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EV literature (RSS feed from PubMed)

Search terms: exosomes OR "extracellular vesicles" OR microvesicles OR microparticles. Direct link to the PubMed search here.

Evidence for liver and peripheral immune cells secreting tumor-suppressive extracellular vesicles in melanoma patients.

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Evidence for liver and peripheral immune cells secreting tumor-suppressive extracellular vesicles in melanoma patients.

EBioMedicine. 2020 Nov 23;62:103119

Authors: Lee JH, Eberhardt M, Blume K, Vera J, Baur AS

Abstract
BACKGROUND: Before and after surgery melanoma patients harbor elevated levels of extracellular vesicles in plasma (pEV), suppressing tumor cell activity. However, due to technical reasons and lack of cell-specific biomarkers, their cellular origin remains obscure.
METHODS: We mimicked the interaction of tumor cells with liver cells and PBMC in vitro, and compared newly secreted EV-associated miRNAs and protein factors with those detected in melanoma patient`s pEV.
FINDINGS: Our results suggest that pEV from melanoma patients are secreted in part by residual or relapsing tumor cells, but also by liver and peripheral blood mononuclear cells (PBMC). Our approach identified factors that were seemingly associated either with tumor cell activity, or the counteracting immune system, including liver cells. Notably, the presence/absence of these factors correlated with the clinical stage and tumor relapse.
INTERPRETATION: Our study may provide new insights into the innate immune defense against tumor cells and implies that residual tumor cells could be more active than previously thought. In addition we provide some preliminary evidence that pEV marker patterns could be used to predict cancer relapse.

PMID: 33242827 [PubMed - as supplied by publisher]

Strategies to expand the therapeutic potential of superoxide dismutase by exploiting delivery approaches.

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Strategies to expand the therapeutic potential of superoxide dismutase by exploiting delivery approaches.

Int J Biol Macromol. 2020 Nov 23;:

Authors: Rosa AC, Bruni N, Meineri G, Corsi D, Calvi N, Gastaldi D, Dosio F

Abstract
The overproduction of free radicals can cause oxidative-stress damage to a range of biomolecules, and thus potentially contribute to several pathologies, from neurodegenerative disorders to cardiovascular diseases and metabolic disorders. Endogenous antioxidant enzymes, such as superoxide dismutase (SOD), play an important role in diminishing oxidative stress. SOD supplementation could therefore be an effective preventive strategy to reduce the risk of free-radical overproduction. However, the efficacy of SOD administration is hampered by its rapid clearance. Several different approaches to improve the bioavailability of SOD have been explored in recent decades. This review intends to describe the rationale that underlie the various approaches and chemical strategies that have led to the most recent advances in SOD delivery. This critical description includes SOD conjugates, SOD loaded into particulate carriers (micelles, liposomes, nanoparticles, microparticles) and the most promising and suitable formulations for oral delivery, with a particular emphasis on reports of preclinical/clinical results. Likely future directions are also considered and reported.

PMID: 33242550 [PubMed - as supplied by publisher]

The suppressive mechanisms are examined in detail in association with AD pathogenesis Hypoperfusion is a potential inducer of immunosuppressive network in Alzheimer's disease.

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The suppressive mechanisms are examined in detail in association with AD pathogenesis Hypoperfusion is a potential inducer of immunosuppressive network in Alzheimer's disease.

Neurochem Int. 2020 Nov 23;:104919

Authors: Salminen A

Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease which causes a non-reversible cognitive impairment and dementia. The primary cause of late-onset AD remains unknown although its pathology was discovered over a century ago. Recently, the vascular hypothesis of AD has received backing from evidence emerging from neuroimaging studies which have revealed the presence of a significant hypoperfusion in the brain regions vulnerable to AD pathology. In fact, hypoxia can explain many of the pathological changes evident in AD pathology, e.g. the deposition of β-amyloid plaques and chronic low-grade inflammation. Hypoxia-inducible factor-1α (HIF-1α) stimulates inflammatory responses and modulates both innate and adaptive immunity. It is known that hypoxia-induced inflammation evokes compensatory anti-inflammatory response involving tissue-resident microglia/macrophages and infiltrated immune cells. Hypoxia/HIF-1α induce immunosuppression by (i) increasing the expression of immunosuppressive genes, (ii) stimulating adenosinergic signaling, (iii) enhancing aerobic glycolysis, i.e. lactate production, and (iv) augmenting the secretion of immunosuppressive exosomes. Interestingly, it seems that these common mechanisms are also involved in the pathogenesis of AD. In AD pathology, an enhanced immunosuppression appears, e.g. as a shift in microglia/macrophage phenotypes towards the anti-inflammatory M2 phenotype and an increase in the numbers of regulatory T cells (Treg). The augmented anti-inflammatory capacity promotes the resolution of acute inflammation but persistent inflammation has crucial effects not only on immune cells but also harmful responses to the homeostasis of AD brain. I will examine in detail the mechanisms of the hypoperfusion/hypoxia-induced immunosuppressive state in general and especially, in its association with AD pathogenesis. These immunological observations support the vascular hypothesis of AD pathology.

PMID: 33242538 [PubMed - as supplied by publisher]

Enrichment of circulating tumor-derived extracellular vesicles from human plasma.

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Enrichment of circulating tumor-derived extracellular vesicles from human plasma.

J Immunol Methods. 2020 Nov 23;:112936

Authors: Yoh KE, Lowe CJ, Mahajan S, Suttmann R, Nguy T, Reichelt M, Yang J, Melendez R, Li Y, Molinero L, Ruppel J, Xu W, Plaks V

Abstract
Extracellular vesicles (EVs) are gaining considerable traction within the liquid biopsy arena, as carriers of information from cells in distant sites that may not be accessible for biopsy. Therefore, there is a need to develop methods to enrich for specific EV subtypes, based on their cells of origin. Here we describe the development of an automated method to enrich tumor-derived EVs from plasma using the CellSearch technology compared to Total EVs isolated using differential ultracentrifugation (DUC). We use a modified CellSearch protocol to enrich EpCAM+ EVs from the plasma of patients with non-small cell lung carcinoma (NSCLC) and triple negative breast cancer (TNBC). As a test case, we examined PD-L1, an immune checkpoint ligand known to be expressed in some tumor tissues, to demonstrate enrichment for EpCAM+ EVs. For this purpose, we developed two custom immunoassays utilizing the Simoa HD-1 analyzer (Quanterix) to detect PD-L1 in EVs and interrogate specific EV populations from human plasma. PD-L1 was present in Total EVs from the plasma of healthy individuals and cancer patients, since it is also expressed on several immune cells. However, EpCAM+ EVs were only detectable from the plasma of cancer patients, suggesting these are tumor-derived EVs. As low as 250 μL of plasma could be used to reliably detect PD-L1 from patient-derived EpCAM+ EVs. In summary, this report demonstrates the development of a robust tumor-derived EV enrichment method from human blood. Furthermore, this proof-of-concept study is extendable to other known cancer-specific proteins expressed on EVs exuded from tumors.

PMID: 33242493 [PubMed - as supplied by publisher]

Biomarkers of drug-induced liver injury: a mechanistic perspective through acetaminophen hepatotoxicity.

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Biomarkers of drug-induced liver injury: a mechanistic perspective through acetaminophen hepatotoxicity.

Expert Rev Gastroenterol Hepatol. 2020 Nov 26;:

Authors: Umbaugh DS, Jaeschke H

Abstract
Introduction: Liver injury induced by drugs is a serious clinical problem. Many circulating biomarkers for identifying and predicting drug-induced liver injury (DILI) have been proposed. Areas covered: Biomarkers are mainly predicated on the mechanistic understanding of the underlying DILI, often in the context of acetaminophen overdose. New panels of biomarkers have emerged that are related to recovery/regeneration rather than injury following DILI. We explore the clinical relevance and limitations of these new biomarkers including recent controversies. Extracellular vesicles have also emerged as a promising vector of biomarkers, although the biological role for EVs may limit their clinical usefulness. New technological approaches for biomarker discovery are also explored. Expert Opinion: Recent clinical studies have validated the efficacy of some of these new biomarkers, cytokeratin-18, macrophage colony stimulating factor receptor, and osteopontin for DILI prognosis. Low prevalence of DILI is an inherent limitation to DILI biomarker development. Furthering mechanistic understanding of DILI and leveraging technological advances (e.g. machine learning and omics approaches) is necessary to improve upon the newest generation of biomarkers. The integration of omics approaches with machine learning has led to novel insights in cancer research and DILI research is poised to leverage these technologies for biomarker discovery and development.

