Exosomes biological significance: A concise review

doi:10.1016/j.bcmd.2005.12.001

Blood Cells, Molecules, and Diseases

Volume 36, Issue 2, March–April 2006, Pages 315-321

https://doi.org/10.1016/j.bcmd.2005.12.001 Get rights and content

Abstract

Exosomes were initially thought to be a mechanism for removing unneeded membrane proteins from reticulocytes. Current studies have shown that the process of exosome formation extends to many mammalian cells. This concise review highlights the findings reported at a Workshop on Exosomes. Full knowledge of the contribution of exosomes to intercellular information transmission and the potential medical application of this knowledge will depend on the ingenuity of future investigators and their insight into biological processes.

Section snippets

Exosomes—current state

The intracellular production of small vesicles containing a highly selective content of plasma membrane proteins was described over 25 years ago in maturing reticulocytes of sheep [1], [2], [3]. Many plasma membrane proteins are known to disappear during the maturation of the reticulocyte to the final, nucleus-free, mitochondria free, concave-disc-shaped mammalian erythrocyte. While the lysosomal compartment has been the generally recognized site for the degradation of unwanted, denatured or

A synopsis of views and outstanding issues from the first workshop on exosomes

Mammalian red cells lose the majority of their intracellular organelles during maturation into reticulocytes [10]. Whether exosome formation is linked to the extrusion and destruction of organelles like the nucleus and mitochondria is still under investigation [11]. Studies by Johnstone and colleagues [12] have concluded that the processes are independent based on the observation that native avian red cells, which retain both their nuclei and mitochondria, still form exosomes upon maturation.

What targets protein elimination via exosomes?

As previously noted, the proteins targeted for elimination by exosomes depend on the cell type. Even in a single type of cell, such as the mammalian red cell, the same protein may be targeted for elimination to a very different extent in different species. For example, while the transferrin receptor is uniformly lost in all known species of adult red cells, sheep cells retain most of their glucose transporters and pig cells retain their nucleoside transporters, but not the reverse, into

Sorting signals to escape degradation in lysosomes

MVB (multivesicular body) formation has been described in yeast as well as a number of mammalian cells as a means for selective sorting and targeting of proteins to the recycling and the degradative pathways respectively. The internal vesicles of the MVB destined for degradation are presumed to undergo monoubiquitination and release into the lysosomal lumen upon fusion of the MVB with the lysosomal membrane. The residual membrane of the MVB, on the other hand, is believed to retain those

Exosomes beyond the blood cell systems

While exosome formation is now well established in red cells and cells of the immune system, an example of an unexpected cell type contributing to exosome release is the intestinal epithelial cell. While engaged in its classical role in nutrient absorption, the intestinal cell has a number of characteristics of a cell of the immune system. Exosomes released from the basolateral surface of enterocytes may carry antigens and act as a link between the local immune system and the digestive tract,

Exosomes and the activation of the immune system

Exosomes derived from the multivesicular bodies of dendritic cells (DC) have taken on important immunological functions. Mature dendritic cell exosomes are two orders of magnitude more effective than those from immature dendritic cells in inducing antigen-specific T-cell activation [32].

While immature DCs derived from spleen produce greater numbers of MVBs and exosomes than mature cells, the former are weaker in their ability to stimulate T cells, presumably indicative of differences in their

Transfer of infectious agents via exosomes

The insidious nature of the propagation of agents of disease by exosomal transfer is self-evident. Such pathways have already been proposed for spread of retroviruses, including HIV [35], [36]. Both Gould [36] and Marsh [35] addressed the retroviral issue at the Exosome Workshop. In primary macrophages of man, HIV may assemble in internal compartments with the characteristics of late endosomal multivesicular compartments [35], which accumulate exosome-like bodies. This type of compartment

Clinical trials and applications of exosomes

While these basic questions are being pursued, attempts to find practical applications for the released exosomes continue to expand. Harvested vesicles, bearing specific protein markers derived from dendritic cells, have already been used to treat metastatic melanoma patients [37], [38]. These exosomes contain functional MHC class II peptide complexes known to be capable of promoting immune responses and tumor rejection. The preliminary results in both man and experimental animals have been

All vesicles may not be exosomes: establishing guidelines for a definition

With red cells and cells of the immune system, exosomes were identified intracellularly in MVBs prior to being released into the extracellular milieu [3], [8], [48], [50]. In addition to size and shape, a number of specific proteins such as tetraspannins, membrane-bound proteins and chaperones have been shown as characteristic residents of this particle from a variety of sources [6], [15], [16], [17], [18], [51], [52]. In many studies with other cells, including most malignant cells, the major

Acknowledgment

This workshop was supported by the Leukemia and Lymphoma Society, White Plains, New York, USA, to whom we express our thanks.

