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Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia-Ischemia.
Stem Cells Transl Med 2016; 5(6):754-63SC

Abstract

Preterm neonates are susceptible to perinatal hypoxic-ischemic brain injury, for which no treatment is available. In a preclinical animal model of hypoxic-ischemic brain injury in ovine fetuses, we have demonstrated the neuroprotective potential of systemically administered mesenchymal stromal cells (MSCs). The mechanism of MSC treatment is unclear but suggested to be paracrine, through secretion of extracellular vesicles (EVs). Therefore, we investigated in this study the protective effects of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) in a preclinical model of preterm hypoxic-ischemic brain injury. Ovine fetuses were subjected to global hypoxia-ischemia by transient umbilical cord occlusion, followed by in utero intravenous administration of MSC-EVs. The therapeutic effects of MSC-EV administration were assessed by analysis of electrophysiological parameters and histology of the brain. Systemic administration of MSC-EVs improved brain function by reducing the total number and duration of seizures, and by preserving baroreceptor reflex sensitivity. These functional protections were accompanied by a tendency to prevent hypomyelination. Cerebral inflammation remained unaffected by the MSC-EV treatment. Our data demonstrate that MSC-EV treatment might provide a novel strategy to reduce the neurological sequelae following hypoxic-ischemic injury of the preterm brain. Our study results suggest that a cell-free preparation comprising neuroprotective MSC-EVs could substitute MSCs in the treatment of preterm neonates with hypoxic-ischemic brain injury, thereby circumventing the potential risks of systemic administration of living cells.

SIGNIFICANCE

Bone marrow-derived mesenchymal stromal cells (MSCs) show promise in treating hypoxic-ischemic injury of the preterm brain. Study results suggest administration of extracellular vesicles, rather than intact MSCs, is sufficient to exert therapeutic effects and avoids potential concerns associated with administration of living cells. The therapeutic efficacy of systemically administered mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) on hypoxia-ischemia-induced injury was assessed in the preterm ovine brain. Impaired function and structural injury of the fetal brain was improved following global hypoxia-ischemia. A cell-free preparation of MSC-EVs could substitute for the cellular counterpart in the treatment of preterm neonates with hypoxic-ischemic brain injury. This may open new clinical applications for "off-the-shelf" interventions with MSC-EVs.

Authors+Show Affiliations

School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands Department of Pediatrics, Maastricht University, Maastricht, The Netherlands.Department of Pediatrics, Maastricht University, Maastricht, The Netherlands School of Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands Department of Pediatrics, Maastricht University, Maastricht, The Netherlands Department of Pediatrics, Máxima Medical Center, Veldhoven, The Netherlands.Department of Pediatrics, Maastricht University, Maastricht, The Netherlands Department of Biomedical Engineering, Maastricht University, Maastricht, The Netherlands.Department of Pediatrics, Maastricht University, Maastricht, The Netherlands Department of Pediatrics, Máxima Medical Center, Veldhoven, The Netherlands.Department of Biomedical Engineering, Maastricht University, Maastricht, The Netherlands School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.Department of Pediatrics, Maastricht University, Maastricht, The Netherlands.School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands Department of Pediatrics, Maastricht University, Maastricht, The Netherlands.Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany b.kramer@maastrichtuniversity.nl bernd.giebel@uk-essen.de.School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands Department of Pediatrics, Maastricht University, Maastricht, The Netherlands School of Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands b.kramer@maastrichtuniversity.nl bernd.giebel@uk-essen.de.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27160705

