M cells and the follicle-associated epithelium

Uptake of macromolecules (e.g., ferritin) by M cells in follicle-associated epithelium in small and large intestine was investigated in three healthy, conventionally raised, 2- to 3-week-old, female Holstein Frisian calves. A 2.5% solution of ferritin was injected into the ligated loops in mid-jejunum, in terminal ileum, in the ascending colon adjacent to the ileocecal junction, and in the proximal loop of the ascending colon containing gut-associated lymphoid tissue. After exposure times that ranged from 82 to 165 minutes, ferritin was detected in M cells of domes in the small intestine, as well as in cells in follicle-associated epithelium of proprial lymphoid nodules and lymphoglandular complexes of colon that morphologically resembled M cells of small intestine. Ferritin was found in apical invaginations, apical vesicles, multivesicular bodies, basal vesicles, and adjacent intercellular spaces. In addition to ferritin, apical vesicles, multivesicular bodies, and intercellular spaces contained 50-nm membrane-bound particles. More ferritin was endocytosed by M cells of the small intestine than by M cells of the large intestine. In the large intestine, higher amounts of ferritin were found in M cells of follicle-associated epithelium overlying proprial lymphoid nodules than in M cells of follicle-associated epithelium in the depth of lymphoglandular complexes. Based on these results, we concluded that M cells of follicle-associated epithelium in the colon of calves provide a route for antigen uptake into the intestinal lymphoid system.

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Development of intestinal M cells and follicle-associated epithelium is regulated by TRAF6-mediated NF-κB signaling

Journal of Experimental Medicine ◽

10.1084/jem.20160659 ◽

2018 ◽

Vol 215 (2) ◽

pp. 501-519 ◽

Cited By ~ 28

Author(s):

Takashi Kanaya ◽

Sayuri Sakakibara ◽

Toshi Jinnohara ◽

Masami Hachisuka ◽

Naoko Tachibana ◽

...

Keyword(s):

Cell Differentiation ◽

Tumor Necrosis Factor Receptor ◽

M Cells ◽

M Cell ◽

Antigen Uptake ◽

Conditional Deletion ◽

Follicle Associated Epithelium ◽

Necrosis Factor

M cells are located in the follicle-associated epithelium (FAE) that covers Peyer’s patches (PPs) and are responsible for the uptake of intestinal antigens. The differentiation of M cells is initiated by receptor activator of NF-κB. However, the intracellular pathways involved in M cell differentiation are still elusive. In this study, we demonstrate that the NF-κB pathway activated by RANK is essential for M cell differentiation using in vitro organoid culture. Overexpression of NF-κB transcription factors enhances the expression of M cell–associated molecules but is not sufficient to complete M cell differentiation. Furthermore, we evaluated the requirement for tumor necrosis factor receptor–associated factor 6 (TRAF6). Conditional deletion of TRAF6 in the intestinal epithelium causes a complete loss of M cells in PPs, resulting in impaired antigen uptake into PPs. In addition, the expression of FAE-associated genes is almost silenced in TRAF6-deficient mice. This study thus demonstrates the crucial role of TRAF6-mediated NF-κB signaling in the development of M cells and FAE.

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Identifying human and murine M cells in vitro

Experimental Biology and Medicine ◽

10.1177/1535370219838674 ◽

2019 ◽

Vol 244 (7) ◽

pp. 554-564 ◽

Cited By ~ 1

Author(s):

