International Journal of Molecular Sciences

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14 pages, 2281 KiB

Open AccessArticle

Pulmonary Biodistribution of Platelet-Derived Regenerative Exosomes in a Porcine Model

by Skylar A. Rizzo, Monique S. Bagwell, Paige Schiebel, Tyler J. Rolland, Ryan C. Mahlberg, Tyra A. Witt, Mary E. Nagel, Paul G. Stalboerger and Atta Behfar

Int. J. Mol. Sci. 2024, 25(5), 2642; https://doi.org/10.3390/ijms25052642 - 24 Feb 2024

Viewed by 1650

Abstract

The purpose of this study was to evaluate the biodistribution of a platelet-derived exosome product (PEP), previously shown to promote regeneration in the setting of wound healing, in a porcine model delivered through various approaches. Exosomes were labeled with DiR far-red lipophilic dye [...] Read more.

The purpose of this study was to evaluate the biodistribution of a platelet-derived exosome product (PEP), previously shown to promote regeneration in the setting of wound healing, in a porcine model delivered through various approaches. Exosomes were labeled with DiR far-red lipophilic dye to track and quantify exosomes in tissue, following delivery via intravenous, pulmonary artery balloon catheter, or nebulization in sus scrofa domestic pigs. Following euthanasia, far-red dye was detected by Xenogen IVUS imaging, while exosomal protein CD63 was detected by Western blot and immunohistochemistry. Nebulization and intravenous delivery both resulted in global uptake of exosomes within the lung parenchyma. However, nebulization resulted in the greatest degree of exosome uptake. Pulmonary artery balloon catheter-guided delivery provided the further ability to localize pulmonary delivery. No off-target absorption was noted in the heart, spleen, or kidney. However, the liver demonstrated uptake primarily in nebulization-treated animals. Nebulization also resulted in uptake in the trachea, without significant absorption in the esophagus. Overall, this study demonstrated the feasibility of pulmonary delivery of exosomes using nebulization or intravenous infusion to accomplish global delivery or pulmonary artery balloon catheter-guided delivery for localized delivery. Full article

(This article belongs to the Special Issue Exosomes 2.0)

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31 pages, 8191 KiB

Open AccessArticle

Multi-Omics Analysis of Circulating Exosomes in Adherent Long-Term Treated OSA Patients

by Abdelnaby Khalyfa, Jose M. Marin, David Sanz-Rubio, Zhen Lyu, Trupti Joshi and David Gozal

Int. J. Mol. Sci. 2023, 24(22), 16074; https://doi.org/10.3390/ijms242216074 - 8 Nov 2023

Cited by 2 | Viewed by 2231

Abstract

Obstructive sleep apnea (OSA) is a highly prevalent chronic disease affecting nearly a billion people globally and increasing the risk of multi-organ morbidity and overall mortality. However, the mechanisms underlying such adverse outcomes remain incompletely delineated. Extracellular vesicles (exosomes) are secreted by most [...] Read more.

Obstructive sleep apnea (OSA) is a highly prevalent chronic disease affecting nearly a billion people globally and increasing the risk of multi-organ morbidity and overall mortality. However, the mechanisms underlying such adverse outcomes remain incompletely delineated. Extracellular vesicles (exosomes) are secreted by most cells, are involved in both proximal and long-distance intercellular communication, and contribute toward homeostasis under physiological conditions. A multi-omics integrative assessment of plasma-derived exosomes from adult OSA patients prior to and after 1-year adherent CPAP treatment is lacking. We conducted multi-omic integrative assessments of plasma-derived exosomes from adult OSA patients prior to and following 1-year adherent CPAP treatment to identify potential specific disease candidates. Fasting morning plasma exosomes isolated from 12 adult patients with polysomnographically-diagnosed OSA were analyzed before and after 12 months of adherent CPAP therapy (mean ≥ 6 h/night) (OSAT). Exosomes were characterized by flow cytometry, transmission electron microscopy, and nanoparticle tracking analysis. Endothelial cell barrier integrity, wound healing, and tube formation were also performed. Multi-omics analysis for exosome cargos was integrated. Exosomes derived from OSAT improved endothelial permeability and dysfunction as well as significant improvement in tube formation compared with OSA. Multi-omic approaches for OSA circulating exosomes included lipidomic, proteomic, and small RNA (miRNAs) assessments. We found 30 differentially expressed proteins (DEPs), 72 lipids (DELs), and 13 miRNAs (DEMs). We found that the cholesterol metabolism (has04979) pathway is associated with lipid classes in OSA patients. Among the 12 subjects of OSA and OSAT, seven subjects had complete comprehensive exosome cargo information including lipids, proteins, and miRNAs. Multi-omic approaches identify potential signature biomarkers in plasma exosomes that are responsive to adherent OSA treatment. These differentially expressed molecules may also play a mechanistic role in OSA-induced morbidities and their reversibility. Our data suggest that a multi-omic integrative approach might be useful in understanding how exosomes function, their origin, and their potential clinical relevance, all of which merit future exploration in the context of relevant phenotypic variance. Developing an integrated molecular classification should lead to improved diagnostic classification, risk stratification, and patient management of OSA by assigning molecular disease-specific therapies. Full article

