Preconditioning Concepts for the Therapeutic Use of Extracellular Vesicles Against Stroke

Abstract

Various preclinical stroke models have demonstrated the neuroprotective effects of extracellular vesicles (EVs) obtained from several types of cells, including neurons, astrocytes, microglia, neuronal progenitor cells, bone marrow stem cells, and mesenchymal stem cells. EVs interfere with key mechanisms in stroke pathophysiology such as cell death, neuroinflammation, autophagy, and angiogenesis. The mode of action and efficacy depend on the specific EV content, including miRNAs, proteins, and lipids, which can be modified through (I) bioengineering methods, (II) choice of source cells, and (III) modification of the source cell environment. Indeed, modifying the environment by preconditioning the EV-secreting cells with oxygen-glucose deprivation or medium modification revealed superior neuroprotective effects in stroke models. Although the concept of preconditioned EVs is relatively novel, it holds promise for the future treatment of ischemic stroke. Here, we give a brief overview about the main mechanisms of EV-induced neuroprotection and discuss the current status of preconditioning concepts for EV-treatment of ischemic stroke.

The dual role of microglia in ischemic stroke and its modulation via extracellular vesicles and stem cells

“…Preconditioning of source cells for EVs has demonstrated an enhanced neuroprotective effect in preclinical stroke studies. 68 Notably, these preconditioned cells also affect the microglial response during post-stroke neuroinflammation. In the following sections, key studies exploring these underlying mechanisms are discussed.…”

“…Moreover, the neuroprotective effects of EVs can be amplified by preconditioning parent cells and loading the vesicles with a specific molecular cargo. 68 Multiple preclinical investigations have underscored the neuroprotective and neuroregenerative capacities of EVs in diverse stroke paradigms, emphasizing their influential role in modulating neuroinflammation via microglial interactions. The subsequent sections review the microglial effects and potential underlying mechanisms.…”

“…Notably, EVs are recognized for their minimal immunogenicity, excellent transport capabilities, negligible tumorigenicity, robust stability, and the capacity to traverse the blood‐brain barrier. Moreover, the neuroprotective effects of EVs can be amplified by preconditioning parent cells and loading the vesicles with a specific molecular cargo 68 . Multiple preclinical investigations have underscored the neuroprotective and neuroregenerative capacities of EVs in diverse stroke paradigms, emphasizing their influential role in modulating neuroinflammation via microglial interactions.…”

Nanomaterial-related hemoglobin-based oxygen carriers, with emphasis on liposome and nano-capsules, for biomedical applications: current status and future perspectives

“…Among these, microglial activation in brain tissue and neutrophil infiltration from peripheral blood into brain tissue are the hallmarks underlying microglial transformation from the M1 to M2 type. In particular, these processes inhibit neutrophil infiltration, which is a potential direction for treating cerebral ischemic injury [ 144 ]. Yin et al [ 145 ] modified MG1 and RVG29 peptide chains based on erythrocyte-derived nanovesicles to prepare engineered nanoerythrocytes (NEMR) to promote microglial reprogramming.…”