PMID: 33242385 [PubMed - as supplied by publisher]

Extracellular Vesicles Derived from Intermittent Hypoxia-Treated Red Blood Cells Impair Endothelial Function Through Regulating eNOS Phosphorylation and ET-1 Expression.

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Extracellular Vesicles Derived from Intermittent Hypoxia-Treated Red Blood Cells Impair Endothelial Function Through Regulating eNOS Phosphorylation and ET-1 Expression.

Cardiovasc Drugs Ther. 2020 Nov 26;:

Authors: Peng L, Li Y, Li X, Du Y, Li L, Hu C, Zhang J, Qin Y, Wei Y, Zhang H

Abstract
PURPOSE: Intermittent hypoxia (IH), a main characteristic of obstructive sleep apnea (OSA) syndrome, has been known as a dominant cause of OSA-related endothelial dysfunction and hypertension. However, the underlying mechanism still remains unclear. Extracellular vesicles (EVs), small vesicles secreted by various cells, can be absorbed by endothelial cells and then influence vascular function. The aim of this research is to clarify whether and how EVs shedding from red blood cells (RBCs) are involved in IH-induced endothelial dysfunction.
METHODS: EVs were extracted by ultracentrifugation. After the identification of property and purity, EVs from IH-exposed RBCs (IH REVs) and normoxia-exposed RBCs (NOR REVs) or from OSA and non-OSA patient RBCs were utilized to treat C57BL/6 mouse aortas or human umbilical vein endothelial cells (HUVECs) for mechanistic exploration.
RESULTS: Functional results demonstrated that REVs from OSA patients dramatically impaired endothelium-dependent relaxations (EDRs). Similarly, in vivo and ex vivo studies showed that IH REVs caused significant endothelial dysfunction compared to control group. Further results presented that IH REVs blocked endothelial nitric oxide synthase (eNOS) phosphorylation through inhibiting PI3K/Akt pathway and enhanced endothelin-1 (ET-1) expression through activating Erk1/2 pathway in endothelial cells. Meanwhile, endothelial dysfunction caused by IH REVs was reversed by Akt activator SC79 as well as Erk kinase inhibitor PD98059, suggesting that PI3K/Akt/eNOS and Erk1/2/ET-1 pathways were implicated in IH REV-induced impaired EDRs.
CONCLUSIONS: This study reveals a novel role of REVs in endothelial dysfunction under IH and dissects the relevant mechanism involved in this process, which will help to establish a comprehensive understanding of OSA or IH-related endothelial dysfunction from a new scope.

PMID: 33242203 [PubMed - as supplied by publisher]

Selective Packaged Circular RNAs in Milk Extracellular Vesicles during Staphylococcus aureus Infection May Have Potential against Bacterial Infection.

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Selective Packaged Circular RNAs in Milk Extracellular Vesicles during Staphylococcus aureus Infection May Have Potential against Bacterial Infection.

RNA Biol. 2020 Nov 26;:

Authors: Ma S, Niu M, Hao Z, Liu M, Tong C, Zhao X

Abstract
Extracellular vesicles (EVs) provide a novel intercellular communication mechanism to transfer biologically important molecules to target cells. Although several pieces of evidence have shown that EVs have potential to respond to bacterial infections, our knowledge about the role of circular RNA (circRNA), an important cargo of EV, behind this process remains poor. In particular, the mechanism by which circRNAs are packaged into EVs remains elusive during bacterial infection. In the present study, EVs from bovine milk samples with or without Staphylococcus aureus (S. aureus) infection were isolated. The presence of circRNAs in milk-derived EVs (MEVs) was validated for the first time by PCR amplification with convergent and divergent primers and the RNase R resistance test. Through high-throughput sequencing, the expression profile of circRNAs in EVs was changed during S. aureus infection. Moreover, we demonstrated that circRNAs were selectively packaged into EVs. Finally, bioinformatic analyses predicted the involvement of differentially expressed circRNAs in immune functions. In summary, our findings offer an insight into the packaging mechanism of EV circRNAs and underscore the potential by which host used the EV circRNAs in response to pathogenic bacterial infections.

PMID: 33241726 [PubMed - as supplied by publisher]

HLA molecule expression on the surface of cells and microparticles in platelet concentrates.

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HLA molecule expression on the surface of cells and microparticles in platelet concentrates.

Transfusion. 2020 Nov 25;:

Authors: Pannetier L, Tamagne M, Bocquet T, Pirenne F, Ansart-Pirenne H, Vingert B

Abstract
BACKGROUND: Platelet (PLT) transfusions are an essential treatment for bleeding disorders. However, immunologic complications can occur, including alloantibody production against Class I HLA molecules. The principal source of HLA molecules in PLT concentrates (PCs) is the PLTs themselves. However, extracellular microparticles (MPs) present in PCs may express HLA molecules.
STUDY DESIGN AND METHODS: We used nanoscale flow cytometry to explore the expression of HLA-A2, HLA-B7, and HLA-B57 on the surface of cells, PLT-derived MPs (PMPs), lymphocyte-derived MPs (LMPs), and monocyte-derived MPs (MMPs) present in PCs. Expression was studied during 7 days of storage.
RESULTS: Platelets were not the only source of HLA molecules in PCs. HLA molecules were present on PMPs, LMPs, and MMPs. The level of HLA Class I molecule expression varied between haplotypes and MPs of different origins and during storage.
CONCLUSION: Platelets or residual cells remaining after leukoreduction are not the only source of HLA Class I molecules in PCs, highlighting the contribution of MPs to alloimmunization mechanisms. These data may be relevant for the development of new transfusion guidelines.

PMID: 33241556 [PubMed - as supplied by publisher]

Shear-Thinning Viscous Materials for Subconjunctival Injection of Microparticles.

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Shear-Thinning Viscous Materials for Subconjunctival Injection of Microparticles.

AAPS PharmSciTech. 2020 Nov 25;22(1):8

Authors: Xia S, Ding Z, Luo L, Chen B, Schneider J, Yang J, Eberhart CG, Stark WJ, Xu Q

Abstract
While drug-loaded microparticles (MPs) can serve as drug reservoirs for sustained drug release and therapeutic effects, needle clogging by MPs poses a challenge for ocular drug delivery via injection. Two polymers commonly used in ophthalmic procedures-hyaluronic acid (HA) and methylcellulose (MC)-have been tested for their applicability for ocular injections. HA and MC were physically blended with sunitinib malate (SUN)-loaded PLGA MPs for subconjunctival (SCT) injection into rat eyes. The HA and MC viscous solutions facilitated injection through fine-gauged needles due to their shear-thinning properties as shown by rheological characterizations. The diffusion barrier presented by HA and MC reduced burst drug release and extended overall release from MPs. The significant level of MP retention in the conjunctiva tissue post-operation confirmed the minimal leakage of MPs following injection. The safety of HA and MC for ocular applications was demonstrated histologically.

PMID: 33241486 [PubMed - in process]

RNAi technology targeting the FGFR3-TACC3 fusion breakpoint: an opportunity for precision medicine.

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RNAi technology targeting the FGFR3-TACC3 fusion breakpoint: an opportunity for precision medicine.

