Bovine milk-derived extracellular vesicles enhance inflammation and promote M1 polarization following agricultural dust exposure in mice

Neuroblastoma (NBL) is a pediatric cancer that accounts for 15% of childhood cancer mortality. Amplification of the oncogene N-Myc occurs in 20% of NBL patients and is considered high risk as it correlates with aggressiveness, treatment resistance and poor prognosis. Even though the treatment strategies have improved in the recent years, the survival rate of high-risk NBL patients remain poor. Hence, it is crucial to explore new therapeutic avenues to sensitise NBL. Recently, bovine milk-derived extracellular vesicles (MEVs) have been proposed to contain anti-cancer properties. However, the impact of MEVs on NBL cells is not understood. In this study, we characterised MEVs using Western blotting, NTA and TEM. Importantly, treatment of NBL cells with MEVs decreased the proliferation and increased the sensitivity of NBL cells to doxorubicin. Temporal label-free quantitative proteomics of NBL cells highlighted the depletion of proteins involved in cell metabolism, cell growth and Wnt signalling upon treatment with MEVs. Furthermore, proteins implicated in cellular senescence and apoptosis were enriched in NBL cells treated with MEVs. For the first time, this study highlights the temporal proteomic profile that occurs in cancer cells upon MEVs treatment.

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Postprandial transfer of colostral extracellular vesicles and their protein and miRNA cargo in neonatal calves

10.21203/rs.2.10032/v1 ◽

2019 ◽

Author(s):

Benedikt Kirchner ◽

Dominik Buschmann ◽

Vijay Paul ◽

Michael W. Pfaffl

Keyword(s):

Extracellular Vesicles ◽

Expression Profiles ◽

Bovine Milk ◽

Cell Types ◽

Specific Protein ◽

In Vivo Experiments ◽

Neonatal Calves ◽

Almost All

Abstract Background Extracellular vesicles (EVs) such as exosomes are key regulators of intercellular communication that can be found in almost all bio fluids. Although studies in the last decade have made great headway in discerning the role of EVs in many physiological and pathophysiological processes, the bioavailability and impact of dietary EVs and their cargo still remain to be elucidated. Due to its widespread consumption and high content of EV-associated microRNAs and proteins, a major focus in this field has been set on EVs in bovine milk and colostrum. Despite promising in vitro studies in recent years that show high resiliency of milk EVs to degradation and uptake of milk EV cargo in a variety of intestinal and blood cell types, in vivo experiments continue to be inconclusive and sometimes outright contradictive. Results To resolve this discrepancy, we assessed the potential postprandial transfer of colostral EVs to the circulation of newborn calves by analysing colostrum-specific protein and miRNAs, including specific isoforms (isomiRs) in cells, EV isolations and unfractionated samples from blood and colostrum. Our findings reveal distinct populations of EVs in colostrum and blood from cows that can be clearly separated by density, particle concentration and protein content (BTN1A1, MFGE8). Postprandial blood samples of calves show a time-dependent increase in EVs that share morphological and protein characteristics of colostral EVs. Analysis of miRNA expression profiles by Next-Generation Sequencing gave a different picture however. Although significant postprandial expression changes could only be detected for calf EV samples, expression profiles show very limited overlap with highly expressed miRNAs in colostral EVs or colostrum in general. Conclusions Taken together our results indicate a selective uptake of membrane-associated protein cargo but not luminal miRNAs from colostral EVs into the circulation of neonatal calves.

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Harnessing the Natural Healing Power of Colostrum: Bovine Milk‐derived Extracellular Vesicles from Colostrum Facilitating the Transition from Inflammation to Tissue Regeneration for Accelerating Cutaneous Wound Healing

Advanced Healthcare Materials ◽

10.1002/adhm.202102027 ◽

2021 ◽

pp. 2102027

Author(s):

Hyosuk Kim ◽

Da Eun Kim ◽

Geonhee Han ◽

Nu Ri Lim ◽

Eun Hye Kim ◽

...

Keyword(s):

Wound Healing ◽

Extracellular Vesicles ◽

Tissue Regeneration ◽

Bovine Milk ◽

Cutaneous Wound Healing ◽

Cutaneous Wound ◽

Healing Power ◽

Natural Healing

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Dietary bovine milk miRNAs transported in extracellular vesicles are partially stable during GI digestion, are bioavailable and reach target tissues but need a minimum dose to impact on gene expression

European Journal of Nutrition ◽

10.1007/s00394-021-02720-y ◽

2021 ◽

Author(s):

María-Carmen López de las Hazas ◽

Lorena del Pozo-Acebo ◽

Maria S. Hansen ◽

Judit Gil-Zamorano ◽

Diana C. Mantilla-Escalante ◽

...

Keyword(s):

Gene Expression ◽

Extracellular Vesicles ◽

Bovine Milk ◽

Minimum Dose

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A8.2 Oral administration of bovine milk-derived extracellular vesicles diminishes cartilage pathology in two arthritis models

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-207259.187 ◽

2015 ◽

Vol 74 (Suppl 1) ◽

pp. A81.2-A82

Author(s):

OJ Arntz ◽

BCH Pieters ◽

MC de Oliveira ◽

MB Bennink ◽

van Lent Plem ◽

...