Citation

Ophelders, Daan R M G., et al. "Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia-Ischemia." Stem Cells Translational Medicine, vol. 5, no. 6, 2016, pp. 754-63.
Ophelders DR, Wolfs TG, Jellema RK, et al. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia-Ischemia. Stem Cells Transl Med. 2016;5(6):754-63.
Ophelders, D. R., Wolfs, T. G., Jellema, R. K., Zwanenburg, A., Andriessen, P., Delhaas, T., ... Kramer, B. W. (2016). Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia-Ischemia. Stem Cells Translational Medicine, 5(6), pp. 754-63. doi:10.5966/sctm.2015-0197.
Ophelders DR, et al. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia-Ischemia. Stem Cells Transl Med. 2016;5(6):754-63. PubMed PMID: 27160705.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia-Ischemia. AU - Ophelders,Daan R M G, AU - Wolfs,Tim G A M, AU - Jellema,Reint K, AU - Zwanenburg,Alex, AU - Andriessen,Peter, AU - Delhaas,Tammo, AU - Ludwig,Anna-Kristin, AU - Radtke,Stefan, AU - Peters,Vera, AU - Janssen,Leon, AU - Giebel,Bernd, AU - Kramer,Boris W, Y1 - 2016/05/09/ PY - 2015/08/12/received PY - 2016/01/25/accepted PY - 2016/5/11/entrez PY - 2016/5/11/pubmed PY - 2016/8/3/medline KW - Brain injury KW - Exosomes KW - Extracellular vesicles KW - Hypoxia-ischemia KW - Mesenchymal stromal cells KW - Preterm SP - 754 EP - 63 JF - Stem cells translational medicine JO - Stem Cells Transl Med VL - 5 IS - 6 N2 - UNLABELLED: Preterm neonates are susceptible to perinatal hypoxic-ischemic brain injury, for which no treatment is available. In a preclinical animal model of hypoxic-ischemic brain injury in ovine fetuses, we have demonstrated the neuroprotective potential of systemically administered mesenchymal stromal cells (MSCs). The mechanism of MSC treatment is unclear but suggested to be paracrine, through secretion of extracellular vesicles (EVs). Therefore, we investigated in this study the protective effects of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) in a preclinical model of preterm hypoxic-ischemic brain injury. Ovine fetuses were subjected to global hypoxia-ischemia by transient umbilical cord occlusion, followed by in utero intravenous administration of MSC-EVs. The therapeutic effects of MSC-EV administration were assessed by analysis of electrophysiological parameters and histology of the brain. Systemic administration of MSC-EVs improved brain function by reducing the total number and duration of seizures, and by preserving baroreceptor reflex sensitivity. These functional protections were accompanied by a tendency to prevent hypomyelination. Cerebral inflammation remained unaffected by the MSC-EV treatment. Our data demonstrate that MSC-EV treatment might provide a novel strategy to reduce the neurological sequelae following hypoxic-ischemic injury of the preterm brain. Our study results suggest that a cell-free preparation comprising neuroprotective MSC-EVs could substitute MSCs in the treatment of preterm neonates with hypoxic-ischemic brain injury, thereby circumventing the potential risks of systemic administration of living cells. SIGNIFICANCE: Bone marrow-derived mesenchymal stromal cells (MSCs) show promise in treating hypoxic-ischemic injury of the preterm brain. Study results suggest administration of extracellular vesicles, rather than intact MSCs, is sufficient to exert therapeutic effects and avoids potential concerns associated with administration of living cells. The therapeutic efficacy of systemically administered mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) on hypoxia-ischemia-induced injury was assessed in the preterm ovine brain. Impaired function and structural injury of the fetal brain was improved following global hypoxia-ischemia. A cell-free preparation of MSC-EVs could substitute for the cellular counterpart in the treatment of preterm neonates with hypoxic-ischemic brain injury. This may open new clinical applications for "off-the-shelf" interventions with MSC-EVs. SN - 2157-6564 UR - https://www.unboundmedicine.com/medline/citation/27160705/Mesenchymal_Stromal_Cell_Derived_Extracellular_Vesicles_Protect_the_Fetal_Brain_After_Hypoxia_Ischemia_ L2 - https://doi.org/10.5966/sctm.2015-0197 DB - PRIME DP - Unbound Medicine ER -