References (57)

R.M. Johnstone
Revisiting the road to the discovery of exosomes
Blood Cells, Mol. Dis.
(2005)
R.M. Johnstone et al.
Vesicle formation during reticulocyte maturation
J. Biol. Chem.
(1987)
L. Blanc et al.
Exosome release by reticulocytes—an integral part of the red blood cell differentiation system
Blood Cells, Mol. Dis.
(2005)
C.M. Fader et al.
Exosome secretion and red cell maturation: exploring molecular components involved in the docking and fusion of multivesicular bodies in K562 cells
Blood Cells, Mol. Dis.
(2005)
J.M. Escola et al.
Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B lymphocytes
J. Biol. Chem.
(1998)
S. Buschow et al.
Exosomes contain ubiquitinated proteins
Blood Cells, Mol. Dis.
(2005)
S.M. Jarvis et al.
Is inosine the physiological energy source of pig erythrocytes?
Biochim. Biophys. Acta
(1980)
R.M. Johnstone et al.
Reticulocyte maturation and exosome release, transferrin receptor-containing exosomes show multiple plasma membrane functions
Blood
(1989)
P. Véron et al.
Accumulation of MFG-E8/lactadherin on exosomes from immature dendritic cells
Blood Cells, Mol. Dis.
(2005)
D.J. Katzmann et al.
Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-1
Cell
(2001)

Cited by (306)

