Extracellular Vesicles: Recent Developments in Aging and Reproductive Diseases

Yu Liu, Liu Y, Qiuzi Shen, Shen Q, Ling Zhang, Zhang L, Wenpei Xiang, Xiang W
Frontiers in cell and developmental biology · 2020 · vol. 8 , pp. 577084 · doi:10.3389/fcell.2020.577084 · PMID:33043012 · PMC7527740 · W3087094365
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This review examines extracellular vesicles' composition, release, separation, and cargo, detailing their roles in aging and reproductive diseases like PCOS and endometriosis as potential biomarkers and therapeutic targets.

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Abstract

Extracellular vesicles (EVs), present in cell culture media and several body fluids, play a prominent role in intercellular communication under physiological and pathological conditions. We performed a systematic literature search to review evidence regarding the existence, composition, and release of different EVs, as well as the biomarkers, cargos, and separation methods. We also reviewed the potential of EVs to transport cargos and alter the function and phenotype of recipient cells associated with aging and reproductive diseases, including polycystic ovary syndrome and endometriosis. In aging, EVs promote inflammatory reactions and offsetting the occurrence of aging. In the polycystic ovary syndrome and endometriosis, EVs and their cargos are involved in the occurrence of diseases, therapeutic strategies, and perform as non-invasive biomarkers. As the study of EVs is still in the early stages, it is not surprising that most of the current literature only describes their possible roles.
Full text 34,137 characters · extracted from pmc-nxml · 11 sections · click to expand

Dna

EVs also contain chromosomal DNA fragments. It has been reported that no matter the cause of cellular senescence, the secretion of DNA-containing exosomes increases with cell senescence ( Takahashi et al., 2017 ). In senescent human cells, the inhibition of exosome-associated DNA secretion by knocking down Alix or Rab27, which are important molecules for the biogenesis ( Baietti et al., 2012 ) and secretion ( Ostrowski et al., 2010 ) of the exosomes, can provoke reactive oxygen species (ROS)-dependent DNA damage due to the accumulation of DNA in the cytoplasm and senescent cell cycle arrest or cell apoptosis. Even in non-senescent cells, the accumulation of cytoplasmic DNA can induce apoptosis. Cytoplasmic DNA has been reported as a danger signal that activates the innate immune response, including the interferon (IFN) pathway ( Abe et al., 2013 ; Hartlova et al., 2015 ) and cGAS-STING-dependent signaling ( Takahashi et al., 2017 ). Meanwhile, exosomes are actively secreted from cells in order to the remove infected adenoviral DNA ( Takahashi et al., 2017 ). Exosomes, are therefore believed to play a critical role in senescence-associated secretory phenotypes. These results suggest that exosome secretion can maintain cellular homeostasis by removing harmful cytoplasmic DNA in senescent and non-senescent cells ( Table 2 ). These findings will provide new insights into the control of cell homeostasis as well as new facets to investigate the involvement of EVs.

C24:1

Ceramide is a sphingolipid produced by the hydrolysis of sphingomyelin, catalyzed by sphingomyelinase ( Wang et al., 2012 ), and has various of forms, such as short-, medium-, long-, and very long-chain. EVs are highly abundant in sphingolipid ceramide ( Wang et al., 2012 ). Lipidomic analyses of serum exosomes indicated that serum exosomes from older women were highly enriched in C24:1 ceramide ( Khayrullin et al., 2019 ). Exosome–associated ceramide has emerged as a key factor in cell death and senescence in a variety of cell types ( Venable et al., 1995 ). Recent studies by Law et al. (2018) revealed that very long-chain ceramides with lipotoxicity can cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes. In vitro experiments have shown that exosomes containing C24: 1 ceramide in serum could induce the senescence of BMSCs ( Khayrullin et al., 2019 ). These results confirm that exosomes containing C24: 1 ceramide may directly lead to the involuntary senescence and apoptosis of cells ( Table 2 ). These animal and human studies provide strong evidence for the relationship between EVs, cargos, and aging. In the future studies, the relationship between other contents of EVs and senescence should be further explored to reveal the potentially unexpected role of EVs.