Neurooncol Adv. 2020 Jan-Dec;2(1):vdaa132

Authors: Parker Kerrigan BC, Ledbetter D, Kronowitz M, Phillips L, Gumin J, Hossain A, Yang J, Mendt M, Singh S, Cogdell D, Ene C, Shpall E, Lang FF

Abstract
Background: Fusion genes form as a result of abnormal chromosomal rearrangements linking previously separate genes into one transcript. The FGFR3-TACC3 fusion gene (F3-T3) has been shown to drive gliomagenesis in glioblastoma (GBM), a cancer that is notoriously resistant to therapy. However, successful targeting of F3-T3 via small molecular inhibitors has not revealed robust therapeutic responses, and specific targeting of F3-T3 has not been achieved heretofore. Here, we demonstrate that depleting F3-T3 using custom siRNA to the fusion breakpoint junction results in successful inhibition of F3-T3+ GBMs, and that exosomes can successfully deliver these siRNAs.
Methods: We engineered 10 unique siRNAs (iF3T3) that specifically spanned the most common F3-T3 breakpoint with varying degrees of overlap, and assayed depletion by qPCR and immunoblotting. Cell viability assays were performed. Mesenchymal stem cell-derived exosomes (UC-MSC) were electroporated with iF3T3, added to cells, and F3-T3 depletion measured by qPCR.
Results: We verified that depleting F3-T3 using shRNA to FGFR3 resulted in decreased cell viability and improved survival in glioma-bearing mice. We then demonstrated that 7/10 iF3T3 depleted F3-T3, and importantly, did not affect levels of wild-type (WT) FGFR3 or TACC3. iF3T3 decreased cell viability in both F3T3+ GBM and bladder cancer cell lines. UC-MSC exosomes successfully delivered iF3T3 in vitro, resulting in F3-T3 depletion.
Conclusion: Targeting F3-T3 using siRNAs specific to the fusion breakpoint is capable of eradicating F3T3+ cancers without toxicity related to inhibition of WT FGFR3 or TACC3, and UC-MSC exosomes may be a plausible vehicle to deliver iF3T3.

PMID: 33241214 [PubMed]

Extracellular Vesicle-Dependent Communication Between Mesenchymal Stromal Cells and Immune Effector Cells.

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Extracellular Vesicle-Dependent Communication Between Mesenchymal Stromal Cells and Immune Effector Cells.

Front Cell Dev Biol. 2020;8:596079

Authors: Bazzoni R, Takam Kamga P, Tanasi I, Krampera M

Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells residing in the stromal tissues of the body and capable of promoting tissue repair and attenuating inflammatory processes through their immunomodulatory properties. Preclinical and clinical observations revealed that not only direct intercellular communication mediates MSC properties; in fact, a pivotal role is also played by the release of soluble and bioactive factors, such as cytokines, growth factor and extracellular vesicles (EVs). EVs are membrane-coated vesicles containing a large variety of bioactive molecules, including lipids, proteins, and nucleic acids, such as RNA. EVs release their contents into target cells, thus influencing cell fate through the control of intracellular processes. In addition, MSC-derived EVs can mediate modulatory effects toward different effector cells belonging to both innate and adaptive immunity. In this review, we will discuss the literature data concerning MSC-derived EVs, including the current standardized methods for their isolation and characterization, the mechanisms supporting their immunoregulatory properties, and their potential clinical application as alternative to MSC-based therapy for inflammatory reactions, such as graft-versus-host disease (GvHD).

PMID: 33240892 [PubMed]

Microglia-Derived Extracellular Vesicles Carrying miR-711 Alleviate Neurodegeneration in a Murine Alzheimer's Disease Model by Binding to Itpkb.

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Microglia-Derived Extracellular Vesicles Carrying miR-711 Alleviate Neurodegeneration in a Murine Alzheimer's Disease Model by Binding to Itpkb.

Front Cell Dev Biol. 2020;8:566530

Authors: Zhang Y, Xu C, Nan Y, Nan S

Abstract
Neurodegeneration in Alzheimer's disease (AD) results in microglial activation, which may participate in the inflammatory cascade accelerating tissue damage. In this study, we sought to characterize the alleviatory role of microRNA-711 (miR-711) encapsulated in microglia-derived extracellular vesicles (EVs) in a model of AD. Ultracentrifugation was employed to extract EVs from microglia (BV2 cells), which were identified using Western blot analysis of the EVs marker proteins Alix and CD63. A repetitive mild traumatic brain injury (rmTBI) mouse model was induced by controlled cortical impact. After overexpressing miR-711 or 1,4,5-trisphosphate 3-kinase B (Itpkb) in BV2 cells, we evaluated the inflammation in BV2 cells and the ratio of microglia M2/M1. Further, we injected BV2 cell-secreted EVs with overexpressed miR-711 or Itpkb into rmTBI mice through a tail vein to investigate the inflammation markers in mouse serum and, the M2/M1 phenotype ratio of microglia in brain tissues, and to evaluate neurological deficit and cognitive function. The EVs obtained by ultracentrifugation were verified by the presence of Alix and CD63 expression. Mechanistic studies suggested that miR-711 targeted and inhibited Itpkb, thereby repressing Tau phosphorylation and increasing the ratio of M2/M1. Furthermore, miR-711-containing EVs reduced the score of neurological deficits and improved cognitive function in rmTBI mice. The administration of microglia-derived EVs loaded with miR-711, which mediated the hyperphosphorylation of Tau protein in the Itpkb pathway, effectively alleviated neurodegenerative changes and cognitive dysfunction in AD.

PMID: 33240878 [PubMed]

Editorial: MSC Signaling in Regenerative Medicine.

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Editorial: MSC Signaling in Regenerative Medicine.

Front Bioeng Biotechnol. 2020;8:614561

Authors: Stoddart MJ, Hofmann S, Holnthoner W

PMID: 33240869 [PubMed]

Pathogenesis of Viral Hepatitis-Induced Chronic Liver Disease: Role of Extracellular Vesicles.

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Pathogenesis of Viral Hepatitis-Induced Chronic Liver Disease: Role of Extracellular Vesicles.

Front Cell Infect Microbiol. 2020;10:587628

Authors: Lim HK, Jeffrey GP, Ramm GA, Soekmadji C

Abstract
Extracellular vesicles are encapsulated lipid nanoparticles secreted by a variety of cell types in living organisms. They are known to carry proteins, metabolites, nucleic acids, and lipids as their cargoes and are important mediators of intercellular communication. The role of extracellular vesicles in chronic liver disease has been reported. Chronic liver disease such as viral hepatitis accounts for a significant mortality and morbidity burden worldwide. Hepatic fibrosis has been commonly associated with the chronic form of viral hepatitis, which results in end-stage liver disease, including cirrhosis, liver failure, and carcinoma in some patients. In this review, we discuss the potential role of extracellular vesicles in mediating communication between infectious agents (hepatitis B and C viruses) and host cells, and how these complex cell-cell interactions may facilitate the development of chronic liver disease. We will further discuss how understanding their biological mechanism of action might be beneficial for developing therapeutic strategies to treat chronic liver disease.

PMID: 33240824 [PubMed - in process]

Biomass-Derived Multilayer-Structured Microparticles for Accelerated Hemostasis and Bone Repair.

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Biomass-Derived Multilayer-Structured Microparticles for Accelerated Hemostasis and Bone Repair.

Adv Sci (Weinh). 2020 Nov;7(22):2002243

Authors: Liu JY, Hu Y, Li L, Wang C, Wang J, Li Y, Chen D, Ding X, Shen C, Xu FJ

Abstract
It is very desirable to develop advanced sustainable biomedical materials with superior biosafety and bioactivity for clinical applications. Herein, biomass-derived multilayer-structured absorbable microparticles (MQ x T y ) composed of starches and plant polyphenols are readily constructed for the safe and effective treatment of bone defects with intractable bleeding by coating multiple layers of quaternized starch (Q+) and tannic acid onto microporous starch microparticles via facile layer-by-layer assembly. MQ x T y microparticles exhibit efficient degradability, low cytotoxicity, and good blood compatibility. Among various MQ x T y microparticles with distinct Q+/T- double layers, MQ2T2 with outmost polyphenol layer possess the unique properties of platelet adhesion/activation and red blood cell aggregation, resulting in the best hemostatic performance. In a mouse cancellous-bone-defect model, MQ2T2 exhibits the favorable hemostatic effect, low inflammation/immune responses, high biodegradability, and promoted bone repair. A proof-of-concept study of beagles further confirms the good performance of MQ2T2 in controlling intractable bleeding of bone defects. The present work demonstrates that such biomass-based multilayer-structured microparticles are very promising biomedical materials for clinical use.

