scholarly journals Mesenchymal Stromal Cell-Derived Extracellular Vesicles – Silver Linings for Cartilage Regeneration?

2020 â—½  
Vol 8 â—½  
Author(s):  
Andrea De Luna â—½  
Alexander Otahal â—½  
Stefan Nehrer
Keyword(s):  
Extracellular Vesicles â—½  
Treatment Options â—½  
Cartilage Regeneration â—½  
Bioactive Molecules â—½  
Paracrine Factors â—½  
Differentiation Potential â—½  
Vast Number â—½  
The Impact

As the world’s population is aging, the incidence of the degenerative disease Osteoarthritis (OA) is increasing. Current treatment options of OA focus on the alleviation of the symptoms including pain and inflammation rather than on restoration of the articular cartilage. Cell-based therapies including the application of mesenchymal stromal cells (MSCs) have been a promising tool for cartilage regeneration approaches. Due to their immunomodulatory properties, their differentiation potential into cells of the mesodermal lineage as well as the plurality of sources from which they can be isolated, MSCs have been applied in a vast number of studies focusing on the establishment of new treatment options for Osteoarthritis. Despite promising outcomes in vitro and in vivo, applications of MSCs are connected with teratoma formation, limited lifespan of differentiated cells as well as rejection of the cells after transplantation, highlighting the need for new cell free approaches harboring the beneficial properties of MSCs. It has been demonstrated that the regenerative potential of MSCs is mediated by the release of paracrine factors rather than by differentiation into cells of the desired tissue. Besides soluble factors, extracellular vesicles are the major component of a cell’s secretome. They represent novel mechanisms by which (pathogenic) signals can be communicated between cell types as they deliver bioactive molecules (nucleic acids, proteins, lipids) from the cell of origin to the target cell leading to specific biological processes upon uptake. This review will give an overview about extracellular vesicles including general characteristics, isolation methods and characterization approaches. Furthermore, the role of MSC-derived extracellular vesicles in in vitro and in vivo studies for cartilage regeneration will be summarized with special focus on transported miRNA which either favored the progression of OA or protected the cartilage from degradation. In addition, studies will be reviewed investigating the impact of MSC-derived extracellular vesicles on inflammatory arthritis. As extracellular vesicles are present in all body fluids, their application as potential biomarkers for OA will also be discussed in this review. Finally, studies exploring the combination of MSC-derived extracellular vesicles with biomaterials for tissue engineering approaches are summarized.

Mesenchymal stem cell-derived extracellular vesicles in the failing heart: past, present, and future

2021 â—½  
Author(s):  
Catherine Karbasiafshar â—½  
Frank W. Sellke â—½  
M. Ruhul Abid
Keyword(s):  
Stem Cell â—½  
Extracellular Vesicles â—½  
Treatment Options â—½  
Current Treatment â—½  
Lifestyle Changes â—½  
Challenges And Opportunities â—½  
Artery Disease â—½  
New Treatment

Cardiovascular disease (CVD) is the leading cause of death globally. Current treatment options include lifestyle changes, medication, and surgical intervention. However, many patients are unsuitable candidates for surgeries due to comorbidities, diffuse coronary artery disease or advanced stages of heart failure. The search for new treatment options has recently transitioned from cell-based therapies to stem-cell derived extracellular vesicles (EVs). A number of challenges remain in the EV field, including the effect of comorbidities, characterization, and delivery, However, recent revolutionary developments and insight into the potential of 'personalizing' EV contents by bioengineering methods to alter specific signaling pathways in the ischemic myocardium hold promise. Here, we discuss the past limitations of cell-based therapies, and recent EV studies involving in vivo, in vitro, and omics, and future challenges and opportunities in EV-based treatments in CVD.

scholarly journals Perspectives for Future Use of Extracellular Vesicles from Umbilical Cord- and Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells in Regenerative Therapies—Synthetic Review

2020 â—½  
Vol 21 (3) â—½  
pp. 799 â—½  
Author(s):  
Joanna Lelek â—½  
Ewa K. Zuba-Surma
Keyword(s):  
Adipose Tissue â—½  
Umbilical Cord â—½  
Extracellular Vesicles â—½  
Stromal Cells â—½  
Tissue Repair â—½  
Molecular Mechanisms â—½  
Skin Diseases â—½  
Differentiation Potential

