Exosomes Derived From Mesenchymal Stem Cells: Novel Effects in the Treatment of Ischemic Stroke

Abstract

Ischemic stroke is defined as an infarction in the brain, caused by impaired cerebral blood supply, leading to local brain tissue ischemia, hypoxic necrosis, and corresponding neurological deficits. At present, revascularization strategies in patients with acute ischemic stroke include intravenous thrombolysis and mechanical endovascular treatment. However, due to the short treatment time window (<4.5 h) and method restrictions, clinical research is focused on new methods to treat ischemic stroke. Exosomes are nano-sized biovesicles produced in the endosomal compartment of most eukaryotic cells, containing DNA, complex RNA, and protein (30-150 nm). They are released into surrounding extracellular fluid upon fusion between multivesicular bodies and the plasma membrane. Exosomes have the characteristics of low immunogenicity, good innate stability, high transmission efficiency, and the ability to cross the blood-brain barrier, making them potential therapeutic modalities for the treatment of ischemic stroke. The seed sequence of miRNA secreted by exosomes is base-paired with complementary mRNA to improve the microenvironment of ischemic tissue, thereby regulating downstream signal transduction activities. With exosome research still in the theoretical and experimental stages, this review aims to shed light on the potential of exosomes derived from mesenchymal stem cells in the treatment of ischemic stroke.

Keywords: exosomes; ischemic stroke; mesenchymal stem cells; miRNAs; treatment.

FIGURE 1

Pathological process of ischemic stroke: (1) Arterial thrombosis or arterial embolism will lead to ischemia and hypoxia of nerve cells, leading to damage of mitochondrial structure and function, decrease of ATP generation, increase of intracellular calcium overload and free radical generation, and aggravation of ischemia and hypoxia. (2) In addition, this process can damage endothelial cells and increase inflammatory response. (3) Mitochondrial structure damage can increase the concentration of OH^–, causing oxidative stress. (4) Reperfusion injury can increase mitochondrial membrane potential (MMP), resulting in increased OH^– production and increased oxidative stress.

FIGURE 2

Ischemia and hypoxia can lead to the polarization of microglia into M1 microglia and M2 microglia. The surface antigens of the two microglias are different. M1 microglia expresses CD16, CD32, and CD86, while M2 microglia expresses CD206. MiRNA in exosomes derived from different types of mesenchymal stem cells can regulate some inflammatory pathways or mechanisms to up-regulate or down-regulate the production of M1 and M2, thereby changing the ratio of M1/M2 in the brain and reducing the inflammatory response and secondary tissue damage involved in M1.

FIGURE 3

The source and function of stem cells: exosomes derived from various mesenchymal stem cells (bone marrow-, adipose-tissue and umbilical cord mesenchymal stem cells) secrete miRNA that can participate in many pathological or physiological processes of ischemic stroke. These miRNAs can reduce inflammation, oxidative stress, cell death/apoptosis, or promote the formation of blood vessels, cells and structures.

FIGURE 4

MiRNAs in exosomes secreted by mesenchymal stem cells promote angiogenesis in ischemic tissue. Meanwhile, CXCL12 secreted by exosomes can bind to CRCX4 and promote the migration of cerebrovascular endothelial cells to ischemic tissue. In addition, miRNAs in exosomes activate PTEN-PIK3-Akt or TRPM7-TIPM3/HIF-1α/VEGF pathways to promote angiogenesis. CXCL12 = SDF-1, Stromal cell derived factor 1; CRCX4, CXC receptor type 4; PTEN, Phosphatase and tensin homolog; PIK3, Phosphatidylinositol 3-kinase; Akt, Protein kinase B; TRPM7, Mg²⁺ transmembrane transport channel; TIPM3, Tissue inhibitor of metalloproteinase 3; HIF-1α, Hypoxia induce factor-1α; VEGF, Vascular endothelial growth factor.

FIGURE 5

MiRNAs in exosomes secreted by mesenchymal stem cells stimulate cell and structure growth. miRNA-133b can down-regulate the expression of CTGF in astrocytes, reduce the formation of glial scar and promote the remodeling of myelin sheath. miRNA-17-92 can down-regulate the expression of PTEN, thereby activating the PIK3-Akt pathway and inactivating GSK-3β, promoting the growth of neuronal axons. miRNA-124 promotes neurogenesis in SVZ and striatum regions. miRNA-22-3p can inhibit KDM6B-mediated KBMP2/BMP pathway and play a neurotrophic role. CTGF, Connective tissue growth factor; PTEN, Phosphatase and tensin homolog; PIK3, Phosphatidylinositol 3-kinase; Akt, Protein kinase B; GSK-3β, Glucogen synthase kinase-3β; SVZ, Subventricular zone; KDM6B, Lysine(K)-specific demethylase 6B; KBMP2, Neurotrophic factor; BMP, Bone morphogenetic protein.