Advances in mesenchymal stem cell exosomes: a review
Stem Cell Research & Therapy volume 12, Article number: 71 (2021)
Stem cells can be used for regenerative medicine and as treatments for disease. The application of tissue engineering-related transplantation, stem cells, and local changes in the microenvironment is expected to solve major medical problems. Currently, most studies focus on tissue repair and regeneration, and mesenchymal stem cells (MSCs) are among the most common research topics. MSCs are applicable as seed cells, and they represent one of the current hot topics in regenerative medicine research. However, due to storage limitations and because cell senescence occurs during in vitro expansion, their clinical application is challenging. Exosomes, which are secreted by MSCs through paracrine signalling, not only have the same effects as MSCs, but they also have the advantages of targeted delivery, low immunogenicity, and high repairability. This article reviews the acquisition methods, characteristics, biological functions, and clinical applications of exosomes.
In 1983, exosomes were discovered in sheep reticulocytes , but they were initially considered cellular waste. In 2007, scholars found that such nanosized vesicles (exosomes) contain proteins, lipids, and RNA, including mRNA and miRNA. Exosomes can be passed to other cells as signalling molecules that exert biological functions, and because of these properties, they will be used in clinical practice in the future (https://ClinicalTrials.gov/). Exosomes are secreted by a variety of cells and exist in almost all body fluids , including the blood, saliva, urine, cerebrospinal fluid, and milk. Exosomes derived from human umbilical cord mesenchymal stem cells (HUC-MSCs) have higher neurolysin activity than exosomes derived from HBMSCs . Compared with canine adipose-derived mesenchymal stem cells, canine bone marrow mesenchymal stem cells release more exosomes . Compared with exosomes derived from human bone marrow mesenchymal stem cells, the yield of exosomes isolated from human amniotic fluid mesenchymal stem cells is higher . Among all the proteins in exosomes that are derived from different types of MSCs, half the proteins are similar .
Studies have shown that 60% of the proteins in exosomes derived from HUMSCs and HBMSCs are the same and that these proteins are related to cell growth and antioxidant stress. However, proteins with similar functions have also been found in exosomes derived from AMSCs. Whether they are the same as those in exosomes derived from the umbilical cord and bone marrow remains to be determined [7, 8]. Exosomes derived from HUC-MSCs and HBMSCs can inhibit the growth and apoptosis of tumour cells. Exosomes secreted by HASCs can promote tumour growth but have no effect on U87 MG glioblastoma cells  (Table 1).
Mesenchymal stem cells (MSCs) have the potential for self-renewal and multidirectional differentiation [10, 11]. Some examples of common MSCs include adipose MSCs (AMSCs), bone marrow MSCs (BMSCs), umbilical cord MSCs (UC-MSCs), and gingival MSCs . MSCs have attracted substantial attention since their discovery in 1968 and have been used in preclinical research for many years . Exosomes are extracellular vesicles with nanoscale bilayer membranes that can be secreted by almost all cell types. Due to the phospholipid bilayer on their surface, exosomes have good stability and permeability. After they enter their target cells, exosomes can regulate the function and signalling of those cells .
Exosomes have a cup-shaped structure under the microscope and contain lipids, proteins, and nucleic acids, such as lncRNAs and miRNAs. Exosomes, which range from 30 to 120 nm in diameter , are approximately 1.13–1.19 g/ml in density . Exosomes are stored long term at − 80℃. Compared with freshly isolated exosomes, exosomes stored in different conditions over a long period of time will exhibit different degrees of diameter enlargement, and different degrees of protein leakage from exosomes in the supernatant are observed [16,17,18].
Various types of mesenchymal stem cells can secrete exosomes under normal and pathological conditions, such as in cancer and viral infections. Exosomes are mainly derived from multivesicular bodies (MVBs), which are formed by the invagination of intracellular lysosomal particles, and are released into the extracellular matrix through paracrine signalling after fusion with the endosomal membrane and the cell membrane through endocytosis. MSC-derived exosomes from different sources have similar synthetic pathways .
Exosomes are produced in very dynamic endosomal organelles in the form of intraluminal vesicles (Fig. 1). First, these organelles undergo different maturation processes to form intraluminal vesicles (ILVs), which are the precursors of exosomes and MVBs . MVBs can fuse with the lysosomal membrane, which causes them to release their contents (including exosomes) into the extracellular matrix . Two secretory mechanisms have been described. The first is the mechanism of sorting complexes from endosomes. The endosomal sorting complex produced by the combination of ILVs and MVBs helps the specific components enter ILVs and form the precursors of exosomes . The other is a complex nonendosomal separation mechanism. This mechanism can assist in the formation of ILVs and MVBs through the auxiliary action of lipids, proteins , and other molecules.
Exosome isolation methods
The following seven methods are currently available for the effective isolation of exosomes: differential centrifugation, precipitation, flushing separation, ultrafiltration, antibody affinity capture, microfluidic separation, and mass spectrometry (MS). These seven methods are compared below (Table 2, Table 3).
The centrifugation speed is either increased in a stepwise manner or lower speeds and higher speeds are alternately applied so that particles with different sedimentation rates are separated in batches at different separation speeds and different centrifugation times. This method is called differential centrifugation. Differential centrifugation is the gold standard for exosome isolation. The latest evidence has shown that the three-time ultracentrifugation method is not only time-consuming and laborious but also fails to achieve good purity. Therefore, scholars have proposed a double ultracentrifugation scheme that involves the addition of 30% sucrose buffer solution during the first centrifugation step. This method has a high yield and slightly lower contamination levels of lipoprotein and AGO2. Therefore, this is a more effective isolation method . The degree of weight balance of exosomes during pregnancy affects term and preterm birth and reflects physiological changes in the ectoderm and can therefore be used as a biomarker and indicator of cell function .
In this process, a solvent is added to the solution to change the polarity and solubility of some components so that they precipitate out into the solution. This method is called precipitation. Differential centrifugation is time-consuming and requires a large amount of sample, but it is the most widely used method. The precipitation method can effectively improve the separation of biological fluids . Methods include isolation using the Serum™, the Exo-Q and Exo-Spin™ blood cell purification kits , the mi-RCURY Exosome Separation Kit , the Exo Quick-TC Exosome™ Precipitation Solution Kit (System Biosciences, USA) , methanol precipitation , and the Total Exosome Isolation kit .