(This article belongs to the Special Issue Exosomes 2.0)

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16 pages, 5701 KiB

Open AccessArticle

MSC−sEV Treatment Polarizes Pro−Fibrotic M2 Macrophages without Exacerbating Liver Fibrosis in NASH

by Bin Zhang, Biyan Zhang, Ruenn Chai Lai, Wei Kian Sim, Kong Peng Lam and Sai Kiang Lim

Int. J. Mol. Sci. 2023, 24(9), 8092; https://doi.org/10.3390/ijms24098092 - 30 Apr 2023

Cited by 6 | Viewed by 3130

Abstract

Mesenchymal stem/stromal cell small extracellular vesicles (MSC−sEVs) have shown promise in treating a wide range of animal models of various human diseases, which has led to their consideration for clinical translation. However, the possibility of contraindication for MSC−sEV use is an important consideration. [...] Read more.

Mesenchymal stem/stromal cell small extracellular vesicles (MSC−sEVs) have shown promise in treating a wide range of animal models of various human diseases, which has led to their consideration for clinical translation. However, the possibility of contraindication for MSC−sEV use is an important consideration. One concern is that MSC−sEVs have been shown to induce M2 macrophage polarization, which is known to be pro−fibrotic, potentially indicating contraindication in fibrotic diseases such as liver fibrosis. Despite this concern, previous studies have shown that MSC−sEVs alleviate high−fat diet (HFD)−induced non−alcoholic steatohepatitis (NASH). To assess whether the pro−fibrotic M2 macrophage polarization induced by MSC−sEVs could worsen liver fibrosis, we first verified that our MSC−sEV preparations could promote M2 polarization in vitro prior to their administration in a mouse model of NASH. Our results showed that treatment with MSC−sEVs reduced or had comparable NAFLD Activity Scores and liver fibrosis compared to vehicle− and Telmisartan−treated animals, respectively. Although CD163⁺ M2 macrophages were increased in the liver, and serum IL−6 levels were reduced in MSC−sEV treated animals, our data suggests that MSC−sEV treatment was efficacious in reducing liver fibrosis in a mouse model of NASH despite an increase in pro−fibrotic M2 macrophage polarization. Full article

(This article belongs to the Special Issue Exosomes 2.0)

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18 pages, 2671 KiB

Open AccessArticle

Neonatal Cardiovascular-Progenitor-Cell-Derived Extracellular Vesicles Activate YAP1 in Adult Cardiac Progenitor Cells

by Lourdes Ceja, Sean S. Escopete, Lorelei Hughes, Larry V. Lopez, Victor Camberos, Paul Vallejos, Nathan R. Wall and Mary Kearns-Jonker

Int. J. Mol. Sci. 2023, 24(9), 8088; https://doi.org/10.3390/ijms24098088 - 30 Apr 2023

Cited by 2 | Viewed by 1749

Abstract

New stem cell and extracellular-vesicle-based therapies have the potential to improve outcomes for the increasing number of patients with heart failure. Since neonates have a significantly enhanced regenerative ability, we hypothesized that extracellular vesicles isolated from Islet-1+ expressing neonatal human cardiovascular progenitors (CPCs) [...] Read more.