Exosomes based strategies for cardiovascular diseases: Opportunities and challenges
2024, Biomaterials
Exosomes, as nanoscale extracellular vesicles (EVs), are secreted by all types of cells to facilitate intercellular communication in living organisms. After being taken up by neighboring or distant cells, exosomes can alter the expression levels of target genes in recipient cells and thereby affect their pathophysiological outcomes depending on payloads encapsulated therein. The functions and mechanisms of exosomes in cardiovascular diseases have attracted much attention in recent years and are thought to have cardioprotective and regenerative potential. This review summarizes the biogenesis and molecular contents of exosomes and details the roles played by exosomes released from various cells in the progression and recovery of cardiovascular disease. The review also discusses the current status of traditional exosomes in cardiovascular tissue engineering and regenerative medicine, pointing out several limitations in their application. It emphasizes that some of the existing emerging industrial or bioengineering technologies are promising to compensate for these shortcomings, and the combined application of exosomes and biomaterials provides an opportunity for mutual enhancement of their performance. The integration of exosome-based cell-free diagnostic and therapeutic options will contribute to the further development of cardiovascular regenerative medicine.
Panel of serum long non-coding RNAs as potential non-invasive biomarkers for gallbladder carcinoma
2024, Non-coding RNA Research
Gallbladder carcinoma (GBC) is a common malignancy and is usually diagnosed in the late stages of the disease. The identification of new effective early diagnostic biomarkers could represent an effective approach in reducing mortality in GBC. Altered expression of long non-coding RNAs (lncRNAs) is believed to be associated with the emergence and development of GBC. Our study aims to identify the expression of a range of circulating lncRNAs, including HOTAIR, ANRIL, H19, CCAT1 and MEG3, in matched serum and tissues of GBC for diagnosis and its association with clinicopathological features. The case and control study included matched serum and tissues from 63 GBC, 19 cholecystitis (CC), and 46 normal controls (NC). RNA extraction and cDNA synthesis from serum and fresh tissue match were performed using commercially available kits. Relative expression was assessed using SYBR Green real-time quantitative polymerase chain reaction. Circulating lncRNA levels including HOTAIR, ANRIL and H19 were upregulated in serum samples, while MEG3 and CCAT1 were downregulated in GBC compared to controls. The trend towards upregulation and downregulation was comparable in the tissue. HOTAIR and MEG3 levels were significantly different between serum CC and early-stage GBC (p = 0.0373, 0.0020), while H19 was significantly upregulated comparing early-stage GBC to advanced-stage GBC (p = 0.018). The expression of ANRIL was significant with M stage (p = 0.0488), H19 with stage (p = 0.009), M stage (p=<0.0001) & stage (0.009) and CCAT1 with M stage (0.044). When distinguishing GBC and NC, AUC for HOTAIR was 0.75, ANRIL 0.78, H19 0.74, CCAT1 0.80 and 0.96 for MEG3. The combination sensitivity for lncRNAs ranged from 84.13% (CI: 72.74–92.12%) to 100.0% (CI: 94.31–100.0%). Significant diagnostic value in discriminating pathologic stage was observed for ANRIL and MEG3 (p = 0.022, p = 0.0005). LncRNA show a significant change in expression in GBC and in discrimination of early stage from late-stage disease. The detection of 2 lncRNAs in panels, in coordination with radiology, could represent a potential serum-based biomarker for early-stage GBC diagnosis.
Cellular evidence of communication strategies for small intestinal high endothelial cells: Ultrastructural insights of nano-scale exosomes and autophagy
2024, Micron
Although several immune related cells of small intestine play an essential role in the intestinal homeostasis. However, information related to ultrastructural evidence of Nano-scale exosomes-multivesicular bodies and autophagic pathway in the high endothelial cells (HECs) of the small intestine in laying birds is still ambiguous. In present study, the HECs secreted the early endosome (ee), late endosome (le) and multivesicular bodies (MVBs) in the lamina propria of layer small intestine was confirmed by transmission electron microscopy. Besides that, in the cytoplasm of HECs showed many autophagosomes were directly associated with lysosomes and mitochondria. Further, the immunohistochemistry and immunofluorescence results showed that, the immunoreactivity and immuno-signaling of Nano-scale exosome related proteins, cluster of differentiation (CD63) and tumor susceptibility gene (TSG101), and autophagic related proteins, autophagic related gene (ATG7) and microtubule-associated protein light chain (LC3) were strong positive expression in the lamina propria of small intestine. These results prove that HECs play a well-known immunological role in the maintenance of intestinal homeostasis. In summary, these findings indicate that the small intestine’s HECs have developed an innovative way of communication.
A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes
2022, Journal of Biological Chemistry
