Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury

Yanlu Zhang Departments of Neurosurgery and

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Michael Chopp Neurology, Henry Ford Hospital, Detroit; and
Department of Physics, Oakland University, Rochester, Michigan

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Yuling Meng Departments of Neurosurgery and

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Mark Katakowski Neurology, Henry Ford Hospital, Detroit; and

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Hongqi Xin Neurology, Henry Ford Hospital, Detroit; and

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Asim Mahmood Departments of Neurosurgery and

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Ye Xiong Departments of Neurosurgery and

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OBJECT

Transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after traumatic brain injury (TBI). In this study the authors tested a novel hypothesis that systemic administration of cell-free exosomes generated from MSCs promotes functional recovery and neurovascular remodeling in rats after TBI.

METHODS

Two groups of 8 Wistar rats were subjected to TBI, followed 24 hours later by tail vein injection of 100 μg protein of exosomes derived from MSCs or an equal volume of vehicle (phosphate-buffered saline). A third group of 8 rats was used as sham-injured, sham-treated controls. To evaluate cognitive and sensorimotor functional recovery, the modified Morris water maze, modified Neurological Severity Score, and foot-fault tests were performed. Animals were killed at 35 days after TBI. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume, neurovascular remodeling (angiogenesis and neurogenesis), and neuroinflammation.

RESULTS

Compared with the saline-treated group, exosome-treated rats with TBI showed significant improvement in spatial learning at 34–35 days as measured by the modified Morris water maze test (p < 0.05), and sensorimotor functional recovery (i.e., reduced neurological deficits and foot-fault frequency) was observed at 14–35 days postinjury (p < 0.05). Exosome treatment significantly increased the number of newly generated endothelial cells in the lesion boundary zone and dentate gyrus and significantly increased the number of newly formed immature and mature neurons in the dentate gyrus as well as reducing neuroinflammation.

CONCLUSIONS

The authors demonstrate for the first time that MSC-generated exosomes effectively improve functional recovery, at least in part, by promoting endogenous angiogenesis and neurogenesis and by reducing inflammation in rats after TBI. Thus, MSC-generated exosomes may provide a novel cell-free therapy for TBI and possibly for other neurological diseases.

ABBREVIATIONS

BrdU = 5-bromo-2′-deoxyuridine; DCX = doublecortin; DG = dentate gyrus; EBA = endothelial barrier antigen; FBS = fetal bovine serum; GFAP = glial fibrillary acidic protein; GFP = green fluorescent protein; miRNA = microRNA; mNSS = modified Neurological Severity Score; MSC = mesenchymal stromal cell; MWM = Morris Water Maze; NeuN = neuron-specific nuclear protein; PBS = phosphate-buffered saline; TBI = traumatic brain injury.
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