse model | Decreased microglia activation, cell death, and tissue loss, and improved behavior |
Gussenhoven et al. 2019 [33] | Human BM-MSCs | PEG, low-speed centrifugation | In utero intravenous | In vivo: HIE ovine model | EVs containing AnnexinA1 restored blood–brain barrier integrity |
Retinopathy of Prematurity (ROP) | |||||
Moisseiev et al. 2017 [42] | Human BM-MSCs | Tangential flow filtration | Intravitreal | In vivo: ROP mouse model | Preserved retinal blood flow and reduced retinal thickening, decreased severity of retinal ischemia |
Xu et al. 2019 [44] | BV2 microglial cells | UC | Intravitreal | In vivo: ROP mouse model | Reduced central avascular area, decreased neovascularization and VEGF, suppressed photoreceptor apoptosis, alleviated ER stress |
Spina Bifida (SB) | |||||
Kumar et al. 2019 [58] | Human P-MSCs | Differential centrifugation | Addition into culture media | In vitro: Human neuroblastoma cell line (SH-SY5Y) | Increased number of neurites, exerted neuroprotective effect mediated through Galectin 1 |
Bronchopulmonary Dysplasia (BPD) | |||||
Lee et al. 2012 [72] | Mouse BM-MSCs and human WJ-MSCs | Ultrafiltration, PEG, size exclusion chromatography, UC | Left jugular vein or tail vein | In vivo: HPH mouse model | Suppressed pulmonary macrophage influx and inhibited pulmonary vascular remodeling |
Braun et al. 2018 [74] | Rat BM-MSCs | UC | Intraperitoneal | In vivo: BPD rat model In vitro: Human umbilical vein endothelial cells | Protected alveolarization and angiogenesis Increased capillary network formation via VEGF |
Ahn et al. 2018 [75] | Human UCB-MSCs | UC | Intratracheal | In vivo: BPD rat model | EVs promoted alveolarization and angiogenesis, decreased cell death, attenuated macrophages and proinflammatory cytokines via VEGF |
Chaubey et al. 2018 [73] | Human WJ-MSCs from mothers delivering preterm babies | Differential centrifugation | Intraperitoneal | In vivo: BPD mouse model | Ameliorated pulmonary inflammation, alveolar–capillary leakage, alveolar simplification, and pulmonary hypertension Improved lung, cardiac, and brain pathology through TSG-6 |
Willis et al. 2018 [70] | Human WJ-MSCs and human BM-MSCs | Flotation on OptiPrep cushion | Intravenous | In vivo: BPD mouse model In vitro: mouse bone marrow-derived macrophages or alveolar macrophages | Promoted alveolarization and angiogenesis, improved pulmonary function, modulated macrophage phenotype (augmenting anti-inflammatory subtype) Reduced proinflammatory markers and promoted anti-inflammatory markers |
Porzionato et al. 2018 [12] | Human umbilical cord MSCs | Tangential flow filtration | Intratracheal | In vivo: BPD rat model | Reduced hyperoxia-induced lung damage, with EVs performing better than parent cells at maintaining alveolarization and lung vascularization |
Necrotizing Enterocolitis (NEC) | |||||
Rager et al. 2016 [85] | Murine BM-MSCs | P100 PureExo Exosome Isolation reagent (in vivo) UC (in vitro) | Intraperitoneal | In vivo: NEC rat model In vitro: intestinal epithelial cell (IEC-6) wound healing assay | Decreased incidence and severity of NEC and preserved gut barrier function Improved cell mobility and wound healing |
Hock et al. 2017 [89] | Rat breastmilk | ExoQuick reagent | Addition into culture media | In vitro: rat small intestine epithelial cells (IEC-18) | Increased cell proliferation and intestinal stem cell activity |
McCulloh et al. 2018 [86] | Rat BM-MSCs, AF-MSCs, AF-NSCs, E-NSCs | UC | Intraperitoneal | In vivo: NEC rat model | All sources of exosomes reduced NEC incidence and severity at a concentration of 4.0 × 108 particles |
Martin et al. 2018 [90] | Human breastmilk | UC | Addition into culture media | In vitro: rat small intestine epithelial cell line (IEC-18) | Protected against oxidative stress |