Keyword(s):

Oral Administration ◽

Extracellular Vesicles ◽

Bovine Milk ◽

Arthritis Models

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Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization

Stem Cell Research & Therapy ◽

10.1186/s13287-020-01937-8 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Jiangmei Wang ◽

Jie Xia ◽

Ruoqiong Huang ◽

Yaoqin Hu ◽

Jiajie Fan ◽

...

Keyword(s):

Extracellular Vesicles ◽

Stromal Cells ◽

Macrophage Polarization ◽

Critical Role ◽

Cell Contact ◽

Central Nervous System Diseases ◽

The Past ◽

Disease Outcomes ◽

M2 Polarization ◽

M1 Polarization

Abstract Mesenchymal stem cells (MSCs) are adult stromal cells that reside in virtually all postnatal tissues. Due to their regenerative and immunomodulatory capacities, MSCs have attracted growing attention during the past two decades. MSC-derived extracellular vesicles (MSC-EVs) are able to duplicate the effects of their parental cells by transferring functional proteins and genetic materials to recipient cells without cell-to-cell contact. MSC-EVs also target macrophages, which play an essential role in innate immunity, adaptive immunity, and homeostasis. Recent studies have demonstrated that MSC-EVs reduce M1 polarization and/or promote M2 polarization in a variety of settings. In this review, we discuss the mechanisms of macrophage polarization and roles of MSC-EV-induced macrophage polarization in the outcomes of cardiovascular, pulmonary, digestive, renal, and central nervous system diseases. In conclusion, MSC-EVs may become a viable alternative to MSCs for the treatment of diseases in which inflammation and immunity play a critical role.

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Oral administration of bovine milk derived extracellular vesicles attenuates arthritis in two mouse models

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201500222 ◽

2015 ◽

Vol 59 (9) ◽

pp. 1701-1712 ◽

Cited By ~ 96

Author(s):

Onno J. Arntz ◽

Bartijn C.H. Pieters ◽

Marina C. Oliveira ◽

Mathijs G.A. Broeren ◽

Miranda B. Bennink ◽

...

Keyword(s):

Oral Administration ◽

Mouse Models ◽

Extracellular Vesicles ◽

Bovine Milk

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Extracellular vesicles derived from CD73 modified human umbilical cord mesenchymal stem cells ameliorate inflammation after spinal cord injury

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01022-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Xiao Zhai ◽

Kai Chen ◽

Huan Yang ◽

Bo Li ◽

Tianjunke Zhou ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Extracellular Vesicles ◽

Inflammatory Cytokines ◽

Human Umbilical Cord ◽

M1 Polarization ◽

Cord Injury

Abstract Background Spinal cord injury (SCI) is an inflammatory condition, and excessive adenosine triphosphate (ATP) is released into the extracellular space, which can be catabolized into adenosine by CD73. Extracellular vesicles have been designed as nano drug carriers in many diseases. However, their impacts on delivery of CD73 after SCI are not yet known. We aimed to construct CD73 modified extracellular vesicles and explore the anti-inflammatory effects after SCI. Methods CD73 engineered extracellular vesicles (CD73+ hucMSC-EVs) were firstly established, which were derived from human umbilical cord mesenchymal stem cells (hucMSCs) transduced by lentiviral vectors to upregulate the expression of CD73. Effects of CD73+ hucMSC-EVs on hydrolyzing ATP into adenosine were detected. The polarization of M2/M1 was verified by immunofluorescence. Furthermore, A2aR and A2bR inhibitors and A2bR knockdown cells were used to investigate the activated adenosine receptor. Biomarkers of microglia and levels of cAMP/PKA were also detected. Repetitively in vivo study, morphology staining, flow cytometry, cytokine analysis, and ELISA assay, were also applied for verifications. Results CD73+ hucMSC-EVs reduced concentration of ATP and promoted the level of adenosine. In vitro experiments, CD73+ hucMSC-EVs increased macrophages/microglia M2:M1 polarization, activated adenosine 2b receptor (A2bR), and then promoted cAMP/PKA signaling pathway. In mice using model of thoracic spinal cord contusion injury, CD73+ hucMSC-EVs improved the functional recovery after SCI through decreasing the content of ATP in cerebrospinal fluid and improving the polarization from M1 to M2 phenotype. Thus, the cascaded pro-inflammatory cytokines were downregulated, such as TNF-α, IL-1β, and IL-6, while the anti-inflammatory cytokines were upregulated, such as IL-10 and IL-4. Conclusions CD73+ hucMSC-EVs ameliorated inflammation after spinal cord injury by reducing extracellular ATP, promoting A2bR/cAMP/PKA pathway and M2/M1 polarization. CD73+ hucMSC-EVs might be promising nano drugs for clinical application in SCI therapy. Graphical Abstract

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