In this case, the sample is added to one end of a chromatographic column, and the mobile phase that is adsorbed or dissolving on the stationary phase is weaker than the components in the sample. This is used as the flushing agent due to the adsorption and dissolution of the components in the sample on the stationary phase. Chromatography separates components in a sample from one another because of the different abilities of the rinsing agent. This method is called flushing separation and provides time- and cost-effective advantages, which makes it a promising method for the clinical application of exosome separation .
Due to the pressure difference between the two sides of an ultrafiltration membrane, which serves as the driving force, this membrane is used as the filter medium. Under a certain pressure, when the original liquid flows over the membrane surface, only water and small molecules can pass through to become the permeate, and the volume is larger than that of the membrane surface. The material with pores is intercepted and becomes a concentrated solution to achieve the purification, separation, and concentration of the original solution. This method is termed ultrafiltration.
Although density gradients can be used to remove impurities such as nonspecific AGO protein , as mentioned earlier, ultracentrifugation can be troublesome for large numbers of samples. Moreover, it may affect the separation of protein and RNA from exosomes . Therefore, ultrafiltration should be combined with centrifugal washing and OPTIPREP™ gradient separation, but the column has limitations in that it cannot be reused . After ultrafiltration, the mRNA in the exosomes can be removed .
Immunomagnetic bead method
In this process, the antigen is solidified on the substrate, and the supernatant of the antibody-containing culture medium is added to wash away the unbound antibody. The antibody bound to the antigen can be labelled with fluorescein. This method is called the immunomagnetic bead method. Shed microvesicles can then be continuously immunopurified with anti-A33- and EPCAM-coupled magnetic beads . Single-domain antibodies (VHHs, nanobodies) are structurally stable, easy to design, and capable of labelling specific residues. They are also cheap to produce on a large scale and are clonally stable . Another advantage is that they can directly attack soluble antigens and cells [37,38,39]. Wang Jing et al.  used CD81-labelled immunomagnetic beads to sort AMSC exosomes. Greening et al. used immunoaffinity capture to isolate exosomes from cells of colorectal cancer patients . Researchers have also used specific markers of exosomes to detect the effects of exosome isolation.
Experimental results have shown that exosome isolation by the antibody affinity capture method is more effective than that by the centrifugation method or the density gradient method . An enzyme-linked immunosorbent assay (ELISA) involves the combination of soluble antigen (Ag) or antibody (Ab) to a solid-phase carrier, such as polystyrene. ELISA is a qualitative and quantitative immune reaction detection method that depends on the specific binding of antigen and antibody.
Microfluidics is a science and technology that is used to precisely control and manipulate fluids on a microscale level. Its main feature is the ability to manipulate fluids in micro/nanoscale spaces. Microfluidics also has basic functions in biological and chemical laboratories, such as in sample preparation. The basic feature and greatest advantage of the ability to scale reactions, separations, and detections to a chip a few square centimetres in size are the flexible combination and large-scale integration of multiple unit technologies on an overall controllable tiny platform. Microfluidics is an interdisciplinary method that involves engineering, physics, chemistry, micro-processing, and bioengineering. This method is called microfluid separation.
Microfluidic technology uses the physical and biochemical properties of dimensional dense bodies for microscale separation, detection, and analysis. In addition to utilising well-established separation methods/influencing factors of separation, this technology uses new sorting mechanisms, such as acoustic, electrophoretic, and electromagnetic operations. The technology is fast and requires only a small amount of sample and few reagents . This technology is not only used to isolate exosomes, but it can also be used in the diagnosis, detection, and differentiation of cancers . Tumour-related exosomes can be detected in the plasma using a microfluidic chip designed with a self-assembled three-dimensional herringbone nanopattern .
The components in the test sample are ionised to generate ions with different charge-to-mass ratios. The ion beam is formed under the action of the accelerating electric field and enters the mass return analyser. The electric field and magnetic field are used to generate opposite velocity dispersion-ion beams. After passing through the electric field, the slower ions will deflect more, while the faster ones will deflect less. In the magnetic field, the ions will be deflected with the opposite angular velocity vector; that is, the slower ions will deflect more and the faster ones will deflect less when the two fields are deflected.
When the effects compensate for each other, their orbits intersect at one point. At the same time, mass separation can occur in the magnetic field so that ions with the same mass-to-charge ratio but with different speeds are focused on the same point. Ions with different mass-to-charge ratios are focused on different points, and they are focused separately to obtain a mass spectrum to determine quality. This method is called separation by mass spectrometry.
Chromatography is used for separation, and MS is used for qualitative detection, and the two are usually performed in combination. Although MS preserves protein profiles, no standard has been established for MS. During experiments, researchers should focus on reducing the risk of introducing experimental artefacts. The use of commercial ED foetal bovine serum (FBS) to remove FBS in exosomes is the first choice for the detection of exosomes using MS because mass spectrometry does not introduce many interfering proteins during detection and provides a good environment for detection. If the correct sample processing method is used, the quality of the MS data is high and can be increased . A method to separate serum exosomes based on QEV column separation is fast and reliable .
Extracellular vesicles can be divided into three types: exosomes  (diameter < 200 nm), microvesicles (100–1000 nm), and apoptotic bodies (diameter > 1000 nm) (Fig. 2). Exosomes are a subset of extracellular vesicles that are generated by the extracellular secretion of MVBs . To clearly understand the interaction between MSC exosomes, it is necessary to evaluate the physical and chemical characteristics of exosomes, such as their shape, size, surface charge, and density. Several techniques are often used to characterise exosomes, including dynamic light scattering (DLS), transmission electron microscopy (TEM), atomic force microscopy (AFM), tunable resistance pulse sensing (TRPS), nanoparticle tracking analysis (NTA), flow cytometry (FCM), and confocal microscopy .
The human body is rich in adipose tissue, and thus, compared with UC-MSCs and BMSCs, AMSCs are abundant with extensive sources and have a high purification yield. Moreover, AMSC removal is painless and inflicts only small trauma, and AMSCs can be obtained from the Plastic Surgery Department. AMSCs can also be used in medical aesthetics. However, AMSCs have strict requirements for storage conditions and have low immunogenicity, which has restricted their clinical application. The membrane structure of exosomes is relatively stable, and AMSC-derived exosomes can be stored for long periods; hence, AMSC-derived exosomes have generated increased interest among researchers .
