The Enigmatic Regulators of Central Nervous System Diseases- Extracellular Vesicles Derived from Mesenchymal Stem Cell

Review Article

Austin Neurosurg Open Access. 2022; 8(1): 1069.

The Enigmatic Regulators of Central Nervous System Diseases- Extracellular Vesicles Derived from Mesenchymal Stem Cell

Sun Y1,2, Zhang Y1,2, Zhang W1,2,3* and Yang Z1,2,3*

¹Department of Neurosurgery, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China

²Guangdong Provincial Engineering and Technology Research Center of Stem Cell Therapy for Pituitary Disease, Guangzhou, China

³Critical Disease Stem Cell Therapy Innovation Team, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China

*Corresponding author: Wei Zhang, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong 510080, China

Zhiqian Yang, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong 510080, China

Received: March 07, 2022; Accepted: March 30, 2022; Published: April 06, 2022


Stem cells can spontaneously secret extracellular vesicle (EVs), which containing proteins, lipids, and nucleic acids. EVs have a broad prospect as a treatment of central nervous system (CNS) diseases, the release and uptake of EVs has important physiological functions and may also contribute to the development and propagation of inflammation, vascular, malignant, trauma and neurodegenerative diseases. This review will detail and discuss the characteristics of EVs and the potential challenges and strategies in the treatment of EVs-based therapies for CNS diseases in the future.

Keywords: Stem cells; Central nervous system; Extracellular vesicles; miRNA; Therapy


CNS has complex anatomy and communicated with diverse cellular populations to respond to environmental stimuli and their metabolic requests. The diversity of CNS diseases can be caused by multifactor, and the existence of the blood-brain barrier has brought great difficulties to the treatment of CNS diseases. Currently, numerous of research developed to promote neurological recovery, but no drugs on the market is available. Increasing evidence is demonstrating that Mesenchymal stem cells (MSCs) derived EVs (MSCs-EVs) shown the positive effects and that the therapeutic value mainly attributed to the miRNA enriched EVs. This review summarized the characteristics of different components of EVs and the main mechanisms involved therapeutic approaches in CNS diseases, focusing on miRNA enriched MSCs-EVs, elucidating how and why miRNA enriched EVs could provide a unique opportunities in CNS diseases therapy, and discussed their clinical potential, neuro restoration could be a viable treatment strategy.

MSC Derived EVs


MSCs are usually obtained from adult bone marrow, peripheral blood, adipose tissue, and placenta, bone marrow is the most frequently used source [1,2]. They can promote tissue repair and remodeling through and secretion of cytokines [3-8], which has become a promising alternative strategy in treatment of CNS diseases [9]. However, the application of MSCs in clinical has some drawbacks, such as unstable phenotype, high costs of generation and processing, ectopic tissue formation [10]. In addition, lodged in the pulmonary microvasculature and caused infusion toxicity [11,12], and cellular rejection or unwanted implantation also have been reported recently [13]. In recent years, some scholars have found that MSCs affects tissue repair rather than cell replacement by stimulating tissue cells through paracrine factors [14]. The main aspect of MSCs response to the disease is the secretion of differ functional molecules stored in EVs and play a significant role in cell-to-cell communication, which generate important actions in development, regeneration, angiogenesis, homeostasis, et al. [15-19].