Mirna

Recently, a new mechanism of intercellular communication mediated by exosome-associated miRNAs has attracted widespread attention ( Valadi et al., 2007 ). miRNAs are short non-coding RNA (ncRNA) molecules that can act as gene regulators by inhibiting translation or binding to the three primes’ untranslated region (3’-UTR) of target messenger RNA (mRNA) to induce degradation of the target mRNA transcripts ( Gasparello et al., 2019 ). miRNAs are therefore believed to be important in a range of physiological processes and the regulation of the development of many diseases. Moreover, Wei et al. (2017) recently analyzed extracellular RNA (exRNA) of EVs secreted by glioblastoma cells in vitro and found that ncRNA composed the majority of exRNA, instead of mRNA. This indicates that miRNAs play a significant and ever-growing role in the implementation of EVs function. Studies have shown that exosome miRNA can be transported to surrounding tissues or cells and exert either a positive or negative impact, as summarized in Table 2 . Several exosome-associated miRNAs are important regulators of senescence and cellular senescence. Exosomal miRNAs from senescent cells can be transported to surrounding cells and lead to aging ( Smith-Vikos and Slack, 2012 ; Urbanelli et al., 2016 ). For example, Davis et al. (2017) treated bone marrow mesenchymal stem cells (BMSCs) of young mice with EVs derived from the bone marrow of aging mice and found that osteogenic differentiation was inhibited and BMSCs senescence was induced. This phenomenon can be mimicked by the transfection of miR-183-5p into BMSCs. Aging of the brain is associated with the loss of myelin, which has been shown to directly cause cognitive decline ( Pusic and Kraig, 2014 ). In this study, serum-derived exosome miRNA in young Wistar rats promoted the differentiation of primary oligodendrocyte precursor cells (OPC) and improved the ability of remyelination in older Wistar rats. In the microenvironment of bone marrow, age-related miRNA changes can inhibit bone formation and promote bone resorption, leading to the osteoporosis. Exosomes derived from older rats BMSCs promoted the occurrence of osteoporosis and had higher levels of miR-31a-5p, compared to that of younger rats. Therefore, exosome miRNA is considered to be as an important mediator in the age-related bone marrow microenvironment ( Xu et al., 2018 ). EVs cargos involved in aging. However, exosomes can also suppress cellular senescence in certain contexts. Exosomes have been considered to be messengers of intercellular communication during angiogenesis. Recent studies have revealed that exosomes containing miR-214, produced by the human microvascular endothelial cell line (HMEC-1), can stimulate receptor cell migration and angiogenesis, thereby preventing the development of senescence. In contrast, the depletion of exosome miR-214 in endothelial cells failed to stimulate these processes and prevent cellular senescence ( van Balkom et al., 2013 ). The study of miRNA in young and senescent cell EVs is helpful to reveal the new mechanisms of senescence. Exosome miRNAs are also considered to be potential attractive biomarkers of aging ( Smith et al., 2015 ). In a study investigating Alzheimer’s disease (AD), Lugli et al. (2015) strongly suggested that plasma exosome miR-1306-5p, which targeted ADAM10, had the best sensitivity and specificity to predict AD, of all indicators examined. In salivary exosomes, miR-24-3p has been identified as a novel candidate biomarker for aging ( Machida et al., 2015 ). The miR-183 cluster of exosomes, comprising miR-96, miR-182, and miR-183, increased during the aging process ( Bertoldi et al., 2018 ). This suggests that the miR-183 clusters have the potential serve as biomarkers of aging.

Author

YL carried out literature search, data collection and analysis, and wrote the manuscript. QS revised the manuscript. LZ carried out design and revised the manuscript. WX took part in design and revised the manuscript. All authors read and approved the manuscript.

