The role of microvesicles and its active molecules in regulating cellular biology

Abstract Cell‐derived microvesicles are membrane vesicles produced by the outward budding of the plasma membrane and released by almost all types of cells. These have been considered as another mechanism of intercellular communication, because they carry active molecules, such as proteins, lipids and nucleic acids. Furthermore, these are present in circulating fluids, such as blood and urine, and are closely correlated to the progression of pathophysiological conditions in many diseases. Recent studies have revealed that microvesicles have a dual effect of damage and protection of receptor cells. However, the nature of the active molecules involved in this effect remains unclear. The present study mainly emphasized the mechanism of microvesicles and the active molecules mediating the different biological effects of receptor cells by affecting autophagy, apoptosis and inflammation pathways. The effective ways of blocking microvesicles and its active molecules in mediating cell damage when microvesicles exert harmful effects were also discussed.


| INTRODUC TI ON
Microvesicles (MVs) are a kind of nanoscale membrane vesicles released during cell activation, apoptosis and mechanical injury, and these are collectively called extracellular vesicles with exosomes and apoptotic bodies. In as early as 1946, Chargaff et al 1 first discovered that plasma contains a subcellular 'factor' that can promote thrombosis, and subsequent studies have mostly used extracellular vesicles to describe this kind of substance. In recent years, the study of exosomes has become more and more mature, while unknown MVs have attracted more and more attention. It was found that MVs carry proteins, lipids, nucleic acids and other active components expressed in source cells, which can promote coagulation, participate in immunomodulation, induce angiogenesis and initiate apoptosis after interactions with target cells. 2 Furthermore, these play an important role in a variety of diseases (such as cardiovascular disease, 3 tumour, kidney disease and immune disease).
Previous studies have shown that MVs exert adverse biological effects when it interacts with target cells. For example, in cardiovascular disease, MVs can cause myocardial hypertrophy and mediate the progression of atherosclerosis and heart disease. 4 In ischaemic encephalopathy, MVs can promote the progression of ischaemic encephalopathy. 5 MVs can induce target cell injury by reducing cell viability, 6 promoting cell dysfunction and inflammation after interaction with cardiomyocytes, 7 endothelial cells and nerve cells. The investigators considered that the damage of MVs may be correlated to the bad state of the source cells. In recent years, it has been found that MVs from mesenchymal stem cells can prevent unilateral ureteral obstruction 8 and that endothelial progenitor cell (EPC)-derived MVs have played a protective role in renal ischaemia-reperfusion injury. 9 Furthermore, adipose tissue mesenchymal stem cell-derived | 7895 LV et aL.
MVs have effects of anti-inflammatory and cartilage protection. 10 The protective effect of MVs may be attributed to the fact that its parent cells are stem cells with regenerative and repairing effects.
As a carrier of transmission between cells, MVs carry specific active components of stem cells, and targets and transfers these protective substances, which causes the biological effects of cells to change to a beneficial direction. Therefore, it was considered that the different functions of MVs may be correlated to its active components.
In general, MVs in different cells in body fluids play a specific role. This role is mainly correlated to the various active components carried by MVs. The present study reviews the mechanism of the biological effects of MVs and its related active molecules in vivo, and the effective ways to alleviate the adverse effects of MVs. The aim of the present study was to explore the mechanism of MVs in regulating cellular biological effects and provide a theoretical basis for finding new therapeutic schemes for clinical diseases.

