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      Bovine milk-derived exosomes enhance goblet cell activity and prevent the development of experimental necrotizing enterocolitis

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          Abstract

          Necrotizing enterocolitis (NEC) is characterized by intestinal injury and impaired mucin synthesis. We recently showed that breast milk exosomes from rodents promote intestinal cell viability, epithelial proliferation, and stem cell activity, but whether they also affect mucus production is unknown. Therefore, the aim of this study was to investigate the effects of bovine milk-derived exosomes on goblet cell expression in experimental NEC and delineate potential underlying mechanisms of action. Exosomes were isolated from bovine milk by ultracentrifugation and confirmed by Nanoparticle Tracking Analysis and through the detection of exosome membrane markers. To study the effect on mucin production, human colonic LS174T cells were cultured and exposed to exosomes. Compared to control, exosomes promoted goblet cell expression, as demonstrated by increased mucin production and relative expression levels of goblet cell expression markers trefoil factor 3 (TFF3) and mucin 2 (MUC2). In addition, exosome treatment enhanced the expression of glucose-regulated protein 94 (GRP94), the most abundant intraluminal endoplasmic reticulum (ER) chaperone protein that aids in protein synthesis. Furthermore, experimental NEC was induced in mouse pups by hyperosmolar formula feeding, lipopolysaccharide administration and hypoxia exposure on postnatal days 5–9. Milk exosomes were given with each gavage feed. NEC was associated with ileal morphological injury and reduction in MUC2+ goblet cells and GRP94+ cells per villus. Exosome administration to NEC pups prevented these changes. This research highlights the potential novel application of milk-derived exosomes in preventing the development of NEC in high-risk infants when breast milk is not available.

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          Most cited references 21

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          Roles and regulation of the mucus barrier in the gut.

          The gastrointestinal tract is coated by a thick layer of mucus that forms the front line of innate host defense. Mucus consists of high molecular weight glycoproteins called mucins that are synthesized and secreted by goblet cells and functions primarily to lubricate the epithelium and protect it from damage by noxious substances. Recent studies have also suggested the involvement of goblet cells and mucins in complex immune functions such as antigen presentation and tolerance. Under normal physiological conditions, goblet cells continually produce mucins to replenish and maintain the mucus barrier; however, goblet cell function can be disrupted by various factors that can affect the integrity of the mucus barrier. Some of these factors such as microbes, microbial toxins and cytokines can stimulate or inhibit mucin production and secretion, alter the chemical composition of mucins or degrade the mucus layer. This can lead to a compromised mucus barrier and subsequently to various pathological conditions like chronic inflammatory diseases. Insight into how these factors modulate the mucus barrier in the gut is necessary in order to develop strategies to combat these disorders.
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            Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondins.

            After its discovery as oncogen and morphogen, studies on Wnt focused initially on its role in animal development. With the finding that the colorectal tumour suppressor gene APC is a negative regulator of the Wnt pathway in (colorectal) cancer, attention gradually shifted to the study of the role of Wnt signalling in the adult. The first indication that adult Wnt signalling controls stem cells came from a Tcf4 knockout experiment: mutant mice failed to build crypt stem cell compartments. This observation was followed by similar findings in multiple other tissues. Recent studies have indicated that Wnt agonists of the R-spondin family provide potent growth stimuli for crypts in vivo and in vitro. Independently, Lgr5 was found as an exquisite marker for these crypt stem cells. The story has come full circle with the finding that the stem cell marker Lgr5 constitutes the receptor for R-spondins and occurs in complex with Frizzled/Lrp.
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              GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum.

              Glucose-regulated protein 94 is the HSP90-like protein in the lumen of the endoplasmic reticulum and therefore it chaperones secreted and membrane proteins. It has essential functions in development and physiology of multicellular organisms, at least in part because of this unique clientele. GRP94 shares many biochemical features with other HSP90 proteins, in particular its domain structure and ATPase activity, but also displays distinct activities, such as calcium binding, necessitated by the conditions in the endoplasmic reticulum. GRP94's mode of action varies from the general HSP90 theme in the conformational changes induced by nucleotide binding, and in its interactions with co-chaperones, which are very different from known cytosolic co-chaperones. GRP94 is more selective than many of the ER chaperones and the basis for this selectivity remains obscure. Recent development of molecular tools and functional assays has expanded the spectrum of clients that rely on GRP94 activity, but it is still not clear how the chaperone binds them, or what aspect of folding it impacts. These mechanistic questions and the regulation of GRP94 activity by other proteins and by post-translational modification differences pose new questions and present future research avenues. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90). Copyright © 2011 Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: Writing – original draft
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Writing – original draft
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Writing – review & editing
                Role: Data curation
                Role: Data curation
                Role: ConceptualizationRole: Data curation
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: SupervisionRole: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                30 January 2019
                2019
                : 14
                : 1
                Affiliations
                [1 ] Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
                [2 ] Division of General and Thoracic Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
                [3 ] Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
                [4 ] Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
                [5 ] Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
                Universita degli Studi di Torino, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-18-27508
                10.1371/journal.pone.0211431
                6353182
                30699187
                © 2019 Li et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 4, Tables: 0, Pages: 12
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Award ID: 353857
                Award Recipient :
                This study was supported by a Canadian Institutes of Health Research (CIHR) Foundation Grant 353857 (AP). AP is the Robert M. Filler Chair of Surgery, The Hospital for Sick Children (HSC). BL is the recipient of Restracomp Fellowship from The Hospital for Sick Children and Early Career Award Program grant from Thrasher Research Fund (14503). RYW is the recipient of a Vanier Graduate Scholarship from the CIHR. PMS is the recipient of a Canada Research Chair in Gastrointestinal Disease and Canadian Institutes of Health Resources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Vesicles
                Exosomes
                Biology and Life Sciences
                Anatomy
                Digestive System
                Gastrointestinal Tract
                Medicine and Health Sciences
                Anatomy
                Digestive System
                Gastrointestinal Tract
                Biology and Life Sciences
                Biochemistry
                Proteins
                Mucin
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Endoplasmic Reticulum
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Secretory Pathway
                Endoplasmic Reticulum
                Biology and Life Sciences
                Nutrition
                Diet
                Beverages
                Milk
                Medicine and Health Sciences
                Nutrition
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                Milk
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Milk
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Milk
                Biology and Life Sciences
                Physiology
                Body Fluids
                Milk
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Milk
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                Nutrition
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                Breast Milk
                Medicine and Health Sciences
                Nutrition
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                Biology and Life Sciences
                Anatomy
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                Medicine and Health Sciences
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                Breast Milk
                Research and Analysis Methods
                Spectrum Analysis Techniques
                Spectrophotometry
                Cytophotometry
                Flow Cytometry
                Biology and Life Sciences
                Anatomy
                Digestive System
                Gastrointestinal Tract
                Ileum
                Medicine and Health Sciences
                Anatomy
                Digestive System
                Gastrointestinal Tract
                Ileum
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