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Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats.

Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M - J. Cereb. Blood Flow Metab. (2013)

Bottom Line: Axonal density and synaptophysin-positive areas were significantly increased along the ischemic boundary zone of the cortex and striatum in MCAo rats treated with exosomes compared with PBS control.Exosome treatment significantly increased the number of newly formed doublecortin (a marker of neuroblasts) and von Willebrand factor (a marker of endothelial cells) cells.Our results suggest that intravenous administration of cell-free MSC-generated exosomes post stroke improves functional recovery and enhances neurite remodeling, neurogenesis, and angiogenesis and represents a novel treatment for stroke.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Henry Ford Health Sciences Center, Henry Ford Hospital, Detroit, Michigan, USA.

ABSTRACT
Here, for the first time, we test a novel hypothesis that systemic treatment of stroke with exosomes derived from multipotent mesenchymal stromal cells (MSCs) promote neurovascular remodeling and functional recovery after stroke in rats. Adult male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo) followed by tail vein injection of 100 μg protein from MSC exosome precipitates or an equal volume of vehicle phosphate-buffered saline (PBS) (n=6/group) 24 hours later. Animals were killed at 28 days after stroke and histopathology and immunohistochemistry were employed to identify neurite remodeling, neurogenesis, and angiogenesis. Systemic administration of MSC-generated exosomes significantly improved functional recovery in stroke rats compared with PBS-treated controls. Axonal density and synaptophysin-positive areas were significantly increased along the ischemic boundary zone of the cortex and striatum in MCAo rats treated with exosomes compared with PBS control. Exosome treatment significantly increased the number of newly formed doublecortin (a marker of neuroblasts) and von Willebrand factor (a marker of endothelial cells) cells. Our results suggest that intravenous administration of cell-free MSC-generated exosomes post stroke improves functional recovery and enhances neurite remodeling, neurogenesis, and angiogenesis and represents a novel treatment for stroke.

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Exosomes increase neurogenesis and angiogenesis in the ischemic boundary zone (IBZ). Compared with phosphate-buffered saline (PBS) treatment, the 5-bromodeoxyuridine (BrdU)-labeled cells in the IBZ were significantly increased after exosome treatment (A row). Representative micrographs show the double-stained cells with doublecortin (DCX) and BrdU (B row) or von Willebrand factor (vWF) and BrdU (C row). Compared with PBS treatment, exosome treatment significantly increased the percentage of BrdU–DCX stained cells (B) and BrdU–endothelial cells stained cells in the IBZ (C) in rats after stroke, respectively. *P<0.05, mean±s.d., n=6/group. Scale bar, 50 μm. DAPI, 4′,6-diamidino-2-phenylindole.
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fig4: Exosomes increase neurogenesis and angiogenesis in the ischemic boundary zone (IBZ). Compared with phosphate-buffered saline (PBS) treatment, the 5-bromodeoxyuridine (BrdU)-labeled cells in the IBZ were significantly increased after exosome treatment (A row). Representative micrographs show the double-stained cells with doublecortin (DCX) and BrdU (B row) or von Willebrand factor (vWF) and BrdU (C row). Compared with PBS treatment, exosome treatment significantly increased the percentage of BrdU–DCX stained cells (B) and BrdU–endothelial cells stained cells in the IBZ (C) in rats after stroke, respectively. *P<0.05, mean±s.d., n=6/group. Scale bar, 50 μm. DAPI, 4′,6-diamidino-2-phenylindole.

Mentions: Middle cerebral artery occlusion increases cell proliferation within the subventricular zone of the adult rat.26 Newly formed neuroblasts migrate from the subventricular zone into the damaged striatum and cortex.27 Compared with PBS treatment, the BrdU-labeled cells in the IBZ were significantly increased after exosome treatment (Figure 4, row A, P<0.05). Doublecortin is a microtubule-associated protein expressed by migrating neuroblasts in the adult brain.28 To examine the effect of exosome treatment on neuroblasts, we measured the percentage of DCX- and BrdU-positive cells. Compared with PBS treatment, exosome treatment significantly increased the percentage of BrdU–DCX-positive cells in the IBZ (Figure 4, row B, P<0.05), suggesting that exosomes promote neurogenesis post stroke.


Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats.

Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M - J. Cereb. Blood Flow Metab. (2013)

Exosomes increase neurogenesis and angiogenesis in the ischemic boundary zone (IBZ). Compared with phosphate-buffered saline (PBS) treatment, the 5-bromodeoxyuridine (BrdU)-labeled cells in the IBZ were significantly increased after exosome treatment (A row). Representative micrographs show the double-stained cells with doublecortin (DCX) and BrdU (B row) or von Willebrand factor (vWF) and BrdU (C row). Compared with PBS treatment, exosome treatment significantly increased the percentage of BrdU–DCX stained cells (B) and BrdU–endothelial cells stained cells in the IBZ (C) in rats after stroke, respectively. *P<0.05, mean±s.d., n=6/group. Scale bar, 50 μm. DAPI, 4′,6-diamidino-2-phenylindole.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824189&req=5

fig4: Exosomes increase neurogenesis and angiogenesis in the ischemic boundary zone (IBZ). Compared with phosphate-buffered saline (PBS) treatment, the 5-bromodeoxyuridine (BrdU)-labeled cells in the IBZ were significantly increased after exosome treatment (A row). Representative micrographs show the double-stained cells with doublecortin (DCX) and BrdU (B row) or von Willebrand factor (vWF) and BrdU (C row). Compared with PBS treatment, exosome treatment significantly increased the percentage of BrdU–DCX stained cells (B) and BrdU–endothelial cells stained cells in the IBZ (C) in rats after stroke, respectively. *P<0.05, mean±s.d., n=6/group. Scale bar, 50 μm. DAPI, 4′,6-diamidino-2-phenylindole.
Mentions: Middle cerebral artery occlusion increases cell proliferation within the subventricular zone of the adult rat.26 Newly formed neuroblasts migrate from the subventricular zone into the damaged striatum and cortex.27 Compared with PBS treatment, the BrdU-labeled cells in the IBZ were significantly increased after exosome treatment (Figure 4, row A, P<0.05). Doublecortin is a microtubule-associated protein expressed by migrating neuroblasts in the adult brain.28 To examine the effect of exosome treatment on neuroblasts, we measured the percentage of DCX- and BrdU-positive cells. Compared with PBS treatment, exosome treatment significantly increased the percentage of BrdU–DCX-positive cells in the IBZ (Figure 4, row B, P<0.05), suggesting that exosomes promote neurogenesis post stroke.

Bottom Line: Axonal density and synaptophysin-positive areas were significantly increased along the ischemic boundary zone of the cortex and striatum in MCAo rats treated with exosomes compared with PBS control.Exosome treatment significantly increased the number of newly formed doublecortin (a marker of neuroblasts) and von Willebrand factor (a marker of endothelial cells) cells.Our results suggest that intravenous administration of cell-free MSC-generated exosomes post stroke improves functional recovery and enhances neurite remodeling, neurogenesis, and angiogenesis and represents a novel treatment for stroke.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Henry Ford Health Sciences Center, Henry Ford Hospital, Detroit, Michigan, USA.

ABSTRACT
Here, for the first time, we test a novel hypothesis that systemic treatment of stroke with exosomes derived from multipotent mesenchymal stromal cells (MSCs) promote neurovascular remodeling and functional recovery after stroke in rats. Adult male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo) followed by tail vein injection of 100 μg protein from MSC exosome precipitates or an equal volume of vehicle phosphate-buffered saline (PBS) (n=6/group) 24 hours later. Animals were killed at 28 days after stroke and histopathology and immunohistochemistry were employed to identify neurite remodeling, neurogenesis, and angiogenesis. Systemic administration of MSC-generated exosomes significantly improved functional recovery in stroke rats compared with PBS-treated controls. Axonal density and synaptophysin-positive areas were significantly increased along the ischemic boundary zone of the cortex and striatum in MCAo rats treated with exosomes compared with PBS control. Exosome treatment significantly increased the number of newly formed doublecortin (a marker of neuroblasts) and von Willebrand factor (a marker of endothelial cells) cells. Our results suggest that intravenous administration of cell-free MSC-generated exosomes post stroke improves functional recovery and enhances neurite remodeling, neurogenesis, and angiogenesis and represents a novel treatment for stroke.

Show MeSH
Related in: MedlinePlus