Morphological characteristics of ASC-derived exosomes
The primary cell morphology of the adipose tissue is not fixed, and primary cells can be either fusiform or circular. Primary cells can adhere to other cells within 1–2 days of cell culture. Around the fifth passage, they form a single layer and grow in a vortex or radial pattern. Their morphology changes into a single long spindle. Exosomes, which have a uniform round cup shape and a diameter of 30–120 nm, can be observed by scanning electron microscopy. These features distinguish them from apoptotic bodies and microvesicles. The culture of primary AMSCs involves enzymatic digestion and tissue block adherence .
Composition of ASC-derived exosomes
Exosomes contain lipids, proteins, and RNA. Since the diameter of exosomes is relatively small, they cannot be accurately detected by ordinary flow cytometry. Therefore, for the identification of exosomes by differential centrifugation, flow cytometry, immunomagnetic bead method, and transmission electron microscopy, the surface proteins on exosomes have the same direction as those on the plasma membrane. Membrane-bound proteins include different clusters of differentiation proteins including CD9, CD10, CD13, CD29, CD44, CD63, CD73, CD90, CD105, enkephalin enzyme, and major histocompatibility complex MHC I molecules, among others. The haematopoietic molecular markers CD3, CD19, and CD45 have not been detected on exosomes. CD44 is similar to CD105 and is expressed in almost all human MSC types. CD90 is highly expressed in various MSCs [11, 49].
In addition, AMSCs express a marker similar to CD81, which is similar to what is expressed in BMSCs. However, no single-specific surface marker of AMSCs has been identified thus far . Exosomes can be characterised with antibody chips that detect certain marker proteins, including annexins (such as FLOT1), ICAM1, EPCAM, fat valve structural proteins (such as ANXA5), and the multivesicular biosynthesis-related proteins ALIX and TSG101. Exosomes do not contain GM130. The cellular origin and formation process of exosomes affect their protein content [47, 50,51,52].
The RNA in exosomes mainly includes mRNA and noncoding RNA. Noncoding RNAs include miRNAs and long noncoding RNAs (lncRNAs). LncRNAs play roles in signal transmission and in the regulation of various diseases . Exosomal lipids include cholesterol, sphingomyelin, ceramide, and phosphatidylserine, and of these, ceramide plays a key role in the formation of exosomes [53,54,55,56].
The umbilical cord, which connects the mother and the foetus and supplies foetal nutrition during pregnancy, is of placental origin. Human MSCs can be divided into four types: HUC-MSCs, human umbilical cord perivascular MSCs (HUCPV-MSCs), human umbilical cord Wharton’s Jelly MSCs (HWJ-MSCs), and human amniotic membrane-derived MSCs (HA-MSCs) .
Morphological characteristics of HUC-MSC-derived exosomes
Primary UC-MSCs are spindle-shaped, and no obvious vortex growth is observed. After 1 day of direct adherent culture by the primary cell tissue mass method, a small number of cells adhere and grow, and the cells show a vortex growth pattern after the second generation. Some cells exhibit a vortex growth pattern during passage to the fifth generation at which point the cells become long and fusiform with the typical characteristics of vortex growth. Exosomes vary in size, but have a diameter of approximately 30–100 nm [2, 58]. They appear as round or elliptical membranous vesicles that can be aggregated and distributed and have clear boundaries around the membranous structure .
Composition of HUC-MSC-derived exosomes
Flow cytometric analysis of HUC-MSCs showed that HUC-MSCs are positive for the cell-specific surface markers CD29, CD44, C/73 (SH3), CD90 (Thy-1), and CD105 (SH2) and negative for CD11b, CD34, and CD45. Exosomes secreted by UC-MSCs express the exosome-specific four-transmembrane protein markers CD9, CD63, and CD81 and the multivesicular biosynthesis-related protein ALIX, as analysed by Western blot. The protein levels of the four transmembrane proteins could be used as biomarkers. Notably, different techniques used to isolate exosomes result in the detection of different expression levels of these proteins. In addition, these exosomes contain lipids and miRNAs, such as miR-26b and miR-206 [57, 59,60,61,62,63,64,65].
These exosomes can interact with many types of cells and are not easily inactivated. BMSCs can be isolated from the bone marrow. BMSCs have the advantages of a low infection rate of pathogenic microorganisms, stable biological performance, low immune rejection after transplantation, and a high number of possible passages .
Morphological characteristics of BMSC-derived exosomes
After 1–2 days of adherent culture under hypoxia and other conditions, some cells become adherent, and the size and shape of the cells are different. The morphology of adherent cells is mostly round. When the cells are cultured for 4–5 days, the number of adherent cells gradually increases, and the cells begin to colonise. Their morphology is still diverse, and cells appear polygonal and fusiform. After the second passage, the morphology changes to that of a single fusiform shape, and the cells tend to grow radially towards the vortex. After passaging to the fourth generation, the MSCs grow in a vortex pattern. These exosomes are uniform in size, 30–100 nm in diameter, and cup-shaped, with a clear model structure around them .
Components of BMSC-derived exosomes
Exosomes secreted by paracrine BMSCs were analysed by Western blot. The exosomes contained cystine, the four-transmembrane proteins CD9, CD63, CD81, HSP70, syntenin-1, and multivesicular biosynthesis-related protein TSG101. Osteoclast-derived exosomes also contain receptor activator of NF-κB (RANK) [66, 67].
Most RNAs in exosomes are pre-microRNAs and include miR-301, miR-let-7a, and miR-22. BMSC surface markers include the antigen integrin family member CD29; the adhesion molecules CD44, CD73, CD90, CD11b, CD105, and CD106; and the Ly-6 antigen family members SCA-1 and Grn94. Grn94 is found only in BMSCs and not in exosomes. BMSC-derived exosomes are negative for CD14, CD34, and CD45 [66,67,68,69].
The function of MSCs depends on their abilities to interact with recipient cells and to transfer their protein, lipid, and RNA content to these cells. MSCs are widely used in tissue repair and in acute and chronic injuries. Exosomes contain specific cell binding sites and can thus transport substances into target cells . The biological functions of exosomes derived from three types of mesenchymal stem cells were summarised (Table 4). No substantial differences were observed in exosomes from these cell types, and these exosomes share similar functions.
