Therapeutic Potentials of Extracellular Vesicles for the Treatment of Diabetes and Diabetic Complications

Extracellular vesicles (EVs), including exosomes and microvesicles, are nano-to-micrometer vesicles released from nearly all cellular types. EVs comprise a mixture of bioactive molecules (e.g., mRNAs, miRNAs, lipids, and proteins) that can be transported to the targeted cells/tissues via the blood or lymph circulation. Recently, EVs have received increased attention, owing to their emerging roles in cell-to-cell communication, or as biomarkers with the therapeutic potential to replace cell-based therapy. Diabetes comprises a group of metabolic disorders characterized by hyperglycemia that cause the development of life-threatening complications. The impacts of conventional clinical treatment are generally limited and are followed by many side effects, including hypoglycemia, obesity, and damage to the liver and kidney. Recently, several studies have shown that EVs released by stem cells and immune cells can regulate gene expression in the recipient cells, thus providing a strategy to treat diabetes and its complications. In this review, we summarize the results from currently available studies, demonstrating the therapeutic potentials of EVs in diabetes and diabetic complications. Additionally, we highlight recommendations for future research.

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Extracellular Vesicles in Cancer Metastasis: Potential as Therapeutic Targets and Materials

International Journal of Molecular Sciences ◽

10.3390/ijms21124463 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4463 ◽

Cited By ~ 2

Author(s):

Akiko Kogure ◽

Yusuke Yoshioka ◽

Takahiro Ochiya

Keyword(s):

Extracellular Vesicles ◽

Cancer Progression ◽

Cancer Metastasis ◽

Therapeutic Potential ◽

Cell Communication ◽

Therapeutic Targets ◽

Bioactive Molecules ◽

Therapeutic Effects ◽

Anticancer Drug Delivery ◽

Lipid Bilayer Vesicles

The vast majority of cancer-related deaths are due to metastasis of the primary tumor that develops years to decades after apparent cures. However, it is difficult to effectively prevent or treat cancer metastasis. Recent studies have shown that communication between cancer cells and surrounding cells enables cancer progression and metastasis. The comprehensive term “extracellular vesicles” (EVs) describes lipid bilayer vesicles that are secreted to outside cells; EVs are well-established mediators of cell-to-cell communication. EVs participate in cancer progression and metastasis by transferring bioactive molecules, such as proteins and RNAs, including microRNAs (miRNAs), between cancer and various cells in local and distant microenvironments. Clinically, EVs functioning as diagnostic biomarkers, therapeutic targets, or even as anticancer drug-delivery vehicles have been emphasized as a result of their unique biological and pathophysiological characteristics. The potential therapeutic effects of EVs in cancer treatment are rapidly emerging and represent a new and important area of research. This review focuses on the therapeutic potential of EVs and discusses their utility for the inhibition of cancer progression, including metastasis.

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Cell-to-Cell Communication by Host-Released Extracellular Vesicles in the Gut: Implications in Health and Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22042213 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2213

Author(s):

Natalia Diaz-Garrido ◽

Cecilia Cordero ◽

Yenifer Olivo-Martinez ◽

Josefa Badia ◽

Laura Baldomà

Keyword(s):

Extracellular Vesicles ◽

Intestinal Mucosa ◽

Current Knowledge ◽

Cell Communication ◽

Bioactive Molecules ◽

Target Cells ◽

Immune Functions ◽

Intestinal Homeostasis ◽

General Terms ◽

Health And Disease

Communication between cells is crucial to preserve body homeostasis and health. Tightly controlled intercellular dialog is particularly relevant in the gut, where cells of the intestinal mucosa are constantly exposed to millions of microbes that have great impact on intestinal homeostasis by controlling barrier and immune functions. Recent knowledge involves extracellular vesicles (EVs) as mediators of such communication by transferring messenger bioactive molecules including proteins, lipids, and miRNAs between cells and tissues. The specific functions of EVs principally depend on the internal cargo, which upon delivery to target cells trigger signal events that modulate cellular functions. The vesicular cargo is greatly influenced by genetic, pathological, and environmental factors. This finding provides the basis for investigating potential clinical applications of EVs as therapeutic targets or diagnostic biomarkers. Here, we review current knowledge on the biogenesis and cargo composition of EVs in general terms. We then focus the attention to EVs released by cells of the intestinal mucosa and their impact on intestinal homeostasis in health and disease. We specifically highlight their role on epithelial barrier integrity, wound healing of epithelial cells, immunity, and microbiota shaping. Microbiota-derived EVs are not reviewed here.

