Exosomal microRNAs as Potential Biomarkers and Therapeutic Agents for Acute Ischemic Stroke: New Expectations

 'May', so lots of research to do on this. WHOM will be doing that?

Exosomal microRNAs as Potential Biomarkers and Therapeutic Agents for Acute Ischemic Stroke: New Expectations

Yingzhi Xu^1,2,3, Yue Hu⁴, Shixin Xu^5,6, Fengzhi Liu³ and Ying Gao^1,2*

• ¹Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, China
• ²Department of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
• ³Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
• ⁴School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
• ⁵Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
• ⁶Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China

The morbidity and mortality rates of ischemic stroke (IS) are very high, and IS constitutes one of the main causes of disability and death worldwide. The pathogenesis of ischemic stroke includes excitotoxicity, calcium overload, oxygen radical injury, inflammatory reactions, necrosis/apoptosis, destruction of the blood-brain barrier (BBB), and other pathologic processes. Recent studies have shown that exosomes are critical to the pathogenesis, diagnosis, and treatment of cerebral infarctions resulting from ischemic stroke; and there is growing interest in the role of exosomes and exosomal miRNAs in the diagnosis and treatment of IS. Exosomes from central nervous system cells can be found in cerebrospinal fluid and peripheral bodily fluids, and exosomal contents have been reported to change with disease occurrence. Exosomes are small membranous extracellular vesicles (EVs), 30–150 nm in diameter, that are released from the cell membrane into the depressions that arise from the membranes of multivesicular bodies. Exosomes carry lipids, proteins, mRNAs, and microRNAs (miRNAs) and transport information to target cells. This exosomal transfer of functional mRNAs/miRNAs and proteins ultimately affects transcription and translation within recipient cells. Exosomes are EVs with a double-membrane structure that protects them from ribonucleases in the blood, allowing exosomal miRNAs to be more stable and to avoid degradation. New evidence shows that exosomes derived from neural cells, endothelial cells, and various stem cells create a fertile environment that supports the proliferation and growth of neural cells and endothelial cells, inhibits apoptosis and inflammatory responses, and promotes angiogenesis. In the present review, we discuss how circulating exosomes—and exosomal miRNAs in particular—may provide novel strategies for the early diagnosis and treatment of ischemic stroke via their potential as non-invasive biomarkers and drug carriers.

Introduction

Ischemic stroke (IS) is one of the major causes of disability and mortality worldwide, and exhibits high rates of incidence and recurrence. In 2019, stroke was ranked second of the 10 leading causes of disability-adjusted life years (DALYs) for both individuals 50–74 years of age and those ≥ 75 years of age (1, 2). IS exhibits high rates of mortality and physical disability, and has become a heavy burden for individuals and society, especially in low-income and middle-income countries. The principal type of stroke is IS, which accounts for 84.4%; primary hemorrhagic stroke accounts for the majority of the remainder (1). Cerebral ischemia can lead to a series of pathologic changes that ultimately lead to irreparable neuronal damage. The accompanying pathogenesis includes excitotoxicity, calcium overload, oxygen-radical injury, inflammatory reactions, necrosis/apoptosis, destruction of the blood-brain barrier (BBB), and other pathologic processes.

Due to the scarcity of treatment methods and the thrombolytic time-window, the thrombolysis rate in stroke patients is very low (3). Thus, clinical diagnosis of IS now primarily depends on magnetic resonance imaging and computed tomography; however, due to a patient's physical manifestations, such as the placement of a metal stent or steel plate implantation, it is not reasonable to accept MRI as the sole modality. In addition, most community medical institutions lack the appropriate professional technicians and testing equipment, which limits the clinical application of MRI. Therefore, an optimized and clinically operable biomarker is needed for the early and accurate diagnosis of IS. Importantly, recent studies have shown that exosomes occupy a significant position in the pathogenesis, diagnosis, and treatment of cerebral infarction. Some nerve cells can synthesize and release exosomes after stroke, which then pass through the BBB. For example, exosomes released from brain cells are detectable in peripheral blood and/or cerebrospinal fluid (CSF) (4–6). In addition, endothelial and blood cells release exosomes into the blood after a stroke, while nerve cells release exosomes into the cerebrospinal fluid; with the latter distributed within and outside the brain through the BBB (7). These exosomes may therefore be useful as biomarkers that reflect stroke-induced pathologic processes, and might have potential as drug carriers for promoting recovery.

An exosome is a small membranous extracellular vesicle (EV) produced by the membrane of multivesicular bodies (MVBs), and when the endosomes or MVBs fuse with the plasma membrane, exosomes are released extracellularly (8). Exosomes have a diameter of 30–150 nm (9, 10), and transfer lipids, proteins, mRNAs, and microRNAs (miRNAs) (11). Furthermore, they play an important role in intercellular communication, maintenance of myelin sheaths, and the elimination of cellular waste (12, 13). Exosomes can cross the BBB and possess a double- membrane structure that protects them from ribonucleases in blood, making exosomal miRNAs highly stable and preventing them from undergoing degradation (14–16). Thus, exosomal miRNAs may represent an ideal biomarker for circulating bodily fluids. As exosomal contents also change commensurately with disease development, neurocyte-derived exosomes that cross the BBB can be used as valuable biomarkers of nervous system diseases (17, 18). Exosomes from miRNA-overexpressing cells—e.g., stem cells and other cultured cells—have been shown to protect against ischemia-induced neural injury, the underlying mechanisms of which are related to inhibiting inflammatory reactions, promoting angiogenesis, regulating autophagy, and promoting neural repair. In this review, we principally discuss the most recent understanding of exosomes and exosomal miRNAs, and introduce the potential of using exosomal miRNAs in treating ischemic diseases. We also examine the mechanisms involving exosomes in these processes and review the research on circulating exosomal miRNAs as potential diagnostic biomarkers for stroke at different stages. Finally, we highlight important characteristics of exosomes and exosomal miRNAs in the potential diagnosis and treatment of IS so as to better understand the potential governing mechanisms and provide more-effective strategies for the use of exosomal miRNA in the diagnosis and treatment of IS.

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