These exosomes are secreted by paracrine cells and play a key role in tissue repair and regeneration. Not only do they promote angiogenesis, but they also upregulate the early inflammatory response to improve transplant rejection reactions and induce osteogenesis and adipogenesis. Cell proliferation [11, 71] will accelerate healing of the skin but will also promote the migration and invasiveness of melanomas [72, 73]. Exosomes can also inhibit apoptosis and regulate the immune system .
HUC-MSCs have stronger in vitro expansion and multidirectional differentiation capabilities than umbilical cord tissue-derived MSCs [75, 76]. Exosomes derived from umbilical cord mesenchymal stem cells can inhibit the secretion of IL-6 by macrophages by knocking down the large-conductance Ca2+ -activated K+ (BKCa) channel to enhance the secretion of exosomes by WJ-MSCs, which then leads to immunoregulation of the inflammatory response . The combination of HUC-MSC-derived exosomes and hydrogels can promote the ossification of mouse osteogenic progenitor cells (mOPCs) .
When exosomes isolated from HUC-MSCs are cocultured with human cutaneous vein endothelial cells in vitro, the tubular structure of endothelial cells is more obvious, and endothelial cells demonstrate better migratory properties. HUC-MSC exosomes can promote new blood vessel growth . Olfactory ensheathing cells are beneficial for nerve regeneration, but they are limited by the hypoxic environment. HUC-MSC-derived exosomes can regulate the pathological damage caused by hypoxia. The combination of both olfactory ensheathing cells and HUC-MSC-derived exosomes also promotes nerve regeneration .
Exosomes secreted by BMSCs can inhibit the secretion of interferon γ by peripheral blood mononuclear cells, such as lymphocytes [69, 81, 82] and have been shown to exhibit immunomodulatory, tissue repair stimulatory, promigratory, proliferative, anti-inflammatory, and antioxidant effects; they have also been shown to contain regulatory proteins. The miRNAs in these exosomes can regulate osteoclast generation, osteogenic proliferation and differentiation of BMSCs .
MSCs can upregulate regulatory T cells (Tregs) and downregulate Th17 cell development through paracrine-secreted exosomes, which participate in immune balance regulation. They can be used as “cell-free” biological therapies, which have opened up new research directions for autoimmune diseases . The clinical application of exosomes derived from three types of mesenchymal stem cells was summarised (Table 5).
Adipose stem cell (ASC)-derived exosomes can enhance the formation of the blood vessels in fat transplantation . Although they can promote wound healing, they can also lead to the migration and invasiveness of melanomas through the fatty acid oxidation pathway. Exosomes have immunomodulatory functions and can regulate microglia polarisation. They can also improve inflammation. Exosomes can regulate albinism and pigmentation in Moynahan syndrome and can also be used in the treatment of diseases, such as multiple sclerodermas; in addition, they can improve the prognosis of melanoma and reduce hair loss . Exosomal miRNAs can be detected in the cell microenvironment and can also be transferred between cells. These miRNAs can inhibit tumours and can also act as cell regulators under various physiological and pathological conditions. The miRNAs and proteins of these exosomes can be used as noninvasive prognostic biomarkers and as in vivo markers of disease detection. Exosomes increase the sensitivity of liver cancer to chemotherapy drugs by transferring miR-122 into cells. MiR-145, which is transported by exosomes, promotes apoptosis of tumour cells and inhibits the proliferation of prostate cancer cells by reducing caspase 3 and 7 pathway activity .
It has been reported that exosomes secreted by MSCs treated with macrophage migration inhibitors can protect the heart with the same long noncoding RNA/microRNA . Exosomes can also be used as potential therapeutic targets for the treatment of Dox-induced cardiomyopathy  and can downregulate the inflammatory response and reduce oxidative stress, which can protect the cartilage matrix in osteoarthritis. The treatment of AMSCs using different methods, such as hypoxia, can promote exosome secretion. Exosomes can effectively treat spinal cord injury by inhibiting the expression of inflammatory factors, which effectively protects motor and sensory functions .
HUC-MSC-derived exosomes are more frequently used in the treatment of various diseases than exosomes secreted by other types of stem cells. Simultaneously, exosomes can accelerate endothelialisation, thereby strengthening the endothelium, inhibit transplanted vein intimal hyperplasia, and promote cell proliferation and migration . MiR-302A in these exosomes can inhibit the proliferation of endometrial cancer cells. In addition, these exosomes have tumour homing abilities .
MiR-206 can reduce neurological damage and brain oedema caused by the BDNF/TRKB/CREB signalling pathway and can inhibit neuronal apoptosis, preventing early brain injury and improving neuroprotection, and when combined with acupuncture in mice, miR-206 has shown a significant anti-ageing effect. If developed well, these exosomes may be used in human aesthetic treatments . HUC-MSC-derived exosomes can inhibit viral replication and inhibit hepatitis C virus (HCV) infection, but the specific mechanisms are not yet defined. One explanation is that a certain RNA or protein may act on a specific target, which can then interfere with the proliferation of the hepatitis C virus. This is because the hepatitis C virus does not easily spread and will not ultimately develop into cirrhosis. These exosomes can also downregulate the “cytokine storm” to restore oxygenation. Finally, these exosomes can be used to develop COVID-19 drugs [91, 92].
The pre-microRNAs found in these exosomes are all associated with immune-related pathways . Exosomes can be beneficial to tumour growth, proliferation, and migration [1, 84]. Gastric cancer cells are more sensitive to exosomes than osteosarcoma cells, and exosomes can be used to treat patients with gastric cancer. BMSC-derived exosomes promote the proliferation of myeloma cells in patients with multiple myeloma. However, some research has shown that exosomes inhibit tumour activity, and exosomes secreted by the normal human bone marrow have been shown to inhibit the proliferation of multiple myeloma cells .
MiR-22 and miR-let-7a are used clinically as immunomodulators, as they are beneficial to the formation of vascular structures, exert neuroprotective effects, and provide haematopoietic support. Exosomes can effectively improve osteoporosis and can treat cartilage damage, osteoarthritis, and Alzheimer’s disease (AD) .