Exosomes are small extracellular vesicles of ∼30 to 150 nm that are secreted by all cells, abundant in all biofluids, and play important roles in health and disease. However, details about the mechanism of exosome biogenesis are unclear. Here, we carried out a cargo-based analysis of exosome cargo protein biogenesis in which we identified the most highly enriched exosomal cargo proteins and then followed their biogenesis, trafficking, and exosomal secretion to test different hypotheses for how cells make exosomes. We show that exosome cargo proteins bud from cells (i) in exosome-sized vesicles regardless of whether they are localized to plasma or endosome membranes, (ii) ∼5-fold more efficiently when localized to the plasma membrane, (iii) ∼5-fold less efficiently when targeted to the endosome membrane, (iv) by a stochastic process that leads to ∼100-fold differences in their abundance from one exosome to another, and (v) independently of small GTPase Rab27a, the ESCRT complex–associated protein Alix, or the cargo protein CD63. Taken together, our results demonstrate that cells use a shared, stochastic mechanism to bud exosome cargoes along the spectrum of plasma and endosome membranes and far more efficiently from the plasma membrane than the endosome. Our observations also indicate that the pronounced variation in content between different exosome-sized vesicles is an inevitable consequence of a stochastic mechanism of small vesicle biogenesis, that the origin membrane of exosome-sized extracellular vesicles simply cannot be determined, and that most of what we currently know about exosomes has likely come from studies of plasma membrane-derived vesicles.
The Complement System
2022, Encyclopedia of Infection and Immunity
This article focuses on major characteristics of the complement system and complement regulatory proteins. Emphasis will be on the following essential questions: (a) How does the complement system activate and amplify? (b) How does the complement system recognize self (host) vs non-self (i.e. pathogens or altered self) in order to induce inflammatory processes, promote phagocytosis, and/or kill pathogens in a targeted manner? (c) What are the main functions of complement in innate and adaptive immunity? (d) How do complement regulatory proteins protect host from complement-mediated damage? (e) How are the main primary or secondary deficiencies, or loss or gain-of-function mutations in the components and regulatory proteins of complement associated to severe infections and/or other diseases? (f) What are the current FDA-approved therapeutics to protect patients from complement-mediated damage? and (g) How are complement protein levels and functions assessed in the clinic? The profound biomedical relevance of the complement system is illustrated through understanding the molecular mechanisms of the pleiotropic functions of this system, how it is regulated, and how it can lead to disease. It is this same understanding that allows for the identification and development of effective therapies, as well as how and when to best apply them.
HDAC8-inhibitor PCI-34051-induced exosomes inhibit human bronchial smooth muscle cell proliferation via miR-381-3p mediated TGFB3
2021, Pulmonary Pharmacology and Therapeutics
The present study aimed to investigate the effects of PCI-34051-induced human bronchial epithelial cells (HBECs)-derived exosomes (PCI-Exo) on human bronchial smooth muscle cells (HBSMCs) and the key exosomal miRNAs involved in this process. Blank exosomes (Exo) and PCI-Exo were extracted from HBECs treated with PBS and PCI-34051, respectively. RNA-sequencing was performed to uncover the miRNA expression profile affected by PCI-Exo. The MTT, flow cytometry and TUNEL assays were performed to reveal the effect of PCI-34051 and PCI-Exo on the proliferation and apoptosis of HBSMCs. Western blotting and qRT-PCR were used for detecting protein and mRNA expression. A total of 25 exosomal miRNAs consisted of 17 down-regulated and eight up-regulated miRNAs were differentially expressed among PCI-Exo and Exo. Target genes of the exosomal miRNAs were mainly associated with signal transduction, cell adhesion, microRNAs in cancer, and ECM receptor interaction. miR-381-3p was identified as the most significant upregulated differential miRNA in PCI-Exo after qRT-PCR validation and could be transferred to HBSMCs by PCI-Exo. PCI-Exo treatment inhibited the proliferation but induced the apoptosis of HBSMCs. TGFβ3 was identified as a target gene of miR-381-3p which could directly bind to the 3′UTR of TGFβ3 mRNA. After transfecting the miR-381-3p mimic into HBSMCs, the proliferation inhibition and apoptosis rate of HBSMCs was significantly increased, and siTGFβ3 transfection showed similar effects. Moreover, miR-381-3p overexpression could not only decrease the expression of α-SMA, FN1 and collagen I but also increase that of E-cadherin in HBSMCs. Our findings suggested that PCI-Exo could hinder the proliferation and obviously induce the apoptosis of HBSMCs, and its mechanisms might partly be attributable to the reduction of TGFβ3 level by up-regulating exosomal miR-381-3p expression. These results may be vital for the treatment of lung related-diseases, especially asthma.

View all citing articles on Scopus

^☆: This review is based on the reports presented at a Workshop on the Biological Significance of Exosomes in Montreal, Canada, May 20–21, 2005. The references in this short report are neither complete nor extensive. The definitive references to each of the topics addressed may be found in the articles cited from Workshop on “Exosomes” published in vol. 34 and 35 in BCMD in 2005.

View full text

Exosomes biological significance: A concise review☆

Abstract

Section snippets

Exosomes—current state

A synopsis of views and outstanding issues from the first workshop on exosomes

What targets protein elimination via exosomes?

Sorting signals to escape degradation in lysosomes

Exosomes beyond the blood cell systems

Exosomes and the activation of the immune system

Transfer of infectious agents via exosomes

Clinical trials and applications of exosomes

All vesicles may not be exosomes: establishing guidelines for a definition

Acknowledgment

Blood Cells, Mol. Dis.

J. Biol. Chem.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

J. Biol. Chem.

Blood Cells, Mol. Dis.

Biochim. Biophys. Acta

Blood

Blood Cells, Mol. Dis.

Cell

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Biochim. Biophys. Acta

Blood

Blood Cells, Mol. Dis.

Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor

Cell

Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes

J. Cell Biol.