Extracellular Vesicles as Biomarkers and Therapeutic Tools: From Pre-Clinical to Clinical Applications

Extracellular vesicles (EVs) are ubiquitous masters of intercellular communication, being detectable in tissues, circulation, and body fluids. Their complex cargo reflects the (patho)physiologic status of the cells from which they originate. Due to these properties, the potential of EVs, and in particular exosomes, to serve as biomarkers or therapeutics has grown exponentially over the past decade. On one side, numerous studies have demonstrated that EV-associated nucleic acids and proteins are implicated in cancer progression, as well as neurodegenerative, infectious, and autoimmune disorders. On the other, the therapeutic use of EVs secreted by various cell types, and in particular stem/progenitor cells, present significant advantages in comparison to the corresponding parental cells, such as the less complex production and storage conditions. In this review, we examine some of the major pre-clinical studies dealing with EVs and exosomes, that led to the development of numerous completed clinical trials.

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The exosome journey: from biogenesis to uptake and intracellular signalling

Cell Communication and Signaling ◽

10.1186/s12964-021-00730-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Sonam Gurung ◽

Dany Perocheau ◽

Loukia Touramanidou ◽

Julien Baruteau

Keyword(s):

Clinical Trials ◽

Plasma Membrane ◽

Scientific Community ◽

Cell Types ◽

Clinical Applications ◽

Clinical Development ◽

Intracellular Signalling ◽

Clinical Settings ◽

Health And Disease ◽

Adequate Definition

AbstractThe use of exosomes in clinical settings is progressively becoming a reality, as clinical trials testing exosomes for diagnostic and therapeutic applications are generating remarkable interest from the scientific community and investors. Exosomes are small extracellular vesicles secreted by all cell types playing intercellular communication roles in health and disease by transferring cellular cargoes such as functional proteins, metabolites and nucleic acids to recipient cells. An in-depth understanding of exosome biology is therefore essential to ensure clinical development of exosome based investigational therapeutic products. Here we summarise the most up-to-date knowkedge about the complex biological journey of exosomes from biogenesis and secretion, transport and uptake to their intracellular signalling. We delineate the major pathways and molecular players that influence each step of exosome physiology, highlighting the routes of interest, which will be of benefit to exosome manipulation and engineering. We highlight the main controversies in the field of exosome research: their adequate definition, characterisation and biogenesis at plasma membrane. We also delineate the most common identified pitfalls affecting exosome research and development. Unravelling exosome physiology is key to their ultimate progression towards clinical applications.

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Application of Stem Cell-Derived Extracellular Vesicles as an Innovative Theranostics in Microbial Diseases

Frontiers in Microbiology ◽

10.3389/fmicb.2021.785856 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hani Keshavarz Alikhani ◽

Bahare Shokoohian ◽

Sama Rezasoltani ◽

Nikoo Hossein-khannazer ◽

Abbas Yadegar ◽

...

Keyword(s):

Stem Cell ◽

Infectious Diseases ◽

Extracellular Vesicles ◽

Cell Types ◽

The Other ◽

Microbial Pathogens ◽

Microbial Diseases ◽

Clinical Complications ◽

Set Up ◽

Novel Therapeutic Strategies

Extracellular vesicles (EVs), as nano-/micro-scale vehicles, are membranous particles containing various cargoes including peptides, proteins, different types of RNAs and other nucleic acids, and lipids. These vesicles are produced by all cell types, in which stem cells are a potent source for them. Stem cell-derived EVs could be promising platforms for treatment of infectious diseases and early diagnosis. Infectious diseases are responsible for more than 11 million deaths annually. Highly transmissible nature of some microbes, such as newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), drives researcher’s interest to set up different strategies to develop novel therapeutic strategies. Recently, EVs-based diagnostic and therapeutic approaches have been launched and gaining momentum very fast. The efficiency of stem cell-derived EVs on treatment of clinical complications of different viruses and bacteria, such as SARS-CoV-2, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), Staphylococcus aureus, Escherichia coli has been demonstrated. On the other hand, microbial pathogens are able to incorporate their components into their EVs. The microbe-derived EVs have different physiological and pathological impacts on the other organisms. In this review, we briefly discussed biogenesis and the fate of EVs. Then, EV-based therapy was described and recent developments in understanding the potential application of stem cell-derived EVs on pathogenic microorganisms were recapitulated. Furthermore, the mechanisms by which EVs were exploited to fight against infectious diseases were highlighted. Finally, the deriver challenges in translation of stem cell-derived EVs into the clinical arena were explored.