Methods

For this review, including three strategies: literature search, study selection, and results summary. We conducted a systematic online literature search of the PubMed and Web of Science databases and searched all published articles since the database’s creation to 2019. We used the following query: (‘extracellular vesicles’ or ‘microvesicles’ or ‘microparticles’ or ‘exosomes’) and (‘comparison of isolation method’ or ‘aging’ or ‘polycystic ovary syndrome’ or ‘endometriosis’). Both animal and human studies were considered suitable for this review. Additionally, all relevant studies were identified and included. These types of EVs do not include “apoptotic bodies” and “apoptotic vesicles”. Any duplicate articles were eliminated. After screening the title and/or abstracts, if the article was found to be unrelated to the study, was excluded. A total of 9072 records were retrieved from the two databases. After removing duplicates titles and other topic articles, the full-text articles of 190 articles were reviewed and 89 were considered relevant and included in this review ( Figure 1 ). Schematic of study selection.

Conflict

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Conclusion

In the recent decades, research on aging and reproductive diseases is mainly based on traditional fields such as genetic alterations and epigenetics. For this reason, many studies have focused on the development of EVs. Advances in the understanding of EVs in recent years have provided remarkable revelations. The relationship between EVs and aging as well as reproductive diseases has attention widespread attention. EVs could have the potential to be a new and non-invasive marker for assessing the condition of aging and reproductive diseases. In-depth research on the role and mechanism of EVs will provide new strategies for delaying aging and treating reproductive diseases and may eventually provide major innovations in their diagnosis and treatment. While EVs have shown potential importance and significance, stronger evidence is needed to support the possibility of EVs as clinical application. In addition, the lack of a gold standard method for EV separation and purification is a challenge and will limit the possibilities and significance of subsequent functional research.

Inflammatory

Inflammation has long been considered a defensive response to microbial agents. It is now clear that an inflammatory response can occur in the absence of infection, in a condition known as “aseptic inflammation” ( Chen and Nunez, 2010 ). Aseptic inflammation is referred to as a chronic systemic inflammatory state during aging ( Franceschi et al., 2000 ), in which EVs are involved ( Table 2 ). EVs can trigger aseptic inflammatory responses by carrying pathogen autoantigens or damage-associated molecular patterns, and are involved in the transmission of inflammatory diseases through EV-associated cytokines, miRNAs, and lipid mediators ( Buzas et al., 2014 ). Boilard et al. (2010) suggested that MPs originating from platelet are able to promote inflammatory reactions and stimulate cytokine responses in synovial fibroblasts via interleukin-1 (IL-1) signaling. Gomes de Andrade et al. (2018) revealed that aging could cause changes in the profiles of circulating exosomes. An age-related increase in CD63 levels was observed in exosomes from cerebrospinal fluid (CSF), and a significant decrease in IL-1β levels was observed in exosomes from the plasma of the older group of male Wistar rats ( Gomes de Andrade et al., 2018 ). These results suggest that changes in IL-1β levels of the exosomes are significantly correlated with age-related inflammatory responses.

Introduction

Intercellular communication has been shown to play an essential role in diverse physiological processes, including cell proliferation, development, and differentiation. Published literature in recent years has revealed a new mechanism of intercellular communication, namely via the release of extracellular vesicles (EVs). Classically, intercellular communication includes endocrine, paracrine, and autocrine or intercellular gap junctions, a kind of direct cell-cell contact, and secreted some factors. In the group of secreted factors, we will focus here on the roles of EVs. EVs secreted outside of the cell can serve as vehicles for the transport of cargo to recipient cells ( Raposo and Stoorvogel, 2013 ). EVs display a diverse range of sizes and are present in cell culture media (under both normal and pathological conditions) and several body fluids ( Caby et al., 2005 ; Admyre et al., 2007 ; Ogawa et al., 2008 ; Gonzales et al., 2009 ). The cargo of EVs contains biologically active molecules, such as nucleic acids (DNA, RNA, microRNAs and long non-coding RNAs), proteins, lipids, and nicotinamide phosphoribosyltransferase (eNAMPT) ( Yoshida et al., 2019 ). EVs have been shown to be involved in numerous biological functions and pathological processes ( Baek et al., 2016 ). Meanwhile, EVs and their cargos act as non-invasive markers of various diseases ( Li et al., 2009 ; Mitchell et al., 2009 ; Choi et al., 2011 ; Saman et al., 2012 ; Ostergaard et al., 2013 ; Jakobsen et al., 2015 ). Abnormal EV levels may be one of the causes of aging and reproductive diseases (including polycystic ovary syndrome (PCOS) and endometriosis), and are closely related to the occurrence, development, and prognosis of these diseases. Moreover, EVs can alleviate aging phenotypes, and promote cell proliferation ( Liu et al., 2019 ). Such developments offer new therapeutic strategies for the treatment of PCOS in the future. The purpose of this review is to describe the present knowledge of the role of EVs as cell-to-cell messengers in aging and reproductive diseases.