Katsuda et al. reported that MSCs can produce exosomes with different contents, which act as signal transmitters and protein transporters between target cells and MSCs . Lopez-Verrilli et al. showed that exosomes from different sources had significantly different effects on the growth of synapses in primary cortical neurons and dorsal root ganglion explants . Additionally, HASCs, HUC-MSCs, and HBMSCs can antagonise the cellular effects of U87 MG glioblastoma cells .
Basic research on exosomes and the exploration of clinical treatments have received extensive attention. Exosomes can be derived from different types of MSCs, and exosomes from different sources have unique characteristics. On the one hand, they share the characteristics of tissue repair, regeneration, and promotion of angiogenesis. On the other hand, AMSC exosomes can be used for wound healing, while HUC-MSC-derived exosomes have tumour homing ability and can also inhibit viral infection and replication. Recent studies have found that exosomes are also effective in the treatment of COVID-19.
According to the results of studies in which exosomes have been used to treat certain diseases, the mechanisms of applying exosomes to different diseases are also different. In tumour research, exosomes have a dual regulatory role. HUC-MSC- and HBMSC-derived exosomes can inhibit the proliferation of glioblastomas and promote apoptosis. However, exosomes secreted by HASCs can promote tumour growth but have no effect on the apoptosis of U87 MG glioblastoma cells . The reason for these completely opposite results of treatment with exosomes from different sources is still unclear.
In terms of neurodegenerative diseases, one of the causes of Alzheimer’s disease is a mutation that causes increased β-amyloid, and neurolysin is a β-amyloid peptide-degrading enzyme. Studies have found that HUMSC-derived exosomes have higher neurolysin activity than HBMSC-derived exosomes. This is the only difference in the function of these exosomes from different sources, which is worthy of further in-depth study. This may provide new ideas for the treatment of Alzheimer’s disease .
In a study of intervertebral disc degeneration, Xia et al. found 150 proteins that are closely related to the enhancement of the inflammatory response . Exosomes can significantly inhibit the inflammatory response of apoptotic nucleus pulposus cells. Proteins in BMSC-derived exosomes can restore function in nucleus pulposus cells with mitochondrial damage, restore normal structure, and reduce the oxidative response of mitochondria. These potential mechanisms mainly serve to promote the anti-inflammatory response, inhibit cell apoptosis, and restore mitochondrial function in the repair of intervertebral disc degeneration, but the detailed mechanism is still unclear.
Studying the mechanism of exosomes in the treatment of diseases is the primary connection to future clinical research. As a new treatment concept, exosomes have special advantages. As a signalling molecule, MSC exosomes not only exert the same effects as MSCs, but they also have a more stable membrane structure than MSCs. Compared with whole-cell therapy, MSC-derived exosomes are well tolerated and have low immunogenicity. These advantages provide broader prospects for disease treatment.
However, according to the data and research results obtained thus far, many unclear links and problems remain. Current problems involve the following: the technology of large-scale culture and isolation of MSCs; the optimal method for the long-term preservation of exosomes; the rapid and accurate determination of the exosome concentration and quality control, purification, and transplantation conditions of exosomes; and the cost and safety of exosomes. Resolution of these issues requires more in-depth analysis for clarification. Although many problems with exosomes still exist, the prospects of basic research and clinical applications are worthy of attention and exploration.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analysed during the current study.
Mesenchymal stem cells
Adipose mesenchymal stem cells
Bone marrow mesenchymal stem cells
Umbilical cord mesenchymal stem cells
Enzyme-linked immunosorbent assay
Foetal bovine serum
Dynamic light scattering
Transmission electron microscopy
Atomic force microscopy
Tunable resistance pulse sensing
Nanoparticle tracking analysis
- MHC I:
Major histocompatibility complex I
Leukocyte differentiation antigen, cluster of differentiation
Programmed cell death 6-interacting protein (PDCD6IP)
Tumour susceptibility gene 101 protein
Golgi matrix protein 130
Intercellular cell adhesion molecule-1
Epithelial cell adhesion molecule
Long non-coding RNA
Human umbilical cord mesenchymal stem cells
Human umbilical cord perivascular mesenchymal stem cells
Human umbilical cord Wharton’s Jelly mesenchymal stem cells
Human amniotic membrane-derived mesenchymal stem cells
Large-conductance Ca2+-activated K+ channel
Mouse osteogenic progenitor cell
Heat shock protein 70
Regulatory T cells
T helper cell
Adipose stem cell
Hepatitis C virus
Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol. 1983;97(2):329–39.
Simpson, Richard J, Kalra, et al. ExoCarta as a resource for exosomal research. J Extracellular Vesicles, 2012, 1 (1): 18374.
Katsuda T, Tsuchiya R, Kosaka N, Yoshioka Y, Takagaki K, Oki K, Takeshita F, Sakai Y, Kuroda M, Ochiya T. Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep. 2013;3:1197.
Villatoro AJ, Alcoholado C, Martín-Astorga MC, Fernández V, Cifuentes M, Becerra J. Comparative analysis and characterization of soluble factors and exosomes from cultured adipose tissue and bone marrow mesenchymal stem cells in canine species. Vet Immunol Immunopathol. 2019;208:6–15.
Tracy SA, Ahmed A, Tigges JC, Ericsson M, Pal AK, Zurakowski D, Fauza DO. A comparison of clinically relevant sources of mesenchymal stem cell-derived exosomes: bone marrow and amniotic fluid. J Pediatr Surg. 2019;54(1):86–90.
van Balkom BW, Gremmels H, Giebel B, Lim SK. Proteomic signature of mesenchymal stromal cell-derived small extracellular vesicles. Proteomics. 2019;19(1–2):1800163.
Angulski AB, Capriglione LG, Batista M, Marcon BH, Senegaglia AC, Stimamiglio MA, et al. The protein content of extracellular vesicles derived from expanded human umbilical cord blood-derived CD133 + and human bone marrow-derived mesenchymal stem cells partially explains why both sources are advantageous for regenerative medicine. Stem Cell Rev Rep. 2017;13(2):244–57.
Eirin A, Zhu X-Y, Puranik AS, Woollard JR, Tang H, Dasari S, et al. Comparative proteomic analysis of extracellular vesicles isolated from porcine adipose tissue-derived mesenchymal stem/stromal cells. Sci Rep. 2016;6:36120.