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Potential Roles of Fungal Extracellular Vesicles during Infection

mSphere ◽

10.1128/msphere.00099-16 ◽

2016 ◽

Vol 1 (4) ◽

Cited By ~ 54

Author(s):

Luna S. Joffe ◽

Leonardo Nimrichter ◽

Marcio L. Rodrigues ◽

Maurizio Del Poeta

Keyword(s):

Immune System ◽

Extracellular Vesicles ◽

Virulence Factors ◽

Cell Types ◽

Fungal Diseases ◽

Host Immune System ◽

The Past ◽

Invasive Fungal Diseases

ABSTRACT Extracellular vesicles (EVs) are produced by virtually all cell types. Within the past few years, work in this field has revealed more information about fungal EVs. Fungal EVs have been shown to carry proteins, lipids, pigments, polysaccharides, and RNA; these components are known virulence factors, a fact which supports the hypothesis that fungal EVs concentrate pathogenic determinants. Extracellular vesicles (EVs) are produced by virtually all cell types. Within the past few years, work in this field has revealed more information about fungal EVs. Fungal EVs have been shown to carry proteins, lipids, pigments, polysaccharides, and RNA; these components are known virulence factors, a fact which supports the hypothesis that fungal EVs concentrate pathogenic determinants. Additionally, recent studies have demonstrated that fungal EVs stimulate the host immune system. In this review, putative roles of fungal EVs are discussed, including their potential as vaccination tools and their possible contribution to pathogenesis in invasive fungal diseases.

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Why the need and how to approach the functional diversity of extracellular vesicles

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0479 ◽

2017 ◽

Vol 373 (1737) ◽

pp. 20160479 ◽

Cited By ~ 116

Author(s):

Mercedes Tkach ◽

Joanna Kowal ◽

Clotilde Théry

Keyword(s):

Plasma Membrane ◽

Extracellular Vesicles ◽

Cell Communication ◽

Membrane Vesicles ◽

Tumour Microenvironment ◽

Efficient Separation ◽

The Past ◽

Therapeutic Tools ◽

Opinion Article ◽

Current Stage

In the past decade, cell-to-cell communication mediated by exosomes has attracted growing attention from biomedical scientists and physicians, leading to several recent publications in top-tier journals. Exosomes are generally defined as secreted membrane vesicles, or extracellular vesicles (EVs), corresponding to the intraluminal vesicles of late endosomal compartments, which are secreted upon fusion of multi-vesicular endosomes with the cell's plasma membrane. Cells, however, were shown to release other types of EVs, for instance, by direct budding off their plasma membrane. Some of these EVs share with exosomes major biophysical and biochemical characteristics, such as size, density and membrane orientation, which impose difficulties in their efficient separation. Despite frequent claims in the literature, whether exosomes really display more important patho/physiological functions, or are endowed with higher potential as diagnostic or therapeutic tools than other EVs, is not yet convincingly demonstrated. In this opinion article, we describe reasons for this lack of precision knowledge in the current stage of the EV field, we review recently described approaches to overcome these caveats, and we propose ways to improve our knowledge on the respective functions of distinct EVs, which will be crucial for future development of well-designed EV-based clinical applications. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

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Effect of infant meal home preparation temperature on surviving of Bacillus cereus sensu lato: A case of Bechar city, Algeria

Acta Universitatis Cibiniensis Series E Food Technology ◽

10.2478/aucft-2021-0018 ◽

2021 ◽

Vol 25 (2) ◽

pp. 201-210

Author(s):

Hassiba Difallah ◽

Mohammed Ziane ◽

Olfa Ben Braïek ◽

Mohammed Bouamra ◽

Habiba Louzim

Keyword(s):

Heat Resistance ◽

Bacillus Cereus ◽

Storage Conditions ◽

The Other ◽

Preparation Temperature ◽

Meal Preparation ◽

Production Preparation ◽

And Storage ◽

Bacterial Concentrations ◽

Bacillus Cereus Sensu Lato

Abstract This work aimed to enumerate the Bacillus cereus sensu lato from infant’s flour sampled at Béchar city and evaluate its resistance to different heating conditions during meal preparation patterns at home. Our findings revealed a prevalence of 74% with 2.4 to 3.9 CFU/g in the analyzed samples. Regarding the heat resistance at 90 °C to 98 °C, our results showed heat resistance variability which depends on the isolate, for example, D90 °C and zT °C values varied from 3.24 to 5.52 min and 11.56 to 89.74 °C respectively. Then, the decimal reduction (n) was calculated at all preparation temperatures (50, 60, 70, 80, 90 and 100 °C). Low “n” was observed with the preparation at T≤50 °C as recommended by the fabricant. However, at the other temperatures, high “n” was observed at 100°C with median and 95th values of 2.22 and 12.36 respectively. Therefore, bacterial concentrations (99th) were estimated at 0.124 log CFU/g for 100 °C. These concentrations could be increased with bacterial growth during meal storage and then achieve critical concentrations. Thus, the results of this work highlight the interest to establish a risk assessment for babies and to improve the production, preparation, and storage conditions of the infant’s flour.