PMID: 33240772 [PubMed]

Comprehensive analysis and identification of key genes and signaling pathways in the occurrence and metastasis of cutaneous melanoma.

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Comprehensive analysis and identification of key genes and signaling pathways in the occurrence and metastasis of cutaneous melanoma.

PeerJ. 2020;8:e10265

Authors: Dai H, Guo L, Lin M, Cheng Z, Li J, Tang J, Huan X, Huang Y, Xu K

Abstract
Background: Melanoma is a malignant tumor of melanocytes, and the incidence has increased faster than any other cancer over the past half century. Most primary melanoma can be cured by local excision, but metastatic melanoma has a poor prognosis. Cutaneous melanoma (CM) is prone to metastasis, so the research on the mechanism of melanoma occurrence and metastasis will be beneficial to diagnose early, improve treatment, and prolong life survival. In this study, we compared the gene expression of normal skin (N), primary cutaneous melanoma (PM) and metastatic cutaneous melanoma (MM) in the Gene Expression Omnibus (GEO) database. Then we identified the key genes and molecular pathways that may be involved in the development and metastasis of cutaneous melanoma, thus to discover potential markers or therapeutic targets.
Methods: Three gene expression profiles (GSE7553, GSE15605 and GSE46517) were downloaded from the GEO database, which contained 225 tissue samples. R software identified the differentially expressed genes (DEGs) between pairs of N, PM and MM samples in the three sets of data. Subsequently, we analyzed the gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of the DEGs, and constructed a protein-protein interaction (PPI) network. MCODE was used to seek the most important modules in PPI network, and then the GO function and KEGG pathway of them were analyzed. Finally, the hub genes were calculated by the cytoHubba in Cytoscape software. The Cancer Genome Atlas (TCGA) data were analyzed using UALCAN and GEPIA to validate the hub genes and analyze the prognosis of patients.
Results: A total of 134, 317 and 147 DEGs were identified between N, PM and MM in pair. GO functions and KEGG pathways analysis results showed that the upregulated DEGs mainly concentrated in cell division, spindle microtubule, protein kinase activity and the pathway of transcriptional misregulation in cancer. The downregulated DEGs occurred in epidermis development, extracellular exosome, structural molecule activity, metabolic pathways and p53 signaling pathway. The PPI network obtained the most important module, whose GO function and KEGG pathway were enriched in oxidoreductase activity, cell division, cell exosomes, protein binding, structural molecule activity, and metabolic pathways. 14, 18 and 18 DEGs were identified respectively as the hub genes between N, PM and MM, and TCGA data confirmed the expression differences of hub genes. In addition, the overall survival curve of hub genes showed that the differences in these genes may lead to a significant decrease in overall survival of melanoma patients.
Conclusions: In this study, several hub genes were found from normal skin, primary melanoma and metastatic melanoma samples. These hub genes may play an important role in the production, invasion, recurrence or death of CM, and may provide new ideas and potential targets for its diagnosis or treatment.

PMID: 33240619 [PubMed]

Definition and review on a category of long non-coding RNA: Atherosclerosis-associated circulating lncRNA (ASCLncRNA).

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Definition and review on a category of long non-coding RNA: Atherosclerosis-associated circulating lncRNA (ASCLncRNA).

PeerJ. 2020;8:e10001

Authors: Lu S, Liang Q, Huang Y, Meng F, Liu J

Abstract
Atherosclerosis (AS) is one of the most common cardiovascular system diseases which seriously affects public health in modern society. Finding potential biomarkers in the complicated pathological progression of AS is of great significance for the prevention and treatment of AS. Studies have shown that long noncoding RNAs (lncRNAs) can be widely involved in the regulation of many physiological processes, and have important roles in different stages of AS formation. LncRNAs can be secreted into the circulatory system through exosomes, microvesicles, and apoptotic bodies. Recently, increasing studies have been focused on the relationships between circulating lncRNAs and AS development. The lncRNAs in circulating blood are expected to be new non-invasive diagnostic markers for monitoring the progression of AS. We briefly reviewed the previously reported lncRNA transcripts which related to AS development and detectable in circulating blood, including ANRIL, SENCR, CoroMarker, LIPCAR, HIF1α-AS1, LncRNA H19, APPAT, KCNQ1OT1, LncPPARδ, LincRNA-p21, MALAT1, MIAT, and UCA1. Further researches and a definition of atherosclerosis-associated circulating lncRNA (ASCLncRNA) were also discussed.

PMID: 33240586 [PubMed]

The influence of secreted factors and extracellular vesicles in ovarian cancer metastasis.

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The influence of secreted factors and extracellular vesicles in ovarian cancer metastasis.

EJC Suppl. 2020 Aug;15:38-48

Authors: Hergueta-Redondo M, Peinado H

Abstract
Ovarian cancer cells mainly metastasise within the peritoneal cavity, the lethal consequence of tumour progression in this cancer type. Classically, changes in tumour cells, such as epithelial to mesenchymal transition, involve the down-regulatinon of E-cadherin, activation of extracellular proteases and integrin-mediated adhesion. However, our current understanding of ovarian tumour progression suggests the implication of both intrinsic and extrinsic factors. It has been proposed that ovarian cancer metastases are a consequence of the crosstalk between cancer cells and the tumour microenvironment by soluble factors and extracellular vesicles. Characterisation of the alterations in both the tumour cells and the surrounding microenvironment has emerged as a new research field to understand ovarian cancer metastasis. In this mini review, we will summarise the most recent findings, focusing our attention on the role of secreted factors and extracellular vesicles in ovarian cancer metastasis.

PMID: 33240441 [PubMed]

Anti-endothelial cell antibodies are associated with apoptotic endothelial microparticles, endothelial sloughing and decrease in angiogenic progenitors in systemic sclerosis.

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Anti-endothelial cell antibodies are associated with apoptotic endothelial microparticles, endothelial sloughing and decrease in angiogenic progenitors in systemic sclerosis.

Postepy Dermatol Alergol. 2020 Oct;37(5):725-735

Authors: Michalska-Jakubus MM, Rusek M, Kowal M, Czop M, Kocki J, Krasowska D

Abstract
Introduction: Evidence has accumulated for the role of endothelial damage in systemic sclerosis (SSc) and the anti-endothelial cell antibodies (AECAs) might underlie vascular injury.
Aim: Since endothelial microparticles (EMPs) and circulating endothelial cells (CECs) reflect endothelial damage, we aimed to investigate their possible relationship with AECAs in SSc. We examined whether AECAs could affect endothelial repair based on the number of endothelial progenitor cells (EPCs).
Material and methods: Forty-seven SSc patients were screened. The AECAs were identified in serum by indirect immunofluorescence. EPCs and CECs were isolated from the peripheral blood using anti-CD34-based immunomagnetic separation, whereas EMPs were analyzed in plasma. Flow cytometry was used to quantify EMPs, CECs and EPCs.
Results: AECAs were found in 21 (44.7%) SSc patients and were significantly associated with higher levels of total as well as apoptotic (AnnV+ and CD51+) EMPs, whereas activated (CD62E+/AnnV-) EMPs did not differ between groups. Patients with AECAs had significantly elevated total CECs as well as activated CD105+ CECs. Total endothelial progenitors did not differ between patients with or without AECAs; however AECAs was negatively associated with the population of EPCs that express VEGFR2 or Tie2 receptors.
Conclusions: We found an association between AECAs and the severity of endothelial damage in SSc based on higher levels of total EMPs and CECs. In our study, AECAs were associated with apoptosis of ECs rather than their activation. We also identified a possible role of AECAs in the impairment of vascular repair in SSc as evidenced by significantly fewer angiogenic EPCs.

PMID: 33240013 [PubMed]

Hypoxic Tumor-Derived Exosomal Circ0048117 Facilitates M2 Macrophage Polarization Acting as miR-140 Sponge in Esophageal Squamous Cell Carcinoma.

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Hypoxic Tumor-Derived Exosomal Circ0048117 Facilitates M2 Macrophage Polarization Acting as miR-140 Sponge in Esophageal Squamous Cell Carcinoma.