Mesenchymal stem/ stromal cells (MSCs) represent progenitor cells of various origin with multiple differentiation potential, representing the most studied population of stem cells in both in vivo pre-clinical and clinical studies. MSCs may be found in many tissue sources including extensively studied adipose tissue (ADSCs) and umbilical cord Wharton’s jelly (UC-MSCs). Most of sanative effects of MSCs are due to their paracrine activity, which includes also release of extracellular vesicles (EVs). EVs are small, round cellular derivatives carrying lipids, proteins, and nucleic acids including various classes of RNAs. Due to several advantages of EVs when compare to their parental cells, MSC-derived EVs are currently drawing attention of several laboratories as potential new tools in tissue repair. This review focuses on pro-regenerative properties of EVs derived from ADSCs and UC-MSCs. We provide a synthetic summary of research conducted in vitro and in vivo by employing animal models and within initial clinical trials focusing on neurological, cardiovascular, liver, kidney, and skin diseases. The summarized studies provide encouraging evidence about MSC-EVs pro-regenerative capacity in various models of diseases, mediated by several mechanisms. Although, direct molecular mechanisms of MSC-EV action are still under investigation, the current growing data strongly indicates their potential future usefulness for tissue repair.

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

2020 â—½  
Vol 21 (20) â—½  
pp. 7688 â—½  
Author(s):  
Ancuta Jurj â—½  
Cecilia Pop-Bica â—½  
Ondrej Slaby â—½  
Cristina D. Ştefan â—½  
William C. Cho â—½  
...  
Keyword(s):  
Extracellular Vesicles â—½  
Molecular Mechanisms â—½  
Recipient Cell â—½  
Cell Communication â—½  
Therapeutic Agents â—½  
Bioactive Molecules â—½  
Cellular Functions â—½  
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.

Induced pluripotent stem cells-derived extracellular vesicles shuttle bioactive molecules with anti-fibrotic potential in vitro and in vivo

2017 â—½  
Vol 66 (1) â—½  
pp. S649-S650
Author(s):  
D. Povero â—½  
E.M. Pinatel â—½  
J. Kim â—½  
N. Goyal â—½  
C.D. Johnson â—½  
...  
Keyword(s):  
Stem Cells â—½  
Induced Pluripotent Stem Cells â—½  
Extracellular Vesicles â—½  
Pluripotent Stem Cells â—½  
Bioactive Molecules â—½  
Induced Pluripotent

scholarly journals Lipopolysaccharide administration alters extracellular vesicles in human lung-cancer cells and mice

2020 â—½  
Author(s):  
Leandra B. Jones â—½  
Sanjay Kumar â—½  
Courtnee’ R. Bell â—½  
Brennetta J. Crenshaw â—½  
Mamie T. Coats â—½  
...  
Keyword(s):  
Membrane Protein â—½  
Bacterial Infection â—½  
Cell Line â—½  
Extracellular Vesicles â—½  
A549 Cells â—½  
Human Lung Cancer â—½  
Diagnostic Tools â—½  
The Impact

AbstractExtracellular vesicles (EVs) play a fundamental role in cell and infection biology and have the potential to act as biomarkers for novel diagnostic tools. In this study, we explored the in vitro impact of bacterial lipopolysaccharide administration on a cell line that represents a target for bacterial infection in the host. Administration of lipopolysaccharide at varying concentrations to this A549 cell line caused only modest changes in cell death, but EV numbers were significantly changed. After treatment with the highest concentration of lipopolysaccharide, EVs derived from A549 cells packaged significantly less interleukin-6 and lysosomal-associated membrane protein 1. We also examined the impact of lipopolysaccharide administration on exosome biogenesis and cargo composition in BALB/c mice. Serum-isolated EVs from lipopolysaccharide-treated mice showed significantly increased lysosomal-associated membrane protein 1 and toll-like receptor 4 levels compared with EVs from control mice. In summary, this study demonstrated that EV numbers and cargo were altered using these in vitro and in vivo models of bacterial infection.

Developments in the Application of 1,2,3-Triazoles in Cancer Treatment

2020 â—½  
Vol 15 (2) â—½  
pp. 92-112 â—½  
Author(s):  
Katerina I. Slavova â—½  
Lozan T. Todorov â—½  
Nataliya P. Belskaya â—½  
Mauricio A. Palafox â—½  
Irena P. Kostova
Keyword(s):  
Drug Discovery â—½  
Cancer Treatment â—½  
Anticancer Activity â—½  
Medical Science â—½  
Modern Society â—½  
Cancer Drug â—½  
Vast Number â—½  
The Impact