Li et al. 2019 [93] | Bovine breastmilk | UC | Orogastric | In vivo: NEC mouse model In vitro: LS174T human colonic cells | Protected ileum from NEC-induced alterations, increased goblet cell expression Promoted goblet cell expression and increased mucin production |
Wang et al. 2019 [92] | Human breastmilk from mothers delivering preterm versus term babies | UC | Orogastric | In vivo: NEC rat model In vitro: Human normal intestinal epithelial FHC | Preterm milk exosomes protected villous integrity, restored enterocyte proliferation Preterm milk exosomes improved proliferation of intestinal epithelial cells compared to term milk exosomes 70 significantly modulated peptides, from 28 parent proteins, were differentially expressed in preterm milk exosomes compared to term milk exosomes |
Cargo Type | Study | EV Source | Disease Model | Factor(s) | Pathways and Biological Functions |
---|---|---|---|---|---|
Proteins | Moisseiev et al. 2017 [42] | Human BM-MSCs | ROP | cAMP response element-binding protein pathway | Prosurvival heat shock protein pathways |
Braun et al. 2018 [74] | Rat BM-MSCs | BPD | VEGF | Lung vascularization and alveolarization | |
Ahn et al. 2018 [75] | Human UCB-MSCs | BPD | VEGF | Lung vascularization and alveolarization, decreased IL-1α, IL-1β, IL- 6, TNF-α | |
Chaubey et al. 2018 [73] | Human WJ-MSCs | BPD | TSG-6 | Decreased proinflammatory cytokines IL- 6, TNF-α, and IL-1β and cell death | |
Wang et at. 2019 [92] | Human breastmilk | NEC | peptides derived from protein domain regions of lactotransferrin (LTF) and lactadherin (MFGE8) | LTF: stimulated intestinal cell proliferation MFGE8: promoted neural stem cell proliferation and migration, regeneration of injured intestinal mucosa by accelerating migration and proliferation through protein kinase C-dependent pathway | |
Gussenhoven et al. 2019 [33] | Human BM-MSCs | HIE | Annexin A1 | Formyl peptide receptor signaling promoting cytoskeletal stability, enhancing tight junction formation, and regulating BBB | |
Kumar et al. 2019 [58] | Human P-MSCs | SB | Galectin 1 | Involved in the adhesion of exosomes to cells | |
Nucleic acids | Lee et al. 2012 [72] | Mouse BM-MSCs | BPD | miRNA-16, miRNA-21, let7b pre-miRNA | Suppressed STAT3 and miR-17 microRNA superfamily, increased miR-204 |
Joerger-Messerli et al. 2018 [37] | Human WJ-MSCs | HIE | let-7-5p miR | Suppressed caspase 3 involved in apoptosis | |
Xu et al. 2019 [44] | BV2 microglial cells | ROP | miR-24-3p | Inhibited the inositol-requiring enzyme 1a (IRE1a)-X-box binding protein 1 (XBP1) cascade that contributes to apoptosis |
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Matei, A.C.; Antounians, L.; Zani, A. Extracellular Vesicles as a Potential Therapy for Neonatal Conditions: State of the Art and Challenges in Clinical Translation. Pharmaceutics 2019, 11, 404. https://doi.org/10.3390/pharmaceutics11080404
Matei AC, Antounians L, Zani A. Extracellular Vesicles as a Potential Therapy for Neonatal Conditions: State of the Art and Challenges in Clinical Translation. Pharmaceutics. 2019; 11(8):404. https://doi.org/10.3390/pharmaceutics11080404
Chicago/Turabian StyleMatei, Andreea C., Lina Antounians, and Augusto Zani. 2019. "Extracellular Vesicles as a Potential Therapy for Neonatal Conditions: State of the Art and Challenges in Clinical Translation" Pharmaceutics 11, no. 8: 404. https://doi.org/10.3390/pharmaceutics11080404
APA StyleMatei, A. C., Antounians, L., & Zani, A. (2019). Extracellular Vesicles as a Potential Therapy for Neonatal Conditions: State of the Art and Challenges in Clinical Translation. Pharmaceutics, 11(8), 404. https://doi.org/10.3390/pharmaceutics11080404