Onco Targets Ther. 2020;13:11883-11897

Authors: Lu Q, Wang X, Zhu J, Fei X, Chen H, Li C

Abstract
Introduction: Hypoxia and tumor-associated macrophage (TAM) are key regulators in remodeling the microenvironment of esophageal squamous cell carcinoma (ESCC). Hypoxia could stimulate tumor cells to secrete more exosomes and activate TAMs to M2 type. Here, we investigated the function and the underlying mechanism of tumor-derived exosomal hsa-circ-0048117 in TAM polarization in ESCC. Collectively, these data indicate that PC cells generate miR-301a-3p-rich exosomes in a hypoxic microenvironment, which then polarize macrophages to promote malignant behaviors of PC cells.
Methods: Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to analyze the physical characteristics of exosomes. High-throughput sequencing and bioinformatic analysis were performed to screen the potential exosomal circRNA. FISH, Ago2 RIP, pull-down and dual-luciferase reporter assay were conducted to figure out the correlation among hsa-circ-0048117, miR-140 and toll-like receptor 4 (TLR4). Flow cytometry and Western blot were used to evaluate their joint effect in macrophages polarization. Then, the invasion and migration ability were evaluated by transwell experiment. At last, serum exo-hsa-circ-0048117 in ESCC patients was compared and the correlation between its expression and T stage, N stage and TNM grades was analyzed.
Results: Hsa-circ-0048117 was significantly upregulated and enriched in exosomes secreted by hypoxia pre-challenged tumor cells and contributed to M2 macrophage polarization. Hsa-circ-0048117 depletion in macrophage led to inhibition of M2 polarization while restoration of hsa-circ-0048117 could rescue the process. Moreover, hsa-circ-0048117 could act as sponge of miR-140 by competing with TLR4 to facilitate the M2 macrophage polarization. Exo-hsa-circ-0048117 could be transmitted to macrophages to promote M2 polarization and M2 macrophages could enhance the ability of invasion and migration of tumor cells by secreting Arg1, IL-10 and TGF-β. Higher serum exo-hsa-circ-0048117 predicted an advanced T and N stage and positively correlated with TNM grade.
Conclusion: Our findings indicated that ESCC cells generate hsa-circ-0048117-rich exosomes in a hypoxic microenvironment; hsa-circ-0048117 was believed to promote M2 macrophage polarization which favors the malignant behaviors of ESCC cells. These results reminded us that exosomal hsa-circ-0048117 may play a key role in remodeling the microenvironment and modulating progression in ESCC.

PMID: 33239890 [PubMed]

Exosomes from gingival mesenchymal stem cells enhance migration and osteogenic differentiation of pre-osteoblasts.

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Exosomes from gingival mesenchymal stem cells enhance migration and osteogenic differentiation of pre-osteoblasts.

Pharmazie. 2020 Nov 01;75(11):576-580

Authors: Jiang S, Xu L

Abstract
Gingival mesenchymal stem cells (GMSCs) have great potential in bone tissue regeneration. However, it is not well known how on exosomes derived from GMSCs affect the functions of bone-related cells. In this study, we explored the impact of GMSCs-derived exosomes (GMSCs-Exos) on pre-osteoblast MC3T3-E1 proliferation, migration and osteogenic differentiation. Results of CCK-8 assay showed that GMSCs-Exos had no effect on proliferation of pre-osteoblasts. Further, we found that GMSCs-Exos promoted the migration of pre-osteoblasts and osteogenic differentiation of MC3T3-E1 as revealed by enhanced Alizarin red staining, elevated alkaline phosphatase (ALP) activity and upregulated expression of osteogenic genes. This study provides new insights into the potential exosome-mediated paracrine mechanism of GMSCs in bone regeneration.

PMID: 33239132 [PubMed - in process]

Noncoding RNAs in subchondral bone osteoclast function and their therapeutic potential for osteoarthritis.

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Noncoding RNAs in subchondral bone osteoclast function and their therapeutic potential for osteoarthritis.

Arthritis Res Ther. 2020 Nov 25;22(1):279

Authors: Duan L, Liang Y, Xu X, Wang J, Li X, Sun D, Deng Z, Li W, Wang D

Abstract
Osteoclasts are the only cells that perform bone resorption. Noncoding RNAs (ncRNAs) are crucial epigenetic regulators of osteoclast biological behaviors ranging from osteoclast differentiation to bone resorption. The main ncRNAs, including miRNAs, circRNAs, and lncRNAs, compose an intricate network that influences gene transcription processes related to osteoclast biological activity. Accumulating evidence suggests that abnormal osteoclast activity leads to the disturbance of subchondral bone remodeling, thus initiating osteoarthritis (OA), a prevalent joint disease characterized mainly by cartilage degradation and subchondral bone remodeling imbalance. In this review, we delineate three types of ncRNAs and discuss their related complex molecular signaling pathways associated with osteoclast function during bone resorption. We specifically focused on the involvement of noncoding RNAs in subchondral bone remodeling, which participate in the degradation of the osteochondral unit during OA progression. We also discussed exosomes as ncRNA carriers during the bone remodeling process. A better understanding of the roles of ncRNAs in osteoclast biological behaviors will contribute to the treatment of bone resorption-related skeletal diseases such as OA.

PMID: 33239099 [PubMed - in process]

Bone marrow mesenchymal stem cell-derived exosomes promote rotator cuff tendon-bone healing by promoting angiogenesis and regulating M1 macrophages in rats.

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Bone marrow mesenchymal stem cell-derived exosomes promote rotator cuff tendon-bone healing by promoting angiogenesis and regulating M1 macrophages in rats.

Stem Cell Res Ther. 2020 Nov 25;11(1):496

Authors: Huang Y, He B, Wang L, Yuan B, Shu H, Zhang F, Sun L

Abstract
BACKGROUND: Rotator cuff tears (RCTs) often require reconstructive surgery. Tendon-bone healing is critical for the outcome of rotator cuff reconstruction, but the process of tendon-bone healing is complex and difficult. Mesenchymal stem cells (MSCs) are considered to be an effective method to promote tendon-bone healing. MSCs have strong paracrine, anti-inflammatory, immunoregulatory, and angiogenic potential. Recent studies have shown that MSCs achieve many regulatory functions through exosomes. The purpose of this study was to explore the role of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) in tendon-bone healing.
METHODS: Our study found that BMSC-Exos promote the proliferation, migration, and angiogenic tube formation of human umbilical vein endothelial cells (HUVECs). The mechanism by which BMSC-Exos achieve this may be through the regulation of the angiogenic signaling pathway. In addition, BMSC-Exos can inhibit the polarization of M1 macrophages and inhibit the secretion of proinflammatory factors by M1 macrophages. After rotator cuff reconstruction in rats, BMSC-Exos were injected into the tail vein to analyze their effect on the rotator cuff tendon-bone interface healing.
RESULTS: It was confirmed that BMSC-Exos increased the breaking load and stiffness of the rotator cuff after reconstruction in rats, induced angiogenesis around the rotator cuff endpoint, and promoted growth of the tendon-bone interface.
CONCLUSION: BMSC-Exos promote tendon-bone healing after rotator cuff reconstruction in rats by promoting angiogenesis and inhibiting inflammation.

PMID: 33239091 [PubMed - in process]

Mapping current research and identifying hotspots on mesenchymal stem cells in cardiovascular disease.

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Mapping current research and identifying hotspots on mesenchymal stem cells in cardiovascular disease.