Background: The impact of cancer on modern society cannot be emphasized enough in terms of both economic and human costs. Cancer treatments are known, unfortunately, for their side effects – frequently numerous and severe. Drug resistance is another issue medical professionals have to tackle when dealing with neoplastic illnesses. Cancer rates are rising worldwide due to various factors - low-quality nutrition, air and water pollution, tobacco use, etc. For those and many other reasons, drug discovery in the field of oncology is a top priority in modern medical science. Objective: To present the reader with the latest in cancer drug discovery with regard to 1,2,3-triazole- containing molecules in a clear, concise way so as to make the present review a useful tool for researchers. Methods: Available information present on the role of 1,2,3-triazoles in cancer treatment was collected. Data was collected from scientific literature, as well as from patents. Results: A vast number of triazole-containing molecules with antiproliferative properties have been proposed, synthesized and tested for anticancer activity both in vitro and in vivo. The substances vary greatly when considering molecular structure, proposed mechanisms of action and affected cancer cell types. Conclusion: Triazole-containing molecules with anticancer activity are being widely synthesized and extensively tested. They vary significantly in terms of both structure and mechanism of action. The methods for their preparation and administration are well established and with proven reproducibility. These facts suggest that triazoles may play an important role in the discovery of novel antiproliferative medications with improved effectiveness and safety profile.

scholarly journals Biological nano-functionalization of titanium-based biomaterial surfaces: a flexible toolbox

2009 â—½  
Vol 7 (suppl_1) â—½  
Author(s):  
René Beutner â—½  
Jan Michael â—½  
Bernd Schwenzer â—½  
Dieter Scharnweber
Keyword(s):  
Calcium Phosphate â—½  
Titanium Oxide â—½  
Surface Functionalization â—½  
Bioactive Molecules â—½  
Main Field â—½  
Vast Number â—½  
Anodic Titanium Oxide â—½  
Biomaterial Surfaces

Surface functionalization with bioactive molecules (BAMs) on a nanometre scale is a main field in current biomaterial research. The immobilization of a vast number of substances and molecules, ranging from inorganic calcium phosphate phases up to peptides and proteins, has been investigated throughout recent decades. However, in vitro and in vivo results are heterogeneous. This may be at least partially attributed to the limits of the applied immobilization methods. Therefore, this paper highlights, in the first part, advantages and limits of the currently applied methods for the biological nano-functionalization of titanium-based biomaterial surfaces. The second part describes a new immobilization system recently developed in our groups. It uses the nanomechanical fixation of at least partially single-stranded nucleic acids (NAs) into an anodic titanium oxide layer as an immobilization principle and their hybridization ability for the functionalization of the surface with BAMs conjugated to the respective complementary NA strands.

scholarly journals Enhanced Suppression of Immune Cells In Vitro by MSC Overexpressing FasL

2020 â—½  
Vol 22 (1) â—½  
pp. 348
Author(s):  
Ana-Maria Vacaru â—½  
Madalina Dumitrescu â—½  
Andrei Mircea Vacaru â—½  
Ioana Madalina Fenyo â—½  
Radu Ionita â—½  
...  
Keyword(s):  
Fas Ligand â—½  
Immunomodulatory Activity â—½  
Proof Of Concept â—½  
Differentiation Potential â—½  
Adenoviral Transduction â—½  
Characteristic Features â—½  
Set Up â—½  
The Impact

Mesenchymal stromal cells (MSC) display several mechanisms of action that may be harnessed for therapeutic purposes. One of their most attractive features is their immunomodulatory activity that has been extensively characterized both in vitro and in vivo. While this activity has proven to be very efficient, it is transient. We aimed to enhance it by transforming MSC to overexpress a first apoptosis signal (Fas) ligand (FasL). In this study, our goal was to induce FasL overexpression through adenoviral transduction in MSC to improve their immunomodulatory activity. We characterized the impact of FasL overexpression on the morphology, proliferation, viability, phenotype, multilineage differentiation potential and immunomodulation of MSC. Moreover, we determined their suppressive properties in mixed reactions with A20 cells, as well as with stimulated splenocytes. Our findings demonstrate that FasL-overexpressing MSC exhibit improved immunosuppressive properties, while maintaining their MSC-characteristic features. In conclusion, we establish, in a proof-of-concept set-up, that FasL-overexpressing MSC represent good candidates for therapeutic intervention targeted at autoimmune disorders.