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Extracellular vesicles as immune mediators in response to kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00336.2017 ◽

2018 ◽

Vol 314 (1) ◽

pp. F9-F21 ◽

Cited By ~ 4

Author(s):

Eva Feigerlová ◽

Shyue-Fang Battaglia-Hsu ◽

Thierry Hauet ◽

Jean-Louis Guéant

Keyword(s):

Extracellular Vesicles ◽

Therapeutic Potential ◽

Kidney Tissue ◽

Kidney Injury ◽

Renal Tissue ◽

Bioactive Molecules ◽

Renal Diseases ◽

Cytokine Signaling ◽

Renal Tubular ◽

Tissue Recovery

Important progress has been made on cytokine signaling in response to kidney injury in the past decade, especially cytokine signaling mediated by extracellular vesicles (EVs). For example, EVs released by injured renal tubular epithelial cells (TECs) can regulate intercellular communications and influence tissue recovery via both regulating the expression and transferring cytokines, growth factors, as well as other bioactive molecules at the site of injury. The effects of EVs on kidney tissue seem to vary depending on the sources of EVs; however, the literature data are often inconsistent. For example, in rodents EVs derived from mesenchymal stem cells (MSC-EVs) and endothelial progenitor cells (EPC-EVs) can have both beneficial and harmful effects on injured renal tissue. Caution is thus needed in the interpretation of these data as contradictory findings on EVs may not only be related to the origin of EVs, they can also be caused by the different methods used for EV isolation and the physiological and pathological states of the tissues/cells under which they were obtained. Here, we review and discuss our current understanding related to the immunomodulatory function of EVs in renal tubular repair in the hope of encouraging further investigations on mechanisms related to their antiinflammatory and reparative role to better define the therapeutic potential of EVs in renal diseases.

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The Power of Extracellular Vesicles in Myeloproliferative Neoplasms: “Crafting” a Microenvironment That Matters

Cells ◽

10.3390/cells10092316 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2316

Author(s):

Lucia Catani ◽

Michele Cavo ◽

Francesca Palandri

Keyword(s):

Extracellular Vesicles ◽

Immune Escape ◽

Myeloproliferative Neoplasms ◽

Cell Communication ◽

Bioactive Molecules ◽

Driver Genes ◽

Hematopoietic Stem ◽

Increased Risk ◽

Patients Experience

Myeloproliferative Neoplasms (MPN) are acquired clonal disorders of the hematopoietic stem cells and include Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis. MPN are characterized by mutations in three driver genes (JAK2, CALR and MPL) and by a state of chronic inflammation. Notably, MPN patients experience increased risk of thrombosis, disease progression, second neoplasia and evolution to acute leukemia. Extracellular vesicles (EVs) are a heterogeneous population of microparticles with a role in cell-cell communication. The EV-mediated cross-talk occurs via the trafficking of bioactive molecules such as nucleic acids, proteins, metabolites and lipids. Growing interest is focused on EVs and their potential impact on the regulation of blood cancers. Overall, EVs have been suggested to orchestrate the complex interplay between tumor cells and the microenvironment with a pivotal role in “education” and “crafting” of the microenvironment by regulating angiogenesis, coagulation, immune escape and drug resistance of tumors. This review is focused on the role of EVs in MPN. Specifically, we will provide an overview of recent findings on the involvement of EVs in MPN pathogenesis and discuss opportunities for their potential application as diagnostic and prognostic biomarkers.

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Extracellular Vesicles as Nanotherapeutics for Parkinson’s Disease

Biomolecules ◽

10.3390/biom10091327 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1327 ◽

Cited By ~ 1

Author(s):

Loredana Leggio ◽

Greta Paternò ◽

Silvia Vivarelli ◽

Francesca L’Episcopo ◽

Cataldo Tirolo ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cell Communication ◽

Bioactive Molecules ◽

Substantia Nigra Pars Compacta ◽

Diagnostic Tools ◽

Target Cells ◽

Small Interfering Rnas ◽

Wide Range ◽

Ligand Interactions ◽

The Central Nervous System

Extracellular vesicles (EVs) are naturally occurring membranous structures secreted by normal and diseased cells, and carrying a wide range of bioactive molecules. In the central nervous system (CNS), EVs are important in both homeostasis and pathology. Through receptor–ligand interactions, direct fusion, or endocytosis, EVs interact with their target cells. Accumulating evidence indicates that EVs play crucial roles in the pathogenesis of many neurodegenerative disorders (NDs), including Parkinson′s disease (PD). PD is the second most common ND, characterized by the progressive loss of dopaminergic (DAergic) neurons within the Substantia Nigra pars compacta (SNpc). In PD, EVs are secreted by both neurons and glial cells, with either beneficial or detrimental effects, via a complex program of cell-to-cell communication. The functions of EVs in PD range from their etiopathogenetic relevance to their use as diagnostic tools and innovative carriers of therapeutics. Because they can cross the blood–brain barrier, EVs can be engineered to deliver bioactive molecules (e.g., small interfering RNAs, catalase) within the CNS. This review summarizes the latest findings regarding the role played by EVs in PD etiology, diagnosis, prognosis, and therapy, with a particular focus on their use as novel PD nanotherapeutics.