Stem Cell Res Ther. 2020 Nov 25;11(1):498

Authors: Chen C, Lou Y, Li XY, Lv ZT, Zhang LQ, Mao W

Abstract
BACKGROUND: Mesenchymal stem cells (MSCs) have important research value and broad application prospects in the cardiovascular disease. This study provides information on the latest progress, evolutionary path, frontier research hotspots, and future research developmental trends in this field.
METHODS: A knowledge map was generated by CiteSpace and VOSviewer analysis software based on data obtained from the literature on MSCs in the cardiovascular field.
RESULTS: The USA and China ranked at the top in terms of the percentage of articles, accounting for 34.306% and 28.550%, respectively. The institution with the highest number of research publications in this field was the University of Miami, followed by the Chinese Academy of Medical Sciences and Harvard University. The research institution with the highest ACI value was Harvard University, followed by the Mayo Clinic and the University of Cincinnati. The top three subjects in terms of the number of published articles were cell biology, cardiovascular system cardiology, and research experimental medicine. The journal with the most publications in this field was Circulation Research, followed by Scientific Reports and Biomaterials. The direction of research on MSCs in the cardiovascular system was divided into four parts: (1) tissue engineering, scaffolds, and extracellular matrix research; (2) cell transplantation, differentiation, proliferation, and signal transduction pathway research; (3) assessment of the efficacy of stem cells from different sources and administration methods in the treatment of acute myocardial infarction, myocardial hypertrophy, and heart failure; and (4) exosomes and extracellular vesicles research. Tissue research is the hotspot and frontier in this field.
CONCLUSION: MSC research has presented a gradual upward trend in the cardiovascular field. Multidisciplinary intersection is a characteristic of this field. Engineering and materials disciplines are particularly valued and have received attention from researchers. The progress in multidisciplinary research will provide motivation and technical support for the development of this field.

PMID: 33239082 [PubMed - in process]

Exosomes derived from three-dimensional cultured human umbilical cord mesenchymal stem cells ameliorate pulmonary fibrosis in a mouse silicosis model.

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Exosomes derived from three-dimensional cultured human umbilical cord mesenchymal stem cells ameliorate pulmonary fibrosis in a mouse silicosis model.

Stem Cell Res Ther. 2020 Nov 25;11(1):503

Authors: Xu C, Zhao J, Li Q, Hou L, Wang Y, Li S, Jiang F, Zhu Z, Tian L

Abstract
BACKGROUND: Silicosis is an occupational respiratory disease caused by long-term excessive silica inhalation, which is most commonly encountered in industrial settings. Unfortunately, there is no effective therapy to delay and cure the progress of silicosis. In the recent years, stem cell therapy has emerged as an attractive tool against pulmonary fibrosis (PF) owing to its unique biological characteristics. However, the direct use of stem cells remains limitation by many risk factors for therapeutic purposes. The exclusive utility of exosomes secreted from stem cells, rather than cells, has been considered a promising alternative to overcome the limitations of cell-based therapy while maintaining its advantages.
METHODS AND RESULTS: In this study, we first employed a three-dimensional (3D) dynamic system to culture human umbilical cord mesenchymal stem cell (hucMSC) spheroids in a microcarrier suspension to yield exosomes from serum-free media. Experimental silicosis was induced in C57BL/6J mice by intratracheal instillation of a silica suspension, with/without exosomes derived from hucMSC (hucMSC-Exos), injection via the tail vein afterwards. The results showed that the gene expression of collagen I (COL1A1) and fibronectin (FN) was upregulated in the silica group as compared to that in the control group; however, this change decreased with hucMSC-Exo treatment. The value of FEV0.1 decreased in the silica group as compared to that in the control group, and this change diminished with hucMSC-Exo treatment. These findings suggested that hucMSC-Exos could inhibit silica-induced PF and regulate pulmonary function. We also performed in vitro experiments to confirm these findings; the results revealed that hucMSC-Exos decreased collagen deposition in NIH-3T3 cells exposed to silica.
CONCLUSIONS: Taken together, these studies support a potential role for hucMSC-Exos in ameliorating pulmonary fibrosis and provide new evidence for improving clinical treatment induced by silica.

PMID: 33239075 [PubMed - in process]

Extracellular vesicles from hydroxycamptothecin primed umbilical cord stem cells enhance anti-adhesion potential for treatment of tendon injury.

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Extracellular vesicles from hydroxycamptothecin primed umbilical cord stem cells enhance anti-adhesion potential for treatment of tendon injury.

Stem Cell Res Ther. 2020 Nov 25;11(1):500

Authors: Li J, Yao Z, Xiong H, Cui H, Wang X, Zheng W, Qian Y, Fan C

Abstract
BACKGROUND: Peritendinous fibrosis represents a fibrotic healing process that usually occurs after tendon injury or surgery. This worldwide challenge hampers the functional rehabilitation and the mobility of extremities. However, effective treatment is still lacking at present. The aim of our study was to explore the effect of extracellular vesicles derived from hydroxycamptothecin primed human umbilical cord stem cells (HCPT-EVs) on post-traumatic tendon adhesion.
METHODS: Extracellular vesicles derived from unprimed human umbilical cord mesenchymal stem cells (Unprimed EVs) or HCPT-EVs were isolated and characterized. A rat model of Achilles tendon injury was used to confirm the anti-adhesion effect of HCPT-EVs and compared with that of Unprimed EVs in vivo. In vitro, the inhibitory effects of HCPT-EVs on fibroblast proliferation, viability, and myofibroblast differentiation upon TGF-β1 stimulation were compared with the effects of Unprimed EVs. For mechanistic analysis, the expression of endoplasmic reticulum stress (ERS)-associated proteins was examined among the effector cargos of HCPT-EVs and Unprimed EVs. The ERS antagonist salubrinal was used to determine the ERS dependence of the anti-adhesion effects of HCPT-EVs.
RESULTS: There were no obvious differences between Unprimed EVs and HCPT-EVs in terms of morphology, particle size, characteristic protein expression, and cellular uptake. HCPT-EVs exhibited a fortified anti-adhesion effect after Achilles tendon injury compared with Unprimed EVs. Fibroblast proliferation and viability and myofibroblast differentiation were all inhibited by HCPT-EVs. These properties were superior for HCPT-EVs relative to Unprimed EVs. Mechanistically, HCPT-EVs contained more ERS-associated protein than Unprimed EVs and activated the ERS pathway in fibroblast to counteract myofibroblast differentiation.
CONCLUSION: This study demonstrates that HCPT-EVs show high anti-adhesion potential for the treatment of tendon injury by provoking ERS in fibroblasts. HCPT-EVs represent a promising strategy for clinical use in treating adhesion-related diseases.

PMID: 33239069 [PubMed - in process]

Mesenchymal stem Cells as a Treatment Strategy for Coronavirus Disease 2019 (COVID-19): Need for Authority Regulations and Clinical Guidelines.

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Mesenchymal stem Cells as a Treatment Strategy for Coronavirus Disease 2019 (COVID-19): Need for Authority Regulations and Clinical Guidelines.

Curr Stem Cell Res Ther. 2020 Nov 24;:

Authors: Tufan AC

Abstract
The cause of coronavirus disease 2019 (COVID-19) known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, formerly designated 2019-nCoV) was first discovered in December 2019 in Wuhan, China. It then spread rapidly worldwide. Investigation for discovery of drugs to cure this disease continues. The currently accepted treatments are supportive but there is no specific disease curing intervention found yet. Since mid-February, therapies involving mesenchymal stem/stromal cells (MSCs) have been proposed for the treatment of patients with COVID-19. In light of these recent developments this review will focus on: i) the mechanism of SARS-CoV-2 action and the subsequent pathology in COVID-19, ii) the proposed mechanism(s) of outcome-improving action of MSCs or MSC-derived extracellular vesicles in COVID-19 pneumonia, iii) registered MSC-based clinical trials and interventions for the treatment of COVID-19, iv) published case studies/series/trials reporting the use of MSC-based treatments in COVID-19 cases, and finally v) the need for authority regulations and clinical guidelines for MSC-based treatment strategies for COVID-19.

PMID: 33238848 [PubMed - as supplied by publisher]

[Research on feasibility of in vitro inflammatory wound microenvironment simulated by using inflammatory wound tissue homogenate of mice].

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[Research on feasibility of in vitro inflammatory wound microenvironment simulated by using inflammatory wound tissue homogenate of mice].

