Mesenchymal stem cell-derived exosomes promote neurogenesis and cognitive function recovery in a mouse model of Alzheimer’s disease

Kuang

et al. 2020

Transl. Stroke Res.

Stem cells such as mesenchymal stem cells (MSCs) enhance neurological recovery in preclinical stroke models by secreting extracellular vesicles (EVs). Since previous reports have focused on the application of MSC-EVs only, the role of the most suitable host cell for EV enrichment and preclinical stroke treatment remains elusive. The present study aimed to evaluate the therapeutic potential of EVs derived from neural progenitor cells (NPCs) following experimental stroke. Using the PEG technique, EVs were enriched and characterized by electron microscopy, proteomics, rt-PCR, nanosight tracking analysis, and Western blotting. Different dosages of NPC-EVs displaying a characteristic profile in size, shape, cargo protein, and non-coding RNA contents were incubated in the presence of cerebral organoids exposed to oxygen-glucose deprivation (OGD), significantly reducing cell injury when compared with control organoids. Systemic administration of NPC-EVs in male C57BL6 mice following experimental ischemia enhanced neurological recovery and neuroregeneration for as long as 3 months. Interestingly, the therapeutic impact of such NPC-EVs was found to be not inferior to MSC-EVs. Flow cytometric analyses of blood and brain samples 7 days post-stroke demonstrated increased blood concentrations of B and T lymphocytes after NPC-EV delivery, without affecting cerebral cell counts. Likewise, a biodistribution analysis after systemic delivery of NPC-EVs revealed the majority of NPC-EVs to be found in extracranial organs such as the liver and the lung. This proof-of-concept study supports the idea of EVs being a general concept of stem cell–induced neuroprotection under stroke conditions, where EVs contribute to reverting the peripheral post-stroke immunosuppression. Electronic supplementary material The online version of this article (10.1007/s12975-020-00814-z) contains supplementary material, which is available to authorized users.

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles Derived from Neural Progenitor Cells––a Preclinical Evaluation for Stroke Treatment in Mice

Zheng

Kuang

et al. 2020

Transl. Stroke Res.

“…At present, mesenchymal stem cells (MSCs), which have powerful anti-inflammatory and wound repair effects, have a wide range of applications in medical field (23)(24)(25)(26). In addition, some studies have found that MSCs can improve the progression of numerous neurological diseases, such as stroke (27)(28)(29), multiple sclerosis (30)(31)(32), and Alzheimer's disease (33)(34)(35). Based on these reports, the potential role of MSCs in protecting the integrity of BBB after burn trauma needs to be further studied.…”

Section: Introductionmentioning

confidence: 99%

Burns Impair Blood-Brain Barrier and Mesenchymal Stem Cells Can Reverse the Process in Mice

Yang

et al. 2020

Front. Immunol.

Neurological syndromes are observed in numerous patients who suffer burns, which add to the economic burden of societies and families. Recent studies have implied that bloodbrain barrier (BBB) dysfunction is the key factor that induces these central nervous system (CNS) syndromes in peripheral traumatic disease, e.g., surgery and burns. However, the effect of burns on BBB and the underlying mechanism remains, largely, to be determined. The present study aimed to investigate the effect of burns on BBB and the potential of umbilical cord-derived mesenchymal stem cells (UC-MSCs), which have strong antiinflammatory and repairing ability, to protect the integrity of BBB. BBB permeability was evaluated using dextran tracer (immunohistochemistry imaging and spectrophotometric quantification) and western blot, interleukin (IL)-6, and IL-1b levels in blood and brain were measured by enzyme-linked immunosorbent assay. Furthermore, transmission electron microscopy (TEM) was used to detect transcellular vesicular transport (transcytosis) in BBB. We found that burns increased mouse BBB permeability to both 10-kDa and 70-kDa dextran. IL-6 and IL-1b levels increased in peripheral blood and CNS after burns. In addition, burns decreased the level of tight junction proteins (TJs), including claudin-5, occludin, and ZO-1, which indicated increased BBB permeability due to paracellular pathway. Moreover, increased vesicular density after burns suggested increased transcytosis in brain microvascular endothelial cells. Finally, administering UC-MSCs at 1 h after burns effectively reversed these adverse effects and protected the integrity of BBB. These results suggest that burns increase BBB permeability through both paracellular pathway and transcytosis, the potential mechanism of which might be through increasing IL-6 and IL-1b levels and decreasing Mfsd2a level, and appropriate treatment with UC-MSCs can reverse these effects and protect the integrity of BBB after burns.

“…In a study, the researchers co-cultured the damaged cortical neurons with adipose stem cells, and found that exosomes secreted by neural stem cells can exert neuroprotective functions by inhibiting neuronal apoptosis, thereby promoting the central nervous system (CNS) regeneration and repair (Hong et al, 2019). Another study showed that mesenchymal stem cellderived exosomes stimulated neurogenesis in the SVZ region and reduced neurological damage (Reza-Zaldivar et al, 2019). In this study, we found that the content of exosomes was increased in the peri-ischemic striatum after EA treatment, accompanied by the improvement of neurological deficits after stroke.…”

Section: Discussionmentioning

confidence: 99%

Electro-Acupuncture Promotes the Differentiation of Endogenous Neural Stem Cells via Exosomal microRNA 146b After Ischemic Stroke

Jin

Wang

et al. 2020

Front. Cell. Neurosci.

Background: Evidences indicate that exosomes-mediated delivery of microRNAs (miRNAs or miRs) is involved in the neurogenesis of stroke. This study was to investigate the role of exosomal miRNAs in non-drug therapy of electro-acupuncture (EA) regulating endogenous neural stem cells for stroke recovery. Methods: The model of focal cerebral ischemia and reperfusion in rats were established by middle cerebral artery occlusion (MCAO) and treated by EA. The exosomes were extracted from peri-ischemic striatum and identified by exosomal biomarkers, and detected differentially expressed miRNAs with microarray chip. Primary stem cells were cultured, and oxygen-glucose deprivation and reperfusion (OGD/R) was used to mimic vitro ischemic injury. Results: The levels of exosomal biomarkers TSG101 and CD81 were increased in peri-ischemic striatum after EA treatment, and we revealed 25 differentially expressed miRNAs in isolated exosomes, of which miR-146b was selected for further analysis, and demonstrated that EA increased miR-146b expression and its inhibitors could block the effects. Subsequently, we confirmed that EA upregulated miR-146b expression to promote neural stem cells differentiation into neurons in peri-ischemic striatum. In vitro, it was verified that OGD/R hindered neural stem cells differentiation, and miR-146b inhibitors furtherly suppressed its differentiation, simultaneously NeuroD1 was involved in neural stem cells differentiation into neurons. Moreover, in vivo we found EA promoted NeuroD1-mediated neural stem cells differentiation via miR-146b. In addition, EA also could improve neurological deficits through miR-146b after ischemic stroke. Conclusion: EA promotes the differentiation of endogenous neural stem cells via exosomal miR-146b to improve neurological injury after ischemic stroke.