Effect of Extracellular Vesicles on Neural Functional Recovery and Immunologic Suppression after Rat Cerebral Apoplexy

Abstract

Background: Previous studies have demonstrated that mesenchymal stem cells (MSCs) can promote the recovery of neural function after cerebral apoplexy by secreting multiple cytokines. In addition, cell factor-derived extracellular vesicles play an important role in recovery of neural function. The aim of this study was to determine the effect of extracellular vesicles on neural functional recovery and brain tissue remodeling after cerebral apoplexy in a rat model. Methods: The rat models with local ischemic stroke was established and three random groups were created. In groups A and B, human bone marrow-derived MSCs and MSC-derived extracellular vesicles were transplanted into rats. In the control group (group C), only normal saline was injected. Then, we evaluated motor coordination ability, pathologic changes of the brain, immune responses in the central and peripheral nervous systems, regeneration of blood vessels, and nervous tissue in 4 weeks after cerebral apoplexy. Results: Obvious regeneration of blood vessels and nervous tissues were identified in groups A and B. There was no significant difference with respect to coordination between groups A and B, but coordination in groups A and B was significantly better than the control group. Immunohistochemical staining of brain tissue showed that extracellular vesicles exerted no effect on infiltration of immune cells in the central nervous system. Weakened immune suppression was noted 1 week after cerebral apoplexy, which provided a favorable environment for remodeling of brain tissue. Conclusion: MSC-derived extracellular vesicles accelerated neural functional recovery after cerebral apoplexy. The weakened immune suppression was beneficial to remodeling of brain tissue.

Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles and Their Potential as Novel Immunomodulatory Therapeutic Agents

“…Coupled to the functional recovery, more neural cells were generated in MSC-EV-treated than in control animals [ 62 , 63 , 68 ]. Comparable to the other organ systems discussed before, MSC-EV treatment reduced apoptosis rates in affected brains, but promoted angiogenesis and neurogenesis instead [ 63 , 66 , 70 , 71 , 73 , 74 ]. Both, systemic pro-inflammatory and neuro-inflammatory cues were reduced following MSC-EV treatment.…”

“…Regarding the brain, impacts of MSC-EV treatment were mainly studied in models for ischemic stroke and traumatic brain injury (TBI) [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. In addition, we studied the therapeutic effects of MSC-EVs in a rat model for inflammation-induced preterm and a sheep model for hypoxia-induced fetal brain injury [ 72 , 73 ].…”

“…Both, systemic pro-inflammatory and neuro-inflammatory cues were reduced following MSC-EV treatment. Amongst others, the number of invading macrophages into the affected brain areas was found to be reduced [ 62 , 63 , 64 , 68 , 70 , 72 , 73 ].…”

Trophic Effects of Mesenchymal Stem Cells in Tissue Regeneration

“…137,147 Both studies found equally positive therapeutic effects of MSCs and EVs. Improvement of neurological impairment, neuroprotection, and neurogenesis and angiogenesis were equally stimulated by the presence of either MSCs or EVs.…”

“…135 Therefore, several studies have evaluated whether stem cell-derived EVs perform similar to MSCs in tissue regeneration in vivo. [136][137][138] The use of MSC derived EVs rather than the cells themselves may avoid possible long-term mal-differentiation of engrafted cells and attenuate many of the safety concerns related to the use of living cells.…”