New stem cell and extracellular-vesicle-based therapies have the potential to improve outcomes for the increasing number of patients with heart failure. Since neonates have a significantly enhanced regenerative ability, we hypothesized that extracellular vesicles isolated from Islet-1+ expressing neonatal human cardiovascular progenitors (CPCs) will induce transcriptomic changes associated with improved regenerative capability when co-cultured with CPCs derived from adult humans. In order to test this hypothesis, we isolated extracellular vesicles from human neonatal Islet-1+ CPCs, analyzed the extracellular vesicle content using RNAseq, and treated adult CPCs with extracellular vesicles derived from neonatal CPCs to assess their functional effect. AKT, ERBB, and YAP1 transcripts were elevated in adult CPCs treated with neonatal CPC-derived extracellular vesicles. YAP1 is lost after the neonatal period but can stimulate cardiac regeneration. Our results demonstrate that YAP1 and additional transcripts associated with improved cardiovascular regeneration, as well as the activation of the cell cycle, can be achieved by the treatment of adult CPCs with neonatal CPC-derived extracellular vesicles. Progenitor cells derived from neonates secrete extracellular vesicles with the potential to stimulate and potentially improve functional effects in adult CPCs used for cardiovascular repair. Full article

(This article belongs to the Special Issue Exosomes 2.0)

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Review

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15 pages, 669 KiB

Open AccessReview

Extracellular Vesicles in the Pathogenesis, Clinical Characterization, and Management of Dermatomyositis: A Narrative Review

by Cristina Ricco, Ahmed Eldaboush, Ming-Lin Liu and Victoria P. Werth

Int. J. Mol. Sci. 2024, 25(4), 1967; https://doi.org/10.3390/ijms25041967 - 6 Feb 2024

Cited by 1 | Viewed by 1864

Abstract

Extracellular vesicles (EVs) are lipid-bilayer particles secreted from cells that primarily assist in cell-to-cell communication through the content of their cargo, such as proteins and RNA. EVs have been implicated in the pathogenesis of various autoimmune diseases, including dermatomyositis (DM), an inflammatory autoimmune [...] Read more.

Extracellular vesicles (EVs) are lipid-bilayer particles secreted from cells that primarily assist in cell-to-cell communication through the content of their cargo, such as proteins and RNA. EVs have been implicated in the pathogenesis of various autoimmune diseases, including dermatomyositis (DM), an inflammatory autoimmune disease characterized by distinct cutaneous manifestations, myopathy, and lung disease. We sought to review the role of EVs in DM and understand how they contribute to the pathogenesis and clinical characterization of the disease. We summarized the research progress on EVs in dermatomyositis based on recent publications. EV cargoes, such as double-stranded DNA, microRNA, and proteins, contribute to DM pathogenesis and mediate the proinflammatory response and cytokine release through signaling pathways such as the stimulator of interferon genes (STING) pathway. These nucleic acids and proteins have been proposed as disease-specific, stable biomarkers to monitor disease activity and responses to therapy. They also correlate with clinical parameters, inflammatory markers, and disease severity scores. Furthermore, some markers show an association with morbidities of DM, such as muscle weakness and interstitial lung disease. The continued study of EVs will help us to further elucidate our understanding of dermatomyositis. Full article

(This article belongs to the Special Issue Exosomes 2.0)

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21 pages, 1864 KiB

Open AccessReview

Exploring the Impact of Exosomal Cargos on Osteosarcoma Progression: Insights into Therapeutic Potential

by Claire C. Chen and Claudia A. Benavente

Int. J. Mol. Sci. 2024, 25(1), 568; https://doi.org/10.3390/ijms25010568 - 1 Jan 2024

Viewed by 1961

Abstract

Osteosarcoma (OS) is a primary malignant bone tumor with high metastasis. Poor prognosis highlights a clinical need for novel therapeutic strategies. Exosomes, also known as extracellular vesicles, have been identified as essential players in the modulation of cancer. Recent studies have suggested that [...] Read more.

Osteosarcoma (OS) is a primary malignant bone tumor with high metastasis. Poor prognosis highlights a clinical need for novel therapeutic strategies. Exosomes, also known as extracellular vesicles, have been identified as essential players in the modulation of cancer. Recent studies have suggested that OS-derived exosomes can drive pro-tumorigenic or anti-tumorigenic phenotypes by transferring specific cargos, including proteins, nucleic acids, and metabolites, to neighboring cells, significantly impacting the regulation of cellular processes. This review discusses the advancement of exosomes and their cargos in OS. We examine how these exosomes contribute to the modulation of cellular phenotypes associated with tumor progression and metastasis. Furthermore, we explore the potential of exosomes as valuable biomarkers for diagnostics and prognostic purposes and their role in shaping innovative therapeutic strategies in OS treatment development. Full article

