Preservation of neuronal functions by exosomes derived from different human neural cell types under ischemic conditions

Abstract

Stem cell-based therapies have been reported in protecting cerebral infarction-induced neuronal dysfunction and death. However, most studies used rat/mouse neuron as model cell when treated with stem cell or exosomes. Whether these findings can be translated from rodent to humans has been in doubt. Here, we used human embryonic stem cell-derived neurons to detect the protective potential of exosomes against ischemia. Neurons were treated with in vitro oxygen-glucose deprivation (OGD) for 1 h. For treatment group, different exosomes were derived from neuron, embryonic stem cell, neural progenitor cell and astrocyte differentiated from H9 human embryonic stem cell and added to culture medium 30 min after OGD (100 μg/mL). Western blotting was performed 12 h after OGD, while cell counting and electrophysiological recording were performed 48 h after OGD. We found that these exosomes attenuated OGD-induced neuronal death, Mammalian target of rapamycin (mTOR), pro-inflammatory and apoptotic signaling pathway changes, as well as basal spontaneous synaptic transmission inhibition in varying degrees. The results implicate the protective effect of exosomes on OGD-induced neuronal death and dysfunction in human embryonic stem cell-derived neurons, potentially through their modulation on mTOR, pro-inflammatory and apoptotic signaling pathways.

Pleiotropic Effects of Exosomes as a Therapy for Stroke Recovery

“…Importantly, exosomes have an ability to cross the BBB [32]. MSC-derived exosomes were detected in infarct tissues after systemic administration, as well as in glial cells and neurons in vivo, indicating that MSC-derived exosomes successfully pass through the BBB and are taken up by endocytosis in cells in ischemic brains [41,[58][59][60]. On the other hand, the current systematic review provided another crucial insight, showing that the therapeutic effects of MSC-derived exosomes for stroke recovery were comparable to the effects of therapy with original MSCs [37,47], suggesting that MSC-derived exosomes, rather than direct interaction of MSCs with brain repair, are responsible for restorative effects of MSCs after stroke.…”

Use of Stem Cell Extracellular Vesicles as a “Holistic” Approach to CNS Repair

“…Addition of these EVs to oxygen-glucose deprived (OGD) human neurons resulted in increased survival rate, reduction of apoptosis, and attenuation of OGD-induced expression of pro-inflammatory factors (e.g., iNOS,and TNFα). Further analysis indicated that EVs also exerted effects on the mammalian target of rapamycin signaling pathway as measured by decreased expression of p-AMPK and increased expression of p-PI3K p85 and p-Akt (Deng M. et al, 2018). From an immunological perspective, Reis et al (2018) were the first to perform a comprehensive analysis of the immunomodulatory effects MSC EVs on the function of human dendritic cells (DCs) in vitro.…”

“…This confers an overall neuroprotective phenotype. Figure adapted from Katsuda and Ochiya (2015) and Deng M. et al (2018). important to note that there are differences in the recipient cell types used and this may impact the ultimate phenotype that is observed upon uptake of EVs.…”

Immunological and non-immunological effects of stem cell-derived extracellular vesicles on the ischaemic brain

“…Evidence for neuroprotective effects of EVs that involved anti-apoptotic actions and improved synaptic transmission were obtained in oxygen-glucose deprivation (OGD) studies in vitro on neurons and astrocytes. 79 , 80 In the immature mammalian brain – that is, in foetal or perinatal hypoxia-ischaemia – EV delivery inhibited caspase-3-dependent apoptotic cell death. 81 , 82 …”

“…Similar to autoimmunity and cancer, the modulation of immune signals also plays a pivotal role in responses to ischaemia. Deng and colleagues studied therapeutic effects of EVs which were obtained from human neurons, embryonic stem cells, NPCs or astrocytes on the survival of human embryonic stem cell-derived neurons that were exposed to OGD for 1 h. 79 Interestingly, all types of EVs yielded significant neuroprotection, which was associated with the inhibition of mammalian target of rapamycin (mTOR) and of various pro-inflammatory signals such as COX-2, iNOS and TNF-α as well as apoptotic signals such as caspase-3 and Bax. On the contrary, Webb and colleagues did find differences between EVs derived from different cell sources.…”