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Extracellular vesicles in pancreatic cancer progression and therapies

Cell Death and Disease ◽

10.1038/s41419-021-04258-7 ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Chao-Hui Chang ◽

Siim Pauklin

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Delayed Diagnosis ◽

Cell Types ◽

Tumour Microenvironment ◽

Ductal Adenocarcinoma ◽

Cancer Hallmarks ◽

Pancreatic Cancers

AbstractPancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide due to delayed diagnosis and limited treatments. More than 90% of all pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC). Extensive communication between tumour cells and other cell types in the tumour microenvironment have been identified which regulate cancer hallmarks during pancreatic tumorigenesis via secretory factors and extracellular vesicles (EVs). The EV-capsuled factors not only facilitate tumour growth locally, but also enter circulation and reach distant organs to construct a pre-metastatic niche. In this review, we delineate the key factors in pancreatic ductal adenocarcinoma derived EVs that mediate different tumour processes. Also, we highlight the factors that are related to the crosstalk with cancer stem cells/cancer-initiating cells (CSC/CIC), the subpopulation of cancer cells that can efficiently metastasize and resist currently used chemotherapies. Lastly, we discuss the potential of EV-capsuled factors in early diagnosis and antitumour therapeutic strategies.

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Cytonemes in Tumourigenesis

10.32545/encyclopedia201912.0004.v1 ◽

2019 ◽

Author(s):

Marta Portela

Keyword(s):

Cancer Progression ◽

Tumour Progression ◽

Cell Signalling ◽

Cell Communication ◽

Cell Types ◽

Wing Disc ◽

Genetic Ablation ◽

The Past ◽

Tumoral Cell ◽

To Receive

Increasing evidence during the past two decades shows that cells interconnect and communicate through cytonemes. These cytoskeleton-driven extensions of specialized membrane territories have emerged as a novel alternative for cell to cell communication that are involved in development, physiology, and disease. Several recent studies have shown that signalling pathways mediated by cytonemes during development, are essential for certain tumoral cell types progression. In Drosophila wing disc EGFR and RET tumour models, cytoneme formation is required to receive signals from the neighbouring cells. Genetic ablation of cytonemes prevents tumour progression, restores apico-basal polarity, and improves survival. Furthermore, cytonemes in the Drosophila glial cells are essential for glioblastoma progression as they alter Wg/Fz1 signalling between glia and neurons. Research on cytoneme formation, maintenance, and cell signalling mechanisms will help to better understand not only physiological developmental processes and tissue homeostasis but also cancer progression.

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Cancer associated-fibroblast-derived exosomes in cancer progression

Molecular Cancer ◽

10.1186/s12943-021-01463-y ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Chao Li ◽

Adilson Fonseca Teixeira ◽

Hong-Jian Zhu ◽

Peter ten Dijke

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Chemotherapy Resistance ◽

Cell Types ◽

Cancer Therapies ◽

Cancer Associated Fibroblast

AbstractTo identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endothelial cells and cancer associated fibroblasts (CAFs), which communicate with cancer cells and each other during tumor progression. CAFs are a dominant and heterogeneous cell type within the TME with a pivotal role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis and chemotherapy resistance. CAFs mediate their effects in part by remodeling the ECM and by secreting soluble factors and extracellular vesicles. Exosomes are a subtype of extracellular vesicles (EVs), which contain various biomolecules such as nucleic acids, lipids, and proteins. The biomolecules in exosomes can be transmitted from one to another cell, and thereby affect the behavior of the receiving cell. As exosomes are also present in circulation, their contents can also be explored as biomarkers for the diagnosis and prognosis of cancer patients. In this review, we concentrate on the role of CAFs-derived exosomes in the communication between CAFs and cancer cells and other cells of the TME. First, we introduce the multiple roles of CAFs in tumorigenesis. Thereafter, we discuss the ways CAFs communicate with cancer cells and interplay with other cells of the TME, and focus in particular on the role of exosomes. Then, we elaborate on the mechanisms by which CAFs-derived exosomes contribute to cancer progression, as well as and the clinical impact of exosomes. We conclude by discussing aspects of exosomes that deserve further investigation, including emerging insights into making treatment with immune checkpoint inhibitor blockade more efficient.

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An Update on Isolation Methods for Proteomic Studies of Extracellular Vesicles in Biofluids

Molecules ◽

10.3390/molecules24193516 ◽

2019 ◽

Vol 24 (19) ◽

pp. 3516 ◽

Cited By ~ 11

Author(s):

Jing Li ◽

Xianqing He ◽

Yuanyuan Deng ◽

Chenxi Yang

Keyword(s):

Extracellular Vesicles ◽

Biomarker Discovery ◽

Future Research ◽

The Past ◽

Analysis Strategies ◽

Isolation Methods ◽

Specific Proteins ◽

Therapeutic Tools ◽

Almost All ◽

Clinical Potential

Extracellular vesicles (EVs) are lipid bilayer enclosed particles which present in almost all types of biofluids and contain specific proteins, lipids, and RNA. Increasing evidence has demonstrated the tremendous clinical potential of EVs as diagnostic and therapeutic tools, especially in biofluids, since they can be detected without invasive surgery. With the advanced mass spectrometry (MS), it is possible to decipher the protein content of EVs under different physiological and pathological conditions. Therefore, MS-based EV proteomic studies have grown rapidly in the past decade for biomarker discovery. This review focuses on the studies that isolate EVs from different biofluids and contain MS-based proteomic analysis. Literature published in the past decade (2009.1–2019.7) were selected and summarized with emphasis on isolation methods of EVs and MS analysis strategies, with the aim to give an overview of MS-based EV proteomic studies and provide a reference for future research.

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