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Therapeutic Potential of Extracellular Vesicles in Hypertension-Associated Kidney Disease

Hypertension ◽

10.1161/hypertensionaha.120.16064 ◽

2021 ◽

Vol 77 (1) ◽

pp. 28-38

Author(s):

Olga Martinez-Arroyo ◽

Ana Ortega ◽

Josep Redon ◽

Raquel Cortes

Keyword(s):

Kidney Disease ◽

Extracellular Vesicles ◽

Renal Damage ◽

Therapeutic Potential ◽

Cell Communication ◽

Cell Types ◽

Organ Damage ◽

Renal Diseases ◽

Biological Processes ◽

Potential Use

Hypertension-mediated organ damage frequently includes renal function decline in which several mechanisms are involved. The present review outlines the state of the art on extracellular vesicles in hypertension and hypertension-related renal damage. Emerging evidence indicates that extracellular vesicles, small vesicles secreted by most cell types and body fluids, are involved in cell-to-cell communication and are key players mediating biological processes such as inflammation, endothelial dysfunction or fibrosis, mechanisms present the onset and progression of hypertension-associated kidney disease. We address the potential use of extracellular vesicles as markers of hypertension-mediated kidney damage severity and their application as therapeutic agents in hypertension-associated renal damage. The capacity of exosomes to deliver a wide variety of cargos to the target cell efficiently makes them a potential drug delivery system for treatment of renal diseases.

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Tiny Actors in the Big Cellular World: Extracellular Vesicles Playing Critical Roles in Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21207688 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7688 ◽

Cited By ~ 2

Author(s):

Ancuta Jurj ◽

Cecilia Pop-Bica ◽

Ondrej Slaby ◽

Cristina D. Ştefan ◽

William C. Cho ◽

...

Keyword(s):

Extracellular Vesicles ◽

Molecular Mechanisms ◽

Recipient Cell ◽

Cell Communication ◽

Therapeutic Agents ◽

Bioactive Molecules ◽

Cellular Functions ◽

Membrane Bound

Communications among cells can be achieved either via direct interactions or via secretion of soluble factors. The emergence of extracellular vesicles (EVs) as entities that play key roles in cell-to-cell communication offer opportunities in exploring their features for use in therapeutics; i.e., management and treatment of various pathologies, such as those used for cancer. The potential use of EVs as therapeutic agents is attributed not only for their cell membrane-bound components, but also for their cargos, mostly bioactive molecules, wherein the former regulate interactions with a recipient cell while the latter trigger cellular functions/molecular mechanisms of a recipient cell. In this article, we highlight the involvement of EVs in hallmarks of a cancer cell, particularly focusing on those molecular processes that are influenced by EV cargos. Moreover, we explored the roles of RNA species and proteins carried by EVs in eliciting drug resistance phenotypes. Interestingly, engineered EVs have been investigated and proposed as therapeutic agents in various in vivo and in vitro studies, as well as in several clinical trials.

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Extracellular Vesicles in NAFLD/ALD: From Pathobiology to Therapy

Cells ◽

10.3390/cells9040817 ◽

2020 ◽

Vol 9 (4) ◽

pp. 817 ◽

Cited By ~ 7

Author(s):

Alejandra Hernández ◽

Juan Pablo Arab ◽

Daniela Reyes ◽

Ainhoa Lapitz ◽

Han Moshage ◽

...

Keyword(s):

