Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke

Abstract

Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate the damage to the brain tissue. Mesenchymal stem cells have been investigated as a promising therapy to improve the recovery after ischemic stroke. The therapeutic effects imparted by MSCs are mostly paracrine. Recently, the role of extracellular vesicles released by these MSCs have been studied as possible carriers of information to the brain. This review focuses on the potential of MSC derived EVs to repair the components of the neurovascular unit (NVU) controlling the BBB, in order to promote overall recovery from stroke. Here, we review the techniques for increasing the effectiveness of MSC-based therapeutics, such as improved homing capabilities, bioengineering protein expression, modified culture conditions, and customizing the contents of EVs. Combining multiple techniques targeting NVU repair may provide the basis for improved future stroke treatment paradigms.

Mesenchymal Stem/Stromal Cell Therapy in Blood–Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects

“…MSC-EVs have functionally analogous efficiency to MSCs [ 182 ] and more smoothly traffic through the BBB [ 183 ]. EVs contain numerous therapeutic elements, including cytokines, growth factors, and miRNAs [ 184 ]. MSC-EV therapy markedly contributes to cerebrovascular barrier integrity following ischemia by restoring components of BBB [ 184 ].…”

“…EVs contain numerous therapeutic elements, including cytokines, growth factors, and miRNAs [ 184 ]. MSC-EV therapy markedly contributes to cerebrovascular barrier integrity following ischemia by restoring components of BBB [ 184 ]. However, the most noticeable disadvantage of applying EVs in vivo is the limited BBB overcome after intravenous transplantation.…”

“…However, the most noticeable disadvantage of applying EVs in vivo is the limited BBB overcome after intravenous transplantation. Novel directions promoting MSC-EV delivery to definite brain regions have been investigated, such as magnetic navigation and MSC modification [ 184 , 185 , 186 ]. Exosome-mimetic nanovesicles (NVs) were generated by a serial extrusion process of stem cells, which either maintain the natural properties of EVs or attain large-scale production [ 187 ].…”

“…NVs can be inserted into many types of resident cells, such as astrocytes, pericytes, BMVECs, and macrophages/microglia, which might be the underlying mechanisms of EV-based benefits [ 184 , 185 , 186 ]. Furthermore, exosomes derived from BBB components are also potential directions, especially when the interrelationships between astrocytes, pericytes, and BMVECs are increasingly elucidated.…”

Stem Cells to the Rescue: Development and Application of Cell-Based Therapy for Microvascular Repair

“…The ubiquitous nature of microvascular damage as a fundamental mechanism of tissue injury is reflected in the variety of organs in which cell-based therapy has been attempted. The disease entities described in this Special Issue include renovascular disease associated with ischemic nephropathy in both humans [10] and pigs [11], lung injury induced with Influenza A virus in mice [12], coronary microvascular repair [13], and ischemic stroke [14,15]. Novel approaches to achieve microvascular repair via the co-transplantation of kidney tissue-forming cells with vessel-forming cells, as well as sophisticated imaging techniques that are capable of illustrating the morphology and function of the renal microcirculation [16], are described [17].…”