Zhonghua Shao Shang Za Zhi. 2020 Nov 20;36(11):1024-1034

Authors: Hao Y, Yang QX, Wang Q, Xu GC, Qi F, Deng CL, Wei ZR, Wang DL

Abstract
Objective: To investigate the feasibility of in vitro inflammatory wound microenvironment simulated by using inflammatory wound tissue homogenate of mice. Methods: (1) Ten eight-week-old C57BL/6 male mice were collected and full-thickness skin tissue with diameter of 1.0 cm on both sides of the midline of the back was taken with a perforator to make the normal skin tissue homogenate supernatant. At 48 h after the full-thickness skin defect wound was established, the wound tissue within 2 mm from the wound edge was taken to make inflammatory wound tissue homogenate supernatant. Two kinds of tissue homogenate supernatant were taken to adjust the total protein concentration to 1 mg/mL, and the tumor necrosis factor α (TNF-α) content was detected by enzyme-linked immunosorbent assay. The number of sample was 6. (2) The primary passage of human umbilical cord mesenchymal stem cells (hUCMSCs) were collected and cultured to the 3rd passage with the normal exosomes being extracted from the hUCMSCs after cultured for 48 h. Another batch of hUCMSCs in the 3rd passage was collected and stimulated with inflammatory wound tissue homogenate supernatant of 30, 50, and 100 μg/mL total protein and normal skin tissue homogenate supernatant of 30, 50, and 100 μg/mL total protein, respectively. After cultured for 48 h, the exosomes stimulated with normal protein of 30, 50, and 100 μg/mL and exosomes stimulated with inflammatory protein of 30, 50, and 100 μg/mL were extracted. Normal exosomes, exosomes stimulated with 30 μg/mL normal protein, and exosomes stimulated with 30 μg/mL inflammatory protein were collected, the morphology was observed by transmission electron microscope, the particle size was detected by nanoparticle tracking analyzer, and the expressions of CD9 and CD63 were detected by Western blotting. (3) Twenty one-day-old C57BL/6 mice were taken to isolate the primary passage of fibroblasts (Fbs) and the 3rd passage of Fbs, whose morphology was observed under the inverted phase contrast microscope. The Fbs of 3rd passage were collected to observe the expression of vimentin by cell crawling method combined with immunofluorescence method at culture hour (CH) 2. (4) The Fbs of 3rd passage were divided into control group, normal exosome group, 30, 50, 100 μg/mL normal protein stimulating exosome group, and 30, 50, 100 μg/mL inflammatory protein stimulating exosome group according to the random number table, with 4 wells in each group. Cells in control group received no treatment, and cells in the other 7 groups were respectively added with normal exosomes, exosomes stimulated with normal protein of 30, 50, and 100 μg/mL, and exosomes stimulated with inflammatory protein of 30, 50, and 100 μg/mL prepared in experiment (2). The final mass concentration of exosomes was adjusted to 10 μg/mL. The cell viability was detected by cell count kit 8 at CH 48. (5) Two batches of Fbs in the 3rd passage were divided and treated as those in experiment (4), with 4 wells in each group, and the final mass concentration of exosomes was adjusted to 1 and 10 μg/mL, respectively. The cell mobility was detected by cell scratch test at CH 6, 12, and 24. (6) Two batches of the Fbs of 3rd passage were collected, divided, and treated as those in experiment (4) except with no control group, with 3 wells in each group, and the final mass concentration of exosomes was respectively adjusted to 1 and 10 μg/mL. The mRNA expression levels of transforming growth factor β(1) (TGF-β(1)), TGF-β(3), and α smooth muscle actin (α-SMA) were detected by real-time fluorescent quantitative reverse transcription polymerase chain reaction at CH 48. Data were statistically analyzed with analysis of variance for repeated measurement, one-way analysis of variance, and Bonferroni method. Results: (1) The content of TNF-α in inflammatory wound tissue homogenate supernatant of mice was (116±3) pg/mL, significantly higher than (97±5) pg/mL in normal skin tissue homogenate supernatant at post injury hour 48 (t=3.306, P<0.05). (2) Normal exosomes, exosomes stimulated with 30 μg/mL normal protein, and exosomes stimulated with 30 μg/mL inflammatory protein of hUCMSCs showed the typical saucer-like shape. The particle sizes of the three exosomes of hUCMSCs were 30-150 nm, which were all within the normal particle size range of exosome. Three exosomes of hUCMSCs positively expressed CD9 and CD63. (3) The primary passage of cells were clearly defined and showed protruding spindle shape, irregular polygon shape, or slender strip shape. The morphology of the 3rd and the primary passage of cells is similar. At CH 2, vimentin in cells was positively expressed, and the cells were identified as Fbs. (4) At CH 48, the cell viability was (137.4±2.8)% in 30 μg/mL inflammatory protein stimulating exosome group, obviously higher than 100%, (107.5±2.4)%, (113.3±3.2)%, (104.0±2.0)%, and (101.9±1.5)% in control group, normal exosome group, 30 μg/mL normal protein stimulating exosome group, and 50 and 100 μg/mL inflammatory protein stimulating exosome groups, respectively (P<0.01), and cell viability in 30 μg/mL normal protein stimulating exosome group was obviously higher than that in control group, normal exosome group, and 50 and 100 μg/mL normal protein stimulating exosome groups [(103.4±2.2)% and (102.5±1.4)%], respectively (P<0.01). (5) At CH 6, 12, and 24, the mobility rate of cells in 30 μg/mL inflammatory protein stimulating exosome group was significantly higher than that in control group, normal exosome group, 30 μg/mL normal protein stimulating exosome group, and 50 and 100 μg/mL inflammatory protein stimulating exosome groups, respectively, when the final mass concentrations of exosome was 1 μg/mL (P<0.05) . At CH 12, the mobility rate of cells in 30 μg/mL normal protein stimulating exosome group was obviously higher than that in control group, normal exosome group, and 50 and 100 μg/mL normal protein stimulating exosome groups, respectively, when the final mass concentration of exosome was 1 μg/mL (P<0.05). At CH 6, the mobility rate of cells in 30 μg/mL inflammatory protein stimulating exosome group was significantly higher than that in control group and normal exosome group (P<0.05), and the mobility rate of cells in 30 μg/mL normal protein stimulating exosome group was significantly higher than that in 50 and 100 μg/mL normal protein stimulating exosome groups, respectively, when the final mass concentration of exosome was 10 μg/mL (P<0.05). At CH 12 and 24, the mobility rate of cells in 30 μg/mL inflammatory protein stimulating exosome group was significantly higher than that in control group, normal exosome group, and 50 and 100 μg/mL inflammatory protein stimulating exosome groups (P<0.05), and the mobility rate of cells in 30 μg/mL normal protein stimulating exosome group was significantly higher than that in control group, normal exosome group, and 50 and 100 μg/mL normal protein stimulating exosome groups, respectively, when the final mass concentration of exosome was 10 μg/mL (P<0.05). (6) There were no statistically significant differences in mRNA expression levels of TGF-β(1), TGF-β(3), and α-SMA of cells among the 7 groups at CH 48 when the final mass concentration of exosome was 1 μg/mL (F=1.123, 1.537, 1.653, P>0.05). There were no statistically significant differences in mRNA expression levels of TGF-β(1) and α-SMA of cells among the 7 groups at CH 48 when the final mass concentration of exosome was 10 μg/mL (F=1.487, 1.308, P>0.05), and mRNA expression level of TGF-β(3) of cells in 50 μg/mL inflammatory protein stimulating exosome group at CH 48 was significantly higher than that in normal exosome group, 50 μg/mL normal protein stimulating exosome group, and 30 and 100 μg/mL inflammatory protein stimulating exosome groups when the final mass concentration of exosome was 10 μg/mL (P<0.05). Conclusions: The pretreatment with inflammatory wound tissue homogenate supernatant of mice has no significant effect on the total protein of hUCMSCs exosomes. The hUCMSCs exosomes stimulated by low concentration inflammatory wound tissue homogenate supernatant can significantly promote the proliferation and migration ability of Fbs. The content of inflammatory mediators in the wound tissue homogenate supernatant during the inflammatory phase is extremely low, which may be the reason that the anti-inflammation and tissue repair paracrine effects of mesenchymal stem cell cannot be effectively started.

PMID: 33238685 [PubMed - in process]

Administration of Human MSC-Derived Extracellular Vesicles for the Treatment of Primary Sclerosing Cholangitis: Preclinical Data in MDR2 Knockout Mice.

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Administration of Human MSC-Derived Extracellular Vesicles for the Treatment of Primary Sclerosing Cholangitis: Preclinical Data in MDR2 Knockout Mice.