Liver Disease ◽

Extracellular Vesicles ◽

Liver Diseases ◽

Experimental Studies ◽

Cell Communication ◽

Cell Types ◽

Bioactive Molecules ◽

Therapeutic Implications ◽

Isolation And Characterization ◽

Liver Disease Progression

In recent years, knowledge on the biology and pathobiology of extracellular vesicles (EVs) has exploded. EVs are submicron membrane-bound structures secreted from different cell types containing a wide variety of bioactive molecules (e.g., proteins, lipids, and nucleic acids (coding and non-coding RNA) and mitochondrial DNA). EVs have important functions in cell-to-cell communication and are found in a wide variety of tissues and body fluids. Better delineation of EV structures and advances in the isolation and characterization of their cargo have allowed the diagnostic and therapeutic implications of these particles to be explored. In the field of liver diseases, EVs are emerging as key players in the pathogenesis of both nonalcoholic liver disease (NAFLD) and alcoholic liver disease (ALD), the most prevalent liver diseases worldwide, and their complications, including development of hepatocellular carcinoma. In these diseases, stressed/damaged hepatocytes release large quantities of EVs that contribute to the occurrence of inflammation, fibrogenesis, and angiogenesis, which are key pathobiological processes in liver disease progression. Moreover, the specific molecular signatures of released EVs in biofluids have allowed EVs to be considered as promising candidates to serve as disease biomarkers. Additionally, different experimental studies have shown that EVs may have potential for therapeutic use as a liver-specific delivery method of different agents, taking advantage of their hepatocellular uptake through interactions with specific receptors. In this review, we focused on the most recent findings concerning the role of EVs as new structures mediating autocrine and paracrine intercellular communication in both ALD and NAFLD, as well as their potential use as biomarkers of disease severity and progression. Emerging therapeutic applications of EVs in these liver diseases were also examined, along with the potential for successful transition from bench to clinic.

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Extracellular vesicles in diagnosis and therapy of kidney diseases

AJP Renal Physiology ◽

10.1152/ajprenal.00429.2016 ◽

2016 ◽

Vol 311 (5) ◽

pp. F844-F851 ◽

Cited By ~ 55

Author(s):

Wei Zhang ◽

Xiangjun Zhou ◽

Hao Zhang ◽

Qisheng Yao ◽

Yutao Liu ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cross Talk ◽

Cultured Cells ◽

Therapeutic Potential ◽

Kidney Diseases ◽

Cell Communication ◽

Therapeutic Effects ◽

Glomerular Diseases ◽

The Cross

Extracellular vesicles (EV) are endogenously produced, membrane-bound vesicles that contain various molecules. Depending on their size and origins, EVs are classified into apoptotic bodies, microvesicles, and exosomes. A fundamental function of EVs is to mediate intercellular communication. In kidneys, recent research has begun to suggest a role of EVs, especially exosomes, in cell-cell communication by transferring proteins, mRNAs, and microRNAs to recipient cells as nanovectors. EVs may mediate the cross talk between various cell types within kidneys for the maintenance of tissue homeostasis. They may also mediate the cross talk between kidneys and other organs under physiological and pathological conditions. EVs have been implicated in the pathogenesis of both acute kidney injury and chronic kidney diseases, including renal fibrosis, end-stage renal disease, glomerular diseases, and diabetic nephropathy. The release of EVs with specific molecular contents into urine and plasma may be useful biomarkers for kidney disease. In addition, EVs produced by cultured cells may have therapeutic effects for these diseases. However, the role of EVs in kidney diseases is largely unclear, and the mechanism underlying EV production and secretion remains elusive. In this review, we introduce the basics of EVs and then analyze the present information about the involvement, diagnostic value, and therapeutic potential of EVs in major kidney diseases.

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Evolving Cell-Based and Cell-Free Clinical Strategies for Treating Severe Human Liver Diseases

Cells ◽

10.3390/cells9020386 ◽

2020 ◽

Vol 9 (2) ◽

pp. 386 ◽

Cited By ~ 4

Author(s):

Viviana Cernigliaro ◽

Rossella Peluso ◽

Beatrice Zedda ◽

Lorenzo Silengo ◽

Emanuela Tolosano ◽

...

Keyword(s):

Stem Cells ◽

Liver Transplantation ◽

Extracellular Vesicles ◽

Liver Diseases ◽

Adult Stem Cells ◽

Embryonic Stem ◽

Hepatic Function ◽

Bioactive Molecules ◽

Cell Based Therapy ◽

End Stage

Liver diseases represent a major global health issue, and currently, liver transplantation is the only viable alternative to reduce mortality rates in patients with end-stage liver diseases. However, scarcity of donor organs and risk of recidivism requiring a re-transplantation remain major obstacles. Hence, much hope has turned towards cell-based therapy. Hepatocyte-like cells obtained from embryonic stem cells or adult stem cells bearing multipotent or pluripotent characteristics, as well as cell-based systems, such as organoids, bio-artificial liver devices, bioscaffolds and organ printing are indeed promising. New approaches based on extracellular vesicles are also being investigated as cell substitutes. Extracellular vesicles, through the transfer of bioactive molecules, can modulate liver regeneration and restore hepatic function. This review provides an update on the current state-of-art cell-based and cell-free strategies as alternatives to liver transplantation for patients with end-stage liver diseases.

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