(This article belongs to the Special Issue Exosomes 2.0)

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15 pages, 887 KiB

Open AccessReview

Exosomes; a Potential Source of Biomarkers, Therapy, and Cure for Type-1 Diabetes

by Jonathan R. T. Lakey, Yanmin Wang, Michael Alexander, Mike K. S. Chan, Michelle B. F. Wong, Krista Casazza and Ian Jenkins

Int. J. Mol. Sci. 2023, 24(21), 15713; https://doi.org/10.3390/ijms242115713 - 28 Oct 2023

Cited by 1 | Viewed by 2294

Abstract

The scourge of type-1 diabetes (T1D) is the morbidity and mortality it and its complications cause at a younger age. This propels the constant search for better diagnostic, treatment, and management strategies, with the ultimate quest being a cure for T1D. Recently, the [...] Read more.

The scourge of type-1 diabetes (T1D) is the morbidity and mortality it and its complications cause at a younger age. This propels the constant search for better diagnostic, treatment, and management strategies, with the ultimate quest being a cure for T1D. Recently, the therapeutic potential of exosomes has generated a lot of interest. Among the characteristics of exosomes of particular interest are (a) their regenerative capacity, which depends on their “origin”, and (b) their “content”, which determines the cell communication and crosstalk they influence. Other functional capacities, including paracrine and endocrine homeostatic regulation, pathogenic response ability resulting in insulin secretory defects or β-cell death under normal metabolic conditions, immunomodulation, and promotion of regeneration, have also garnered significant interest. Exosome “specificity” makes them suitable as biomarkers or predictors, and their “mobility” and “content” lend credence to drug delivery and therapeutic suitability. This review aims to highlight the functional capacities of exosomes and their established as well as novel contributions at various pathways in the onset and progression of T1D. The pathogenesis of T1D involves a complex crosstalk between insulin-secreting pancreatic β-cells and immune cells, which is partially mediated by exosomes. We also examine the potential implications for type 2 diabetes (T2D), as the link in T2D has guided T1D exploration. The collective landscape presented is expected to help identify how a deeper understanding of exosomes (and their cargo) can provide a framework for actionable solutions to prevent, halt, or change the very course of T1D and its complications. Full article

(This article belongs to the Special Issue Exosomes 2.0)

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15 pages, 2411 KiB

Open AccessReview

Role of Pancreatic Tumour-Derived Exosomes and Their Cargo in Pancreatic Cancer-Related Diabetes

by Helen B. Binang, Chamini J. Perera and Minoti V. Apte

Int. J. Mol. Sci. 2023, 24(12), 10203; https://doi.org/10.3390/ijms241210203 - 15 Jun 2023

Cited by 5 | Viewed by 2217

Abstract

One of the most common and deadly types of pancreatic cancer (PC) is pancreatic ductal adenocarcinoma (PDAC), with most patients succumbing to the disease within one year of diagnosis. Current detection strategies do not address asymptomatic PC; therefore, patients are diagnosed at an [...] Read more.

One of the most common and deadly types of pancreatic cancer (PC) is pancreatic ductal adenocarcinoma (PDAC), with most patients succumbing to the disease within one year of diagnosis. Current detection strategies do not address asymptomatic PC; therefore, patients are diagnosed at an advanced stage when curative treatment is often no longer possible. In order to detect PC in asymptomatic patients earlier, the risk factors that could serve as reliable markers need to be examined. Diabetic mellitus (DM) is a significant risk factor for this malignancy and can be both a cause and consequence of PC. Typically, DM caused by PC is known as new-onset, pancreatogenic, pancreoprivic, or pancreatic cancer-related diabetes (PCRD). Although PCRD is quite distinct from type 2 DM (T2DM), there are currently no biomarkers that differentiate PCRD from T2DM. To identify such biomarkers, a better understanding of the mechanisms mediating PCRD is essential. To this end, there has been a growing research interest in recent years to elucidate the role of tumour-derived exosomes and their cargo in the pathogenesis of PCRD. Exosomes derived from tumours can be recognized for their specificity because they reflect the characteristics of their parent cells and are important in intercellular communication. Their cargo consists of proteins, lipids, and nucleic acids, which can be transferred to and alter the behaviour of recipient cells. This review provides a concise overview of current knowledge regarding tumour-derived exosomes and their cargo in PCRD and discusses the potential areas worthy of further study. Full article

(This article belongs to the Special Issue Exosomes 2.0)

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