MiR-126 Mediates Brain Endothelial Cell Exosome Treatment–Induced Neurorestorative Effects After Stroke in Type 2 Diabetes Mellitus Mice
Open accessAbstract
Background and Purpose—: Stroke patients with type 2 diabetes mellitus (T2DM) exhibit increased vascular and white matter damage and have worse prognosis compared with nondiabetic stroke patients. We investigated the neurorestorative effects of exosomes derived from mouse brain endothelial cells (EC-Exo) as treatment for stroke in T2DM mice and investigated the role of miR-126 in mediating EC-Exo–derived therapeutic benefits in T2DM-stroke mice. Methods—: Adult, male BKS.Cg-m+/+Lepr db /J (T2DM) mice were subjected to photothrombotic stroke model. T2DM mice were intravenously injected at 3 days after stroke with (1) PBS; (2) liposome mimic (vehicle control, 3×10 10 ); (3) EC-Exo (3×10 10 ); (4) knockdown of miR-126 in EC-Exo (miR-126 − /− EC-Exo, 3×10 10 ). Behavioral and cognitive tests were performed, and mice were sacrificed at 28 days after stroke. Results—: Compared with non-DM stroke mice, T2DM-stroke mice exhibit significantly decreased serum and brain tissue miR-126 expression. Endothelial cells and EC-Exo contain high levels of miR-126 compared with other cell types or exosomes derived from other types of cells, respectively (smooth muscle cells, astrocytes, and marrow stromal cells). Compared with PBS or liposome mimic treatment, EC-Exo treatment of T2DM-stroke mice significantly improves neurological and cognitive function, increases axon density, myelin density, vascular density, arterial diameter, as well as induces M2 macrophage polarization in the ischemic boundary zone. MiR-126 −/− EC-Exo treatment significantly decreases miR-126 expression in serum and brain, as well as attentuates EC-Exo treatment–induced functional improvement and does not significantly increase axon and myelin density, vascular density, arterial diameter or induce M2 macrophage polarization in T2DM-stroke mice. In vitro, EC-Exo treatment significantly increases primary cortical neuron axonal outgrowth and increases endothelial capillary tube formation whereas miR-126 −/− EC-Exo attentuates EC-Exo induced capillary tube formation and axonal outgrowth. Conclusions—: EC-Exo treatment of stroke promotes neurorestorative effects in T2DM mice. MiR-126 may mediate EC-Exo–induced neurorestorative effects in T2DM mice. Visual Overview—: An online visual overview is available for this article.
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Cites a retracted work: 10.1177/0271678x17708917
InfoThe cited work was retracted on 2020-12-11 (notice 10.1177/0271678x20976843), not before this paper was published (2019-10).
Cited work 10.1177/0271678x17708917 · retracted 2020-12-11 · notice 10.1177/0271678x20976843 · this paper published 2019-10
“Otero-Ortega, L, Gomez de Frutos, MC, Laso-Garcia, F, Rodriguez-Frutos, B, Medina-Gutierrez, E, Lopez, JA, et al. Exosomes promote restoration after an experimental animal model of intracerebral hemorrhage. J Cereb Blood Flow Metab. 2017;38:767–779.”
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- Authors
- Venkat, P., Cui, C., Chopp, M., Zacharek, A., Wang, F., Landschoot-Ward, J., Shen, Y., & Chen, J.
- Affiliations
- Henry Ford Hospital (US)
- Oakland University (US)
- From the Department of Neurology, Henry Ford Hospital, Detroit, MI (P.V., C.C., M.C., A.Z., F.W., J.L.-W., Y.S., J.C.)
- Corresponding author
- Chen, Jieli
- Venue
- Stroke
- Published
- 2019-10
- Volume
- 50
- Issue
- 10
- Pages
- 2865-2874
- ISSN
- 0039-2499 (ISSN-L)
- 1524-4628
- PMC
- PMC6756941
- OpenAlex
- W2969048789
- Semantic Scholar
- dc5835f576f1408ac136968a6872ec48c9149fd7
- Cited by
- 172
- References
- 39
- Citations by year
- 2026: 16 · 2025: 19 · 2024: 28 · 2023: 36 · 2022: 34 · 2021: 23 · 2020: 15 · 2019: 1
- FWCI
- 5.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Stroke (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Henry Ford Health System
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL143432)
- National Institute of Neurological Disorders and Stroke (R01NS099030)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- miR-126, exosomes, brain endothelial cells, type 2 diabetes, neurorestoration, M2 macrophage polarization, axon growth, capillary tube formation, neurovascular unit, diabetic stroke, microRNA knockdown, photothrombotic stroke, cognitive function
- MeSH terms
- Animals, Brain, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Male, Stroke, MicroRNAs, Endothelial Cells, Mice, Exosomes
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