EVs comprise a large variety of membranous structures released from almost all types of cells. The accumulated historical data and recent research have indicated that the contents, EVs are heterogeneous and dynamic existed in EV’s size, content, membrane composition and function, according to their cellular source, physiological status, and most importantly environmental conditions. Increasing research on EVs has increased understanding of their variety and complexity. EVs are lipid bilayer and comprise a heterogeneous population of membrane vesicles, by fusion of multivesicular bodies and the plasma membrane or formed from the direct budding or microvesicles. At present, three main subgroups of EVs have been defined by The International Society of Extracellular Vesicles, and they can be broadly classified based on size or origin: microvesicles (MVs, and exosomes) and apoptotic bodies [20,21]. MVs, which are typically larger in size (ranging from 100 to 1,000 nm) and are formed as the result of the outward budding of the plasma membrane. Exosomes generally representing smallest EVs of 150nm or less. Exosomes generally representing smallest EVs of 150nm or less, and derived from early endosomes by invagination of the recruited membrane, inward budding, and scission. Apoptotic bodies characterized by a dimension ranging from 1,000 to 5,000 nm, and that released as blebs from cells undergoing programmed death cell [22-24]. EVs contain various specific molecules, such as, DNA, miRNA, mRNA, long noncoding RNA, lipids, proteins, and genetic materials from viruses or prions, depending on the different cellular origin and the function of putative target [25,26]. The best characterized of EVs were firstly described in the early ‘80s [27]. Later, a small vesicle was founded in reticulocytes, It has a circular or concave cup shape under the electron microscope with a lipid bilayer structure, small vesicles fuse with the plasma membrane and release their contents to the outside of the cell in the process of exocytosis [28]. This was coined for 40- 100 nm vesicles released during reticulocyte differentiation by fusion of multivesicular endosomes (MVEs) with the plasma membrane [29,30]. To unify the nomenclature throughout, we will, therefore, use the term EVs for all types of vesicles in this review.

In the past 20 years, EVs were demonstrated that be produced and released by B lymphocytes and dendritic cells through differential centrifugation and described the role of EVs in antigen presentation in vivo and able to induce T cell responses [31,32]. Recently research found that all cell types are able to secrete EVs, including mesenchymal stem cell (MSC) [33], hematopoietic stem cell [34], cardiac progenitor cells [35], embryonic stem cell [36], pancreatic cancer cell [37] and liver cancer cell [38] et al. EVs are also found in physiological and pathological fluids, including pleural effusions, plasma [39], ocular effluent and aqueous humor [40], breast milk [41], broncho-alveolar lavage [42], synovial fluid [43], bile [44], urine [45,46] and sputum [46], ascites [47], amniotic fluid [48], semen (“prostasomes” and “epididymosomes”) [49-51], nasal secretions [52], CSF [53].

EVs have recently gained much attention for their application to CNS diseases, EVs participate in the regulation of normal physiological processes and disease pathology, not only including tissue homeostasis, such as stem cell maintenance, development, repair, regeneration, as well as pathophysiology [54-57], but also modulate immune system and protect apoptosis via multiple pathways [58,59]. In addition, EVS plays a significant role in cancer and cardiovascular disease [23]. Increasing interest in the development of EVs (Figure 1). Its therapeutic effect for central nervous system diseases have been used in pre-clinical and clinical settings over the last decade, administration of MSCs-EVs has beneficial effects in numerous animal models of CNS diseases, including stroke, intracerebral hemorrhage (ICH), traumatic brain injury (TBI), glioblastoma (GBM), spinal cord injury (SCI) et al. The therapeutic effect of EVs in CNS diseases can be ascribed to the modulation of variety processes, including angiogenesis, neurogenesis, apoptosis, immune response, and reprogram in physiological and pathological status [60]. Compare with MSCs: EVs are smaller diameter and less complex content, so they are easier to produce and store, and will be more potential to address contentious regulatory issues [61]. Interestingly, purified EVs from MSCs exerted most, the key mechanism by which MSC contribute to tissue repair and regeneration is through their paracrine function, EVs are one of the major factors that are secreted [62-64]. Other studies have also showed that the treatment effects of MSCs are mostly attributed to cell-secreted paracrine factors rather than target and direct action of transplanted cells [65-67]. Moreover, paracrine factors can induce revascularization and promote proliferation of tissue cells [68,69].

Citation: Sun Y, Zhang Y, Zhang W and Yang Z. The Enigmatic Regulators of Central Nervous System Diseases-Extracellular Vesicles Derived from Mesenchymal Stem Cell. Austin Neurosurg Open Access. 2022; 8(1): 1069.