Ana Klisuric ◽

Benjamin Thierry ◽

Ludivine Delon ◽

Clive A Prestidge ◽

Rachel J Gibson

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

In Vitro Models ◽

Oral Drug ◽

M Cells ◽

Cell Marker ◽

M Cell ◽

Follicle Associated Epithelium

M cells are an epithelial cell population found in the follicle-associated epithelium overlying gut-associated lymphoid tissues. They are specialized in the transcytosis of luminal antigens. Their transcytotic capacity and location in an immunocompetent environment has prompted the study of these cells as possible targets for oral drug delivery systems. Currently, the models most commonly used to study M cells are restricted to in vivo experiments conducted in mice, and in vitro studies conducted in models comprised either of primary epithelial cells or established cell lines of murine or human origin. In vitro models of the follicle-associated epithelium can be constructed in several ways. Small intestinal Lgr5+ stem cells can be cultured into a 3D organoid structure where M cells are induced with RANKL administration. Additionally, in vitro models containing an “M cell-like” population can be obtained through co-culturing intestinal epithelial cells with cells of lymphocytic origin to induce the M cell phenotype. The evaluation of the efficiency of the variations of these models and their relevance to the in vivo human system is hampered by the lack of a universal M cell marker. This issue has also hindered the advancement of M cell-specific targeting approaches aimed at improving the bioavailability of orally administered compounds. This critical review discusses the different approaches utilized in the literature to identify M cells, their efficiency, reliability and relevance, in the context of commonly used models of the follicle-associated epithelium. The outcome of this review is a clearly defined and universally recognized criteria for the assessment of the relevance of models of the follicle-associated models currently used. Impact statement The study of M cells, a specialized epithelial cell type found in the follicle-associated epithelium, is hampered by the lack of a universal M cell marker. As such, many studies lack reliable and universally recognized methods to identify M cells in their proposed models. As a result of this it is difficult to ascertain whether the effects observed are due to the presence of M cells or an unaccounted variable. The outcome of this review is the thorough evaluation of the many M cell markers that have been used in the literature thus far and a proposed criterion for the identification of M cells for future publications. This will hopefully lead to an improvement in the quality of future publications in this field.

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Ultrastructural Study on the Differentiation and the Fate of M cells in Follicle-Associated Epithelium of Rat Peyer's Patch

Journal of Veterinary Medical Science ◽

10.1292/jvms.69.501 ◽

2007 ◽

Vol 69 (5) ◽

pp. 501-508 ◽

Cited By ~ 14

Author(s):

Sachiko ONISHI ◽

Toshifumi YOKOYAMA ◽

Keigi CHIN ◽

Midori YUJI ◽

Tetsurou INAMOTO ◽

...

Keyword(s):

Ultrastructural Study ◽

M Cells ◽

Peyer’S Patch ◽

Peyer's Patch ◽

Follicle Associated Epithelium

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Immune cells associated with M cells in the follicle-associated epithelium of Peyer's patches in the rat

Cell and Tissue Research ◽

10.1007/bf00224111 ◽

1989 ◽

Vol 255 (2) ◽

Cited By ~ 37

Author(s):

Anne Jarry ◽

Michel Robaszkiewicz ◽

Nicole Brousse ◽

Fran�ois Potet

Keyword(s):

Immune Cells ◽

Peyer's Patches ◽

Peyer’S Patches ◽

M Cells ◽

Follicle Associated Epithelium

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Gut-associated Lymphoid Tissue in the Large Intestine of Calves. II. Electron Microscopy

Veterinary Pathology ◽

10.1177/030098588802500615 ◽

1988 ◽

Vol 25 (6) ◽

pp. 509-515 ◽

Cited By ~ 14

Author(s):

E. M. Liebler ◽

J. F. Pohlenz ◽

N. F. Cheville

Keyword(s):

Electron Microscopy ◽

Large Intestine ◽

Lymphoid Tissue ◽

Cell Types ◽

Goblet Cells ◽

M Cells ◽

Muscularis Mucosae ◽

Transmission Electron ◽

Luminal Side ◽

Follicle Associated Epithelium

Scanning electron microscopy of lymphoid tissue in the large intestine of three germfree calves (age 3, 6, and 7 days) revealed two different units: propria nodules and lymphoglandular complexes (LGC). Propria nodules had lymphoid tissue predominantly in lamina propria and were covered by distinct follicle-associated epithelium which lacked goblet cells; nodules were surrounded by wide crypts, which were also lined by follicle-associated epithelium towards the luminal side. Lymphoglandular complexes had lymphoid follicles in the tunica submucosa; epithelial diverticulae extended through the muscularis mucosae branching into the lymphoid nodule. In centers of lymphoglandular complexes, protrusions of lymphoid tissue were covered with distinct follicle-associated epithelium. By transmission electron microscopy cells compatible with M cells in the small intestine of calves and cells with characteristics of both enteroabsorptive and M cells were found. Follicle-associated epithelium of propria nodules and lymphoglandular complexes differed only in the relative frequency of cell types.

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