Lopez-Verrilli MA, Caviedes A, Cabrera A, et al. Mesenchymal stem cell-derived exosomes from different sources selectively promote neuritic outgrowth. Neuroscience. 2016;320:129–39.
Williams KJ, Picou AA, Kish SL, et al. Isolation and characterization of porcine adipose tissue-derived adult stem cells. Cells Tissues Organs. 2008;188(3):251–8.
Liao HT, Chen CT. Osteogenic potential: comparison between bone marrow and adipose-derived mesenchymal stem cells. World J Stem Cells. 2014;6(3):288–95.
Jing W, Xia C, Zhiguo W, et al. Isolation and identification of exosomes derived from human adipose mesenchymal stem cells. Chinese Tissue Engineering Research. 2019;23(17):33–40.
Pegtel D M , Garde M D B V D , Middeldorp J M. Viral miRNAs exploiting the endosomal–exosomal pathway for intercellular cross-talk and immune evasion. Biochim Biophys Acta, 2011, 1809 (11–12): 0–721.
Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C, et al. Sorting it out: regulation of exosome loading. Semin Cancer Biol. 2014;28:3–13.
Zhang J, Li S, Li L, et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics. 2015;13(1):17–24.
Maroto R, Zhao Y, Jamaluddin M, Popov VL, Wang H, Kalubowilage M, Zhang Y, Luisi J, Sun H, Culbertson CT, Bossmann SH, Motamedi M, Brasier AR. Effects of storage temperature on airway exosome integrity for diagnostic and functional analyses. J Extracell Vesicles. 2017;6(1):1359478.
Yuana Y, Böing AN, Grootemaat AE, van der Pol E, Hau CM, Cizmar P, Buhr E, Sturk A, Nieuwland R. Handling and storage of human body fluids for analysis of extracellular vesicles. J Extracell Vesicles. 2015;4:29260.
Ge Q, Zhou Y, Lu J, Bai Y, Xie X, Lu Z. miRNA in plasma exosome is stable under different storage conditions. Molecules. 2014;19(2):1568–75.
Kowal J, Tkach M, Théry C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. 2014;29:116–25.
Roberta P, Guillaume VN. To be or not to be. Secreted as exosomes, a balance finely tuned by the mechanisms of biogenesis. Essays Biochem. 2018;62(2):177–91.
Vakhshiteh F, Atyabi F, Ostad SN. Mesenchymal stem cell exosomes: a two-edged sword in cancer therapy. Int J Nanomedicine. 2019;14:2847–59.
McCullough J, Frost A, Sundquist WI. Structures, functions, and dynamics of ESCRT-III/Vps4 membrane remodeling and fission complexes. Annu Rev Cell Dev Biol. 2018;34:85–109.
Bajimaya S, Frankl T, Hayashi T, et al. Cholesterol is required for stability and infectivity of influenza A and respiratory syncytial viruses. Virology. 2017;510:234–41.
Langevin SM, Kuhnell D, Orr-Asman MA, et al. Balancing yield, purity and practicality: a modified differential ultracentrifugation protocol for efficient isolation of small extracellular vesicles from human serum. RNA Biol. 2019;16(1):5–12.
Menon R, Dixon CL, Sheller-Miller S, et al. Quantitative proteomics by SWATH-MS of maternal plasma exosomes determine pathways associated with term and preterm birth. Endocrinology. 2019;160(3):639–50.
Soares Martins T, Catita J, Martins Rosa I, A B da Cruz E Silva O, Henriques AG. Exosome isolation from distinct biofluids using precipitation and column-based approaches. PLoS One. 2018; 13 (6): e0198820.
Buschmann D, Kirchner B, Hermann S, et al. Evaluation of serum extracellular vesicle isolation methods for profiling miRNAs by next-generation sequencing [published correction appears in J Extracell Vesicles. 2019 Mar 08;8(1):1581487]. J Extracell Vesicles. 2018; 7 (1): 1481321.
Zhao L, Yu J, Wang J, Li H, Che J, Cao B. Isolation and identification of miRNAs in exosomes derived from serum of colon cancer patients. J Cancer. 2017;8(7):1145–52.
Semreen MH, Alniss HY, Mousa MK, El-Awady R, Khan F, Al-Rub KA. Quantitative determination of doxorubicin in the exosomes of A549/MCF-7 cancer cells and human plasma using ultra performance liquid chromatography-tandem mass spectrometry. Saudi Pharm J. 2018;26(7):1027–34.
Ying G, Bo N, Xiuwei W, et al. Comparison of exosome extracting methods from human umbilical cord mesenchymal stem cells. Chinese Tissue Engineering Research. 2018;022(009):1382–8.
H. Cheng, H. Fang, R.-D. Xu, et al. Development of a rinsing separation method for exosome isolation and comparison to conventional methods: 2019; 23 (12): 5074–5083.
Van Deun J, Mestdagh P, Sormunen R, et al. The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling. J Extracell Vesicles. 2014;3:24858.
Lamparski HG, Metha-Damani A, Yao JY, Patel S, Hsu DH, Ruegg C, et al. Production and characterization of clinical grade exosomes derived from dendritic cells. J Immunol Methods. 2002;270:211–26.
Lobb RJ, Becker M, Wen SW, et al. Optimized exosome isolation protocol for cell culture supernatant and human plasma. J Extracell Vesicles. 2015;4:27031.
Que RS, Lin C, Ding GP, Wu ZR, Cao LP. Increasing the immune activity of exosomes: the effect of miRNA-depleted exosome proteins on activating dendritic cell/cytokine-induced killer cells against pancreatic cancer. J Zhejiang Univ Sci B. 2016;17(5):352–60.
Ji H, Chen M, Greening DW, et al. Deep sequencing of RNA from three different extracellular vesicle (EV) subtypes released from the human LIM1863 colon cancer cell line uncovers distinct miRNA-enrichment signatures. PLoS One. 2014;9(10):e110314.
Djender S, Schneider A, Beugnet A, Crepin R, et al. Bacterial cytoplasm as an effective cell compartment for producing functional VHH-based affinity reagents and camelidae IgG-like recombinant antibodies. Microb Cell Factories. 2014;13:140.
Monegal A, Ami D, Martinelli C, et al. Immunological applications of single-domain llama recombinant antibodies isolated from a naive library. Protein Eng Des Sel. 2009;22:273–80.