scholarly journals Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema

2021 â—½  
Vol 9 â—½  
Author(s):  
Mariana A. Antunes â—½  
Cassia L. Braga â—½  
Tainá B. Oliveira â—½  
Jamil Z. Kitoko â—½  
Ligia L. Castro â—½  
...  
Keyword(s):  
Extracellular Vesicles â—½  
Mesenchymal Stromal Cells â—½  
Stromal Cells â—½  
Therapeutic Potential â—½  
Chronic Obstructive â—½  
Severe Emphysema â—½  
Arginase 1 â—½  
The Impact

Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) from patients with chronic obstructive pulmonary disease (COPD) appear to be phenotypically and functionally similar to BM-MSCs from healthy sources in vitro, the impact of COPD on MSC metabolism and mitochondrial function has not been evaluated. In this study, we aimed to comparatively characterize MSCs from healthy and emphysematous donors (H-MSCs and E-MSCs) in vitro and to assess the therapeutic potential of these MSCs and their extracellular vesicles (H-EVs and E-EVs) in an in vivo model of severe emphysema. For this purpose, C57BL/6 mice received intratracheal porcine pancreatic elastase once weekly for 4 weeks to induce emphysema; control animals received saline under the same protocol. Twenty-four hours after the last instillation, animals received saline, H-MSCs, E-MSCs, H-EVs, or E-EVs intravenously. In vitro characterization demonstrated that E-MSCs present downregulation of anti-inflammatory (TSG-6, VEGF, TGF-β, and HGF) and anti-oxidant (CAT, SOD, Nrf2, and GSH) genes, and their EVs had larger median diameter and lower average concentration. Compared with H-MSC, E-MSC mitochondria also exhibited a higher respiration rate, were morphologically elongated, expressed less dynamin-related protein-1, and produced more superoxide. When co-cultured with alveolar macrophages, both H-MSCs and E-MSCs induced an increase in iNOS and arginase-1 levels, but only H-MSCs and their EVs were able to enhance IL-10 levels. In vivo, emphysematous mice treated with E-MSCs or E-EVs demonstrated no amelioration in cardiorespiratory dysfunction. On the other hand, H-EVs, but not H-MSCs, were able to reduce the neutrophil count, the mean linear intercept, and IL-1β and TGF-β levels in lung tissue, as well as reduce pulmonary arterial hypertension and increase the right ventricular area in a murine model of elastase-induced severe emphysema. In conclusion, E-MSCs and E-EVs were unable to reverse cardiorespiratory dysfunction, whereas H-EVs administration was associated with a reduction in cardiovascular and respiratory damage in experimental severe emphysema.

scholarly journals Extracellular Vesicles Derived From Human Corneal Endothelial Cells Inhibit Proliferation of Human Corneal Endothelial Cells

2021 â—½  
Author(s):  
Mohit Parekh â—½  
Hefin Rhys â—½  
Tiago Ramos â—½  
Stefano Ferrari â—½  
Sajjad Ahmad
Keyword(s):  
Endothelial Cells â—½  
Extracellular Vesicles â—½  
Ex Vivo â—½  
Treatment Options â—½  
Proliferative Capacity â—½  
Corneal Endothelial Cells â—½  
Human Corneal Endothelial Cells â—½  
The Media

Abstract Corneal endothelial cells (CEnCs) are a monolayer of hexagonal cells that are responsible for maintaining the function and transparency of the cornea. Damage or dysfunction of CEnCs could lead to blindness. Human CEnCs (HCEnCs) have shown limited proliferative capacity in vivo hence, their maintenance is crucial. Extracellular vesicles (EVs), are responsible for inter- and intra-cellular communication, proliferation, cell-differentiation, migration, and many other complex biological processes. Therefore, we investigated the effect of EVs (derived from human corneal endothelial cell line – HCEC-12) on corneal endothelial cells. HCEC-12 cells were starved with serum-depleted media for 72 hours. The media was ultracentrifuged at 100,000xg to isolate the EVs. EV counting, characterization, internalization and localization were performed using NanoSight, flow cytometry, Dil labelling and confocal microscopy respectively. HCEC-12 and HCEnCs were cultured with media supplemented with EVs. Extracted EVs showed a homogeneous mixture of exosomes and microvesicles. Cells with EVs decreased the proliferation rate; increased apoptosis and cell size; showed poor wound healing response in vitro and on ex vivo human, porcine, and rabbit CECs. Thirteen miRNAs were found in the EV sample using next generation sequencing. We observed that increased cellular uptake of EVs by CECs limit the proliferative capacity of HCEnCs. These preliminary data may help in understanding the pathology of corneal endothelial dysfunction and provide further insights in the development of future therapeutic treatment options.

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