| Characteristics of MVs under different conditions
Microvesicles are spherical membranous vesicles encapsulated by a lipid molecular layer, and the cell spontaneously or, under certain conditions, the cell membrane phosphate ester serine valgus, which is redistributed to the outer side of the membrane in the bud and is released to the cell outside the subcellular component. 11  shown that MVs can be derived from many types of cells, such as endothelial cells, erythrocytes, leucocytes, platelets and nerve cells, 12 and in response to different stimuli, the release level of MVs in diseases is significantly higher than normal levels, such as the elevated level of endothelial microvesicles (EMVs) in cardiovascular disease, 13 and hepatocyte from patients with hepatocellular carcinoma releases more MVs than normal hepatocytes. 14 These phenomena indicate that MV release is correlated to the risk factors of cell exposure. Different environmental stimuli can not only change the number of particles, but also change the active ingredients carried by particles.
An interesting study revealed that the co-culture of normal bone marrow mesenchymal cell-derived MVs with multiple myeloma cells can reduce the viability, proliferation and migration of multiple myeloma cells, while MVs from multiple myeloma patients can enhance these biological effects. 15 This shows that MVs produced in diseases are not only different in number from the normal state, but also have different biological effects. The main reason for these different effects is correlated to the changes in bioactive components carried by MVs.
Microvesicles come from many types of cells, carry active ingredients that have similarity with maternal cell components and contain some active analogous components and specific markers of the source cells. 16,17 The data are summarized in Table 1. Therefore, the same cellderived MVs should carry the same active components of parent cells.
However, an interesting phenomenon was found. It was detected that MVs derived from apoptosis mainly carried CD31/annexin V, while MVs produced when endothelial cells were activated mainly carried CD105 or CD62E. 18 In addition, the components of endothelial MV expression in different diseases are not the same. For patients with sleep disorders, EMVs mainly carried CD3, CD62E, CD42B, PECAM and E-selectin. 19,20 In acute ischaemic stroke, EMVs mainly carried CD105, CD54, CD45, CD144, CD41A and CD4. 21 In viral myocarditis, EMVs mainly carry CD31, CD144, CD3 and CD62E. 22 This phenomenon reveals that in same cells in different environments or disease conditions, the derivative of MV-borne active molecules varies. Therefore, there is reason to consider that MVs carry different active molecules and play an important role in different biological effects in cells.

| Active molecules carried by MVs
Microvesicles comprise of a phospholipid bilayer derived from the parental cell plasma membrane, secretory proteins and genetic material transmitted in the cytoplasm. These specific molecules TA B L E 1 Bioactive substances produced by MVs from different cell sources and their biological effects on target cells  24 The main reason is that When the active molecules were inhibited, the effect of MVs on the biological effects of receptor cells was significantly reduced.

| Lipid active molecules and their biological effects
Lipids expressed by MVs mainly come from the plasma membrane components of parental cells, including sphingosine-1-phosphate, phosphatidylserine (PS), cholesterol and arachidonic acid. These active lipids have many biological functions in body, such as asthma, cancer, haemostasis, immunity and inflammation. The data are summarized in Figure 1. Arachidonic acid and other polyunsaturated fatty acid signalling molecules have been identified as biomarkers and determined to be involved in regulating distal immune response. 26,27 In addition, the pro-coagulant cascade and mediating cartilage regeneration are also important physiological functions of active lipids. Phosphatidylserine and tissue factor (TF), which are expressed by MVs, are directly involved in the activation of the coagulation cascade in the body. 28 TF is inhibited in resting cells. Furthermore, sphingosine is hydrolysed after stress injury, thereby eliminating the inhibition of TF, which leads to TF activation, 29

| Nucleic acid active molecules and their biological effects
Nucleic acid is one of the most basic substances to maintain normal life. It is also one of the most important active components carried by MVs, which include microRNA, mRNA, RNA and DNA. As Furthermore, the activated PI3K-Akt signal acts on the downstream substrate endothelial nitric oxide synthase (eNOS). The eNOS is an important regulator of angiogenesis and vascular tension, which can trigger the process of angiogenesis, leading to cell proliferation, differentiation and angiogenesis. 46 MVs activate the PI3K-Akt autophagy signalling pathway, and play a protective role in target cells. 47 However, when the autophagy signal is overexpressed or autophagy is inhibited, 48,49 MVs can induce apoptosis and damage cells. Different cell-derived MVs and its expressed active molecules activate the PI3K-Akt pathway in receptor cells and regulate target cells to produce different biological effects.

| MVs and its active molecules regulate apoptosis through the Fas/FasL pathway
FasL is a cytokine that can bind to the death receptor TNFRSF6/FAS.
In recent years, Fas and its ligand FasL been the most deeply studied membrane surface molecules related to apoptosis. FasL and TNF-re- ASC plays an important role in activating caspase-1, which is different from FAS/FASL-induced programmed cell death and considered to be the pathological death of cells under inflammatory and stress conditions. 59

| EFFEC TIVE WAYS OF B LO CKING CELL DAMAG E MED IATED BY MVS AND ITS AC TIVE MOLECULE S
As

| Mediated MV clearance
In response to various stimuli (such as oxidative stress, inflamma-

| Reduce harmful MV release
In order to maintain the stability of the internal environment, the body clears the increased MVs in body fluids to a certain extent, but

| PROS PEC TS
Cell-derived MVs have received increasing attention in the scientific community due to their potential to serve as biomarkers of intracel-

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.

AUTH O R CO NTR I B UTI O N S
Conception and design: YingMei Lv, Jin Tan, Qiang Zhang. Wrote the paper: YingMei Lv. Language modification and guidance: Yuyang Miao. All authors have read and approved the final manuscript.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.