Crepin R, Gentien D, Duche A, et al. Nanobodies against surface biomarkers enable the analysis of tumor genetic heterogeneity in uveal melanoma patient-derived xenografts. Pigment Cell Melanoma Res. 2017;30:317–27.
Greening DW, Xu R, Ji H, Tauro BJ, Simpson RJ. A protocol for exosome isolation and characterization: evaluation of ultracentrifugation, density-gradient separation, and immunoaffinity capture methods. Methods Mol Biol. 2015;1295:179–209.
Popovic M, Mazzega E, Toffoletto B, de Marco A. Isolation of anti-extra-cellular vesicle single-domain antibodies by direct panning on vesicle-enriched fractions. Microb Cell Factories. 2018;17(1):6.
Gurunathan S, Kang MH, Jeyaraj M, Qasim M, Kim JH. Review of the isolation, characterization, biological function, and multifarious therapeutic approaches of exosomes. Cells. 2019;8(4):307.
Iliescu FS, Vrtačnik D, Neuzil P, Iliescu C. Microfluidic technology for clinical applications of exosomes. Micromachines (Basel). 2019;10(6):392.
Zhang P, Zhou X, He M, et al. Ultrasensitive detection of circulating exosomes with a 3D-nanopatterned microfluidic chip. Nat Biomed Eng. 2019;3(6):438–51.
Abramowicz A, Marczak L, Wojakowska A, et al. Harmonization of exosome isolation from culture supernatants for optimized proteomics analysis. PLoS One. 2018;13(10):e0205496.
Al-Khawaga S, Abdelalim EM. Potential application of mesenchymal stem cells and their exosomes in lung injury: an emerging therapeutic option for COVID-19 patients. Stem Cell Res Ther. 2020;11(1):437.
Navajas R, Corrales FJ, Paradela A. Serum exosome isolation by size-exclusion chromatography for the discovery and validation of preeclampsia-associated biomarkers 2019; 1959: 39–50.
Toyserkani NM, Christensen ML, Sheikh SP, et al. Adipose-derived stem cells: new treatment for wound healing? Annals of Plastic Surgery, 2014, 75 (1): 117.
Hongchao L, Yinpeng J, Xi W, et al. Isolation and identification of human adipose stem cells and their exosomes. Chinese Tissue Engineering Research. 2018;022(013):2033–8.
Jianqing Z, Jialin J, Xinming C, et al. Isolation, culture and identification of mouse epididymal adipose stem cells. Chinese Tissue Engineering Research. 2014;18(28):4535–41.
Lee RH, Kim B, Choi I, et al. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem. 2004;14(4–6):311–24.
Wu R, Gao W, Yao K, Ge J, et al. Roles of exosomes derived from immune cells in cardiovascular diseases. Front Immunol. 2019;10:648.
Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol, 2015; 77: 13–27.
Vlassov AV, Magdaleno S, Setterquist R, et al. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials[J]. Biochim Biophys Acta. 2012;1820(7):940–8.
Trajkovic K, Hsu C, Chiantia S, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319:1244–7.
Raposo G, Stoorvogel W. Extracellular vesicles: Exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373–83.
Subra C, Grand D, Laulagnier K, et al. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J Lipid Res. 2010;51:2105–20.
Mobius W, Van Donselaar E, Ohno-Iwashita Y, et al. Recycling compartments and the internal vesicles of multivesicular bodies harbor most of the cholesterol found in the endocytic pathway. Traffic. 2003;4:222–31.
Xiaoyue G, Yuquan Z, Xiaoqing Y, et al. Research progress of human umbilical cord mesenchymal stem cells repairing the damaged tissue[J]. Biomedical Engineering and Clinical. 2018;022(002):208–13.
Gaomiyang L, Xinghua P, Falian H, et al. Comparison of two methods for the isolation of exosomes derived from human umbilical cord mesenchymal stem cells[J]. Chinese J Cells Stem Cells. 2017;7(2):81–6 f3-f8.
Wang D, Na Q, Song GY, Wang L. Human umbilical cord mesenchymal stem cell-derived exosome-mediated transfer of microRNA-133b boosts trophoblast cell proliferation, migration and invasion in preeclampsia by restricting SGK1. Cell Cycle. 2020;19(15):1869–83.
Liyan G, Peilong L, Suxia G, et al. Regulatory effects of exosomes derived from human umbilical cord mesenchymal stem cells on Treg and TH17 cells[J]. Chinese J Experimental Hematol. 2019;27(01):233–8.
Weijie Y, Jiazhao L, Liangjian C, et al. Isolation and identification of human umbilical cord mesenchymal stem cell exosomes and their hemolytic performance[J]. J Nanjing Medical University: Natural Science Edition. 2019;39(02):7–12.
Yuxian S, Dongya Z, Yujun X, et al. Regulatory effect of human umbilical cord mesenchymal stem cells-derived exosomes on macrophage polarization[J]. China Tissue Engineering Research. 2019;023(013):2002–8.
Ping Z, Bo N, Rui G, et al. Exosomes derived from human umbilical cord mesenchymal stem cells promote myocardial repair after myocardial infarction under hypoxia. China Tissue Engineering Res. 2019;023(017):2630–6.
Wei H. Study on the effect and mechanism of exosomes derived from bone marrow mesenchymal stem cells in promoting bone regeneration: Nanchang University; 2018.
Huan C, Gai S, Siyue T, et al. Stable and efficient culture of mouse bone marrow mesenchymal stem cells and extraction of exosomes[J]. Journal of Anhui Medical University. 2020;055(004):518–22.
Li Z, Liu F, He X, Yang X, Shan F, Feng J. Exosomes derived from mesenchymal stem cells attenuate inflammation and demyelination of the central nervous system in EAE rats by regulating the polarization of microglia. Int Immunopharmacol. 2019;67:268–80.
de Munter JPJM, Mey J, Strekalova T, Kramer BW, Wolters EC. Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail? J Neural Transm (Vienna). 2020;127(5):715–27.
Shilei W, Yong L, Zengwu S, et al. Research status of the effects of bone tissue exosomes on bone metabolism. Chinese Electronic J Geriatric Orthopedics Rehabilitation. 2018;4(05):58–61.