Int J Mol Sci. 2020 Nov 23;21(22):

Authors: Angioni R, Calì B, Vigneswara V, Crescenzi M, Merino A, Sánchez-Rodríguez R, Liboni C, Hoogduijn MJ, Newsome PN, Muraca M, Russo FP, Viola A

Abstract
Primary Sclerosing Cholangitis (PSC) is a progressive liver disease for which there is no effective medical therapy. PSC belongs to the family of immune-mediated biliary disorders and it is characterized by persistent biliary inflammation and fibrosis. Here, we explored the possibility of using extracellular vesicles (EVs) derived from human, bone marrow mesenchymal stromal cells (MSCs) to target liver inflammation and reduce fibrosis in a mouse model of PSC. Five-week-old male FVB.129P2-Abcb4tm1Bor mice were intraperitoneally injected with either 100 µL of EVs (± 9.1 × 109 particles/mL) or PBS, once a week, for three consecutive weeks. One week after the last injection, mice were sacrificed and liver and blood collected for flow cytometry analysis and transaminase quantification. In FVB.129P2-Abcb4tm1Bor mice, EV administration resulted in reduced serum levels of alkaline phosphatase (ALP), bile acid (BA), and alanine aminotransferase (ALT), as well as in decreased liver fibrosis. Mechanistically, we observed that EVs reduce liver accumulation of both granulocytes and T cells and dampen VCAM-1 expression. Further analysis revealed that the therapeutic effect of EVs is accompanied by the inhibition of NFkB activation in proximity of the portal triad. Our pre-clinical experiments suggest that EVs isolated from MSCs may represent an effective therapeutic strategy to treat patients suffering from PSC.

PMID: 33238629 [PubMed - in process]

Extracellular Vesicles from SOD3-Transduced Stem Cells Exhibit Improved Immunomodulatory Abilities in the Murine Dermatitis Model.

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Extracellular Vesicles from SOD3-Transduced Stem Cells Exhibit Improved Immunomodulatory Abilities in the Murine Dermatitis Model.

Antioxidants (Basel). 2020 Nov 23;9(11):

Authors: Yang JW, Seo Y, Shin TH, Ahn JS, Oh SJ, Shin YY, Kang MJ, Lee BC, Lee S, Kang KS, Hur J, Kim YS, Kim TY, Kim HS

Abstract
The immunoregulatory abilities of mesenchymal stem cells (MSCs) have been investigated in various autoimmune and allergic diseases. However, the therapeutic benefits observed in preclinical settings have not been reproducible in clinical trials. This discrepancy is due to insufficient efficacy of MSCs in harsh microenvironments, as well as batch-dependent variability in potency. Therefore, to achieve more beneficial and uniform outcomes, novel strategies are required to potentiate the therapeutic effect of MSCs. One of simple strategies to augment cellular function is genetic manipulation. Several studies showed that transduction of antioxidant enzyme into cells can increase anti-inflammatory effects. Therefore, we evaluated the immunoregulatory abilities of MSCs introduced with extracellular superoxide dismutase 3 (SOD3) in the present study. SOD3-overexpressed MSCs (SOD3-MSCs) reduced the symptoms of murine model of atopic dermatitis (AD)-like inflammation, as well as the differentiation and activation of various immune cells involved in AD progression. Interestingly, extracellular vesicles (EVs) isolated from SOD3-MSCs delivered SOD3 protein. EVs carrying SOD3 also exerted improved therapeutic efficacy, as observed in their parent cells. These results suggest that MSCs transduced with SOD3, an antioxidant enzyme, as well as EVs isolated from modified cells, might be developed as a promising cell-based therapeutics for inflammatory disorders.

PMID: 33238520 [PubMed]

Secretory Phospholipase A2-IIA Protein and mRNA Pools in Extracellular Vesicles of Bronchoalveolar Lavage Fluid from Patients with Early Acute Respiratory Distress Syndrome: A New Perception in the Dissemination of Inflammation?

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Secretory Phospholipase A2-IIA Protein and mRNA Pools in Extracellular Vesicles of Bronchoalveolar Lavage Fluid from Patients with Early Acute Respiratory Distress Syndrome: A New Perception in the Dissemination of Inflammation?

Pharmaceuticals (Basel). 2020 Nov 23;13(11):

Authors: Papadopoulos S, Kazepidou E, Antonelou MH, Leondaritis G, Tsapinou A, Koulouras VP, Avgeropoulos A, Nakos G, Lekka ME

Abstract
Secretory phospholipase-IIA A2 (sPLA2-IIA) is expressed in a variety of cell types under inflammatory conditions. Its presence in the bronchoalveolar lavage (BAL) fluid of patients with acute respiratory distress syndrome (ARDS) is associated with the severity of the injury. Exosomal type extracellular vesicles, (EVs), are recognized to perform intercellular communication. They may alter the immune status of recipient target cells through cargo shuttling. In this work, we characterized the exosomal type EVs isolated from BAL fluid of patients with early and late ARDS as compared to control/non-ARDS patients, through morphological (confocal and electron microscopy) and biochemical (dynamic light scattering, qRT-PCR, immunoblotting) approaches. We provide evidence for the presence of an sPLA2-IIA-carrying EV pool that coprecipitates with exosomes in the BAL fluid of patients with ARDS. PLA2G2A mRNA was present in all the samples, although more prominently expressed in early ARDS. However, the protein was found only in EVs from early phase ARDS. Under both forms, sPLA2-IIA might be involved in inflammatory responses of recipient lung cells during ARDS. The perception of the association of sPLA2-IIA to the early diagnosis of ARDS or even with a mechanism of development and propagation of lung inflammation can help in the adoption of appropriate and innovative therapeutic strategies.

PMID: 33238426 [PubMed]

Targeting TRAF3IP2, Compared to Rab27, is More Effective in Suppressing the Development and Metastasis of Breast Cancer.

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Targeting TRAF3IP2, Compared to Rab27, is More Effective in Suppressing the Development and Metastasis of Breast Cancer.

Sci Rep. 2020 06 01;10(1):8834

Authors: Alt EU, Wörner PM, Pfnür A, Ochoa JE, Schächtele DJ, Barabadi Z, Lang LM, Srivastav S, Burow ME, Chandrasekar B, Izadpanah R

Abstract
Here we investigated the roles of Rab27a, a player in exosome release, and TRAF3IP2, an inflammatory mediator, in development and metastasis of breast cancer (BC) in vivo. Knockdown (KD) of Rab27a (MDAKDRab27a) or TRAF3IP2 (MDAKDTRAF3IP2) in triple negative MDA-MB231 cells reduced tumor growth by 70-97% compared to wild-type tumors (MDAw). While metastasis was detected in MDAw-injected animals, none was detected in MDAKDRab27a- or MDAKDTRAF3IP2-injected animals. Interestingly, micrometastasis was detected only in the MDAKDRab27a-injected group. In addition to inhibiting tumor growth and metastasis, silencing TRAF3IP2 disrupted inter-cellular inflammatory mediator-mediated communication with mesenchymal stem cells (MSCs) injected into contralateral mammary gland, evidenced by the lack of tumor growth at MSC-injected site. Of translational significance, treatment of pre-formed MDAw-tumors with a lentiviral-TRAF3IP2-shRNA not only regressed their size, but also prevented metastasis. These results demonstrate that while silencing Rab27a and TRAF3IP2 each inhibited tumor growth and metastasis, silencing TRAF3IP2 is more effective; targeting TRAF3IP2 inhibited tumor formation, regressed preformed tumors, and prevented both macro- and micrometastasis. Silencing TRAF3IP2 also blocked interaction between tumor cells and MSCs injected into the contralateral gland, as evidenced by the lack of tumor formation on MSCs injected site. These results identify TRAF3IP2 as a novel therapeutic target in BC.

PMID: 32483202 [PubMed - indexed for MEDLINE]

Foreword.

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Foreword.

Biol Pharm Bull. 2020;43(4):575

Authors: Ishida T, Kawakami S, Hosoya KI

PMID: 32238699 [PubMed - indexed for MEDLINE]

 

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