Nicotinamide

Nicotinamide adenine dinucleotide (NAD) is the basic chemical involved in energy metabolism in all living organisms. The expression of NAD + , the oxidized form of NAD, in worms, various rodent tissues (fat, skeletal muscle, liver, pancreas, kidney, brain and heart), skin, and neurosensory retina is decreased with age ( Braidy et al., 2011 ; Gomes et al., 2013 ; Mouchiroud et al., 2013 ; Khan et al., 2014 ; Canto et al., 2015 ; Verdin, 2015 ; Lin et al., 2018 ; Rajman et al., 2018 ; Yoshino et al., 2018 ). eNAMPT is an essential NAD + biosynthetic enzyme in mammals. In recent years, NAD + metabolism has become a hot topic in the field of aging ( Canto et al., 2015 ; Rajman et al., 2018 ). Through the enrichment of several exosome markers, such as Flotillin-1, TSG101, CD9, CD63, and CD81, as well as the use of electron microscopy, Yoshida et al. (2019) demonstrated that both mouse and human plasma exosomes contained eNAMPT, which was internalized into target cells to directly enhance cellular NAD + biosynthesis. Moreover, in aging mouse plasma, exosome-containing eNAMPT content can be changed. This is a novel inter-organizational communication mechanism that maintains NAD + levels through exosome-mediated eNAMPT transport. eNAMPT promotes the biosynthesis of systemic NAD + , offsets the occurrence of aging, and can be used as a new potential anti-aging intervention pathway ( Table 2 ).

Extracellular

The clinical application of EVs is based on four aspects ( Table 4 ). First, treatment tools. EVs can increase the secretion of proinflammatory cytokines ( Prado et al., 2008 ), and thus reducing the production or absorption of EVs may be a new strategy for the treatment of diseases. Secondly, EVs are promising biomarkers for diagnostic diseases ( Lugli et al., 2015 ; Machida et al., 2015 ; Muth et al., 2015 ; Carvalho et al., 2017b ; Bertoldi et al., 2018 ; Kyselova et al., 2019 ). EVs from bodily fluid have gained significant interest as a potential diagnostic biomarker for various diseases. Thirdly, EVs can be utilized as drug delivery tools. EVs can transport cargos to adjacent cells and be internalized into cells ( Yoshida et al., 2019 ). Lastly, EVs may be applied to vaccinations. EVs have the potential to improve immune function ( Raposo et al., 1996 ; Zitvogel et al., 1998 ; Chaput and Thery, 2011 ). The properties of EVs regulate the immune system, and thus give them the possibility to be involved in vaccinations. EVs application in clinical and basic research. In basic research, on the one hand, EVs contribute to disease pathophysiology. EVs and cargos include protein, miRNAs and lncRNAs that promote the development of the disease by influencing inflammation, angiogenesis, steroidogenesis and macrophage phagocytic ability ( Mesri and Altieri, 1998 ; Boilard et al., 2010 ; Harp et al., 2016 ; Munros et al., 2017 ; Gomes de Andrade et al., 2018 ; Khalaj et al., 2019 ; Li et al., 2019 ; Qiu et al., 2019 ; Sun et al., 2019 ). This effect may be mediated by the NF-κB signaling pathway ( Li et al., 2019 ; Zhang et al., 2019 ). On the other hand, EVs can also alleviate disease development ( Wu et al., 2018 ; Liu et al., 2019 ; Mobarak et al., 2019 ; Yoshida et al., 2019 ; Zhao et al., 2019 ). It may also be a new pathway to treatment diseases.

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endometriosis

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