Han Y, Ren J, Bai Y, et al. Exosomes from hypoxia-treated human adipose-derived mesenchymal stem cells enhance angiogenesis through VEGF/VEGF-R. Int J Biochem Cell Biol. 2019;109:59–68.
Chen B, Cai J, Wei Y, et al. Exosomes are comparable to source adipose stem cells in fat graft retention with up-regulating early inflammation and angiogenesis. Plast Reconstr Surg. 2019; 144 (5): 816e-827e.
Liu Y, Wang H, Wang J. Exosomes as a novel pathway for regulating development and diseases of the skin. Biomed Rep. 2018;8(3):207–14.
Shukla L, Yuan Y, Shayan R, Greening DW, Karnezis T. Fat therapeutics: the clinical capacity of adipose-derived stem cells and exosomes for human disease and tissue regeneration. Front Pharmacol. 2020; 11: 158. Published 2020 Mar 3.
Kupcova SH. Proteomic techniques for characterisation of mesenchymal stem cell secretome. Biochimie. 2013;95(12):2196–211.
Fong CY, Subramanian A, Biswas A, et al. Derivation efficiency, cell proliferation, freeze–thaw survival, stem-cell properties and differentiation of human Wharton’s jelly stem cells. Reproductive Biomedicine Online. 2010;21(3):391–401.
Song A, Wang J, Tong Y, et al. BKCa channels regulate the immunomodulatory properties of WJ-MSCs by affecting the exosome protein profiles during the inflammatory response. Stem Cell Res Ther. 2020;11(1):440.
Wang L, Wang J, Zhou X, Sun J, Zhu B, Duan C, Chen P, Guo X, Zhang T, Guo H. A new self-healing hydrogel containing hucMSC-derived exosomes promotes bone regeneration. Front Bioeng Biotechnol. 2020;8:564731.
Zhao Y, Sun X, Cao W, et al. Exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury. Stem Cells Int. 2015;2015:761643.
Zhang Y, Wang WT, Gong CR, et al. Combination of olfactory ensheathing cells and human umbilical cord mesenchymal stem cell-derived exosomes promotes sciatic nerve regeneration. Neural Regen Res. 2020;15(10):1903–11.
Tuca AC, Ertl J, Hingerl K, et al. Comparisonof Matrigel and Matriderm as a carrier for human amnion-derived mesenchymal stem cells in wound healing. Placenta. 2016;48:99–103.
Ying F, Shihong L, Xin W, et al. Characteristics of exosomes secreted by mesenchymal stem cells derived from human bone marrow. Chinese J Experimental Hematology. 2014;22(3):595–9.
Wei H, Rongchun C, Fangjun Z, et al. Study on bone regeneration mechanism of exosomes derived from bone marrow mesenchymal stem cells. Chinese J Osteoporosis. 2019;025(004):477–83.
Ghaemmaghami AB, Mahjoubin-Tehran M, Movahedpour A, et al. Role of exosomes in malignant glioma: microRNAs and proteins in pathogenesis and diagnosis. Cell Commun Signal. 2020;18(1):120.
Zhuang L, Xia W, Chen D, et al. Exosomal LncRNA-NEAT1 derived from MIF-treated mesenchymal stem cells protected against doxorubicin-induced cardiac senescence through sponging miR-221-3p. J Nanobiotechnology. 2020;18(1):157.
Lei H, Jiaqi S, Chao L, et al. Research progress of exosomes derived from mesenchymal stem cells in malignant tumors[J]. Chinese Journal of Oncology. 2019;46(22):1185–8.
Takahara K, Ii M, Inamoto T, et al. microRNA-145 mediates the inhibitory effect of adipose tissue-derived stromal cells on prostate cancer. Stem Cells Dev. 2016;25:1290–8.
Xia W, Chen H, Xie C, Hou M. Long-noncoding RNA MALAT1 sponges microRNA-92a-3p to inhibit doxorubicin-induced cardiac senescence by targeting ATG4a. Aging (Albany NY). 2020;12(9):8241–60.
Shao M, Jin M, Xu S, et al. Exosomes from long noncoding RNA-Gm37494-ADSCs repair spinal cord injury via shifting microglial M1/M2 polarization [published online ahead of print, 2020 Apr 19]. Inflammation. 2020;.
Qu Q, Pang Y, Zhang C, et al. Exosomes derived from human umbilical cord mesenchymal stem cells inhibit vein graft intimal hyperplasia and accelerate reendothelialization by enhancing endothelial function. Stem Cell. 2020;11(1):133.
Zhang K, Yu L, Li FR, et al. Topical application of exosomes derived from human umbilical cord mesenchymal stem cells in combination with sponge spicules for treatment of photoaging. Int J Nanomedicine. 2020;15:2859–2872. Published 2020 Apr 23.
Qian X, Xu C, Fang S, et al. Exosomal microRNAs derived from umbilical mesenchymal stem cells inhibit hepatitis C virus infection. Stem Cells Transl Med. 2016;5(9):1190–203.
Sengupta V, Sengupta S, Lazo A Jr, Woods P, Nolan A, Bremer N. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19 [published online ahead of print, 2020 May 12]. Stem Cells Dev. 2020;https://doi.org/10.1089/scd.2020.0080.
Chao T, Fang C. The relationship between exosomes of human bone marrow-derived mesenchymal stem cells and tumor growth. Genomics Applied Biol. 2019;038(006):2842–8.
Xia C, Zeng Z, Fang B, Tao M, Gu C, Zheng L, Wang Y, Shi Y, Fang C, Mei S, Chen Q, Zhao J, Lin X, Fan S, Jin Y, Chen P. Mesenchymal stem cell-derived exosomes ameliorate intervertebral disc degeneration via anti-oxidant and anti-inflammatory effects. Free Radic Biol Med. 2019;143:1.
We would like to thank the Nature Research Editing Service (http://bit.ly/NRES-LS) for the English language editing.
This work was supported by the National Natural Science Foundation of China (31700154), the Major Science and Technology Special Project of Yunnan Province (Biomedicine) (2018ZF006), and the Chinese Academy of Medical Sciences Medicine and Health Technology Innovation Project (2016-I2 M-3-026).
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Tang, Y., Zhou, Y. & Li, HJ. Advances in mesenchymal stem cell exosomes: a review. Stem Cell Res Ther 12, 71 (2021). https://doi.org/10.1186/s13287-021-02138-7