Extracellular Vesicles in Regeneration and Rehabilitation Recovery after Stroke

Abstract

Patients that survive after a stroke event may present disabilities that can persist for a long time or permanently after it. If stroke prevention fails, the prompt and combinatorial intervention with pharmacological and rehabilitation therapy is pivotal for the optimal recovery of patients and the reduction of disabilities. In the present review, we summarize some key features of the complex events that occur in the brain during and after the stroke event, with a special focus on extracellular vesicles (EVs) and their role as both carriers of biomarkers and potential therapeutics. EVs have already demonstrated their ability to be used for diagnostic purposes for multiple brain disorders and could represent valuable tools to track the regenerative and inflammatory processes occurring in the injured brain after stroke. Last, but not least, the use of artificial or stem cell-derived EVs were proved to be effective in stimulating brain remodeling and ameliorating recovery after stroke. Still, effective biomarkers of recovery are needed to design robust trials for the validation of innovative therapeutic strategies, such as regenerative rehabilitation approaches.

Keywords: biomarkers; extracellular vesicles; precision medicine; recovery; regeneration; rehabilitation; stroke.

Figure 1

(a) Schematic representation of the cellular events occurring in the acute phase that follows a stroke event. Neurons, astrocytes, and microglia are the neural cells mostly involved in the response to injury. Astrocytes and microglia modify their metabolism and morphology towards an activated phenotype. Neurons in the ischemic core might undergo irreversible damage and liquefactive necrosis, while in the penumbra, salvageable neurons undergo acidophilic transformation and oxidative damage. (b) Concise summary of some of the main events occurring after stroke. Regenerative rehabilitation can significantly ameliorate stroke patient conditions leading to better therapeutic outcome and functional recovery. (c) Schematic illustration of the EV-mediated crosstalk occurring between neural and endothelial cells after stroke. Monocytes are recruited in the injured area. Rehabilitation and exercise stimulate EV release by skeletal muscle cells; muscle EVs that reach the brain tissue can favor recovery and resolution of inflammation. Created with BioRender.com.

Figure 2

Schematic representation of the 4 phases of the rehabilitation process involving (1) assessment, (2) goal setting, (3) intervention, and (4) reassessment [17]. The introduction of the rehabilomics approach could accelerate the identification of a personalized intervention (precision medicine) in order to overcome the “reassessment” step (shaded).