Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells.,Gastroenterology

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Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells.
Gastroenterology ( IF 25.7 ) Pub Date : 2020-04-01 , DOI: 10.1053/j.gastro.2020.03.053
Siyuan Ding ₁ , Yanhua Song ₂ , Kevin F Brulois ₃ , Junliang Pan ₃ , Julia Y Co ₄ , Lili Ren ₅ , Ningguo Feng ₆ , Linda L Yasukawa ₆ , Liliana Sánchez-Tacuba ₆ , Jonathan E Wosen ₇ , Elizabeth D Mellins ₇ , Denise M Monack ₈ , Manuel R Amieva ₄ , Calvin J Kuo ₉ , Eugene C Butcher ₃ , Harry B Greenberg ₆

Affiliation

Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri.
Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, California; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, California; Department of Microbiology and Immunology, Stanford University, Stanford, California; Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China.
Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, California; Department of Pathology, Stanford University, Stanford, California.
Department of Microbiology and Immunology, Stanford University, Stanford, California; Department of Pediatrics, Stanford University, Stanford, California.
School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, China.
Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, California; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, California; Department of Microbiology and Immunology, Stanford University, Stanford, California.
Department of Pediatrics, Stanford University, Stanford, California.
Department of Microbiology and Immunology, Stanford University, Stanford, California.
Department of Medicine, Division of Hematology, Stanford University, Stanford, California.

Background & Aims

Intestinal microfold (M) cells are a unique subset of intestinal epithelial cells in the Peyer’s patches that regulate mucosal immunity, serving as portals for sampling and uptake of luminal antigens. The inability to efficiently develop human M cells in cell culture has impeded studies of the intestinal immune system. We aimed to identify signaling pathways required for differentiation of human M cells and establish a robust culture system using human ileum enteroids.

Methods

We analyzed transcriptome data from mouse Peyer’s patches to identify cell populations in close proximity to M cells. We used the human enteroid system to determine which cytokines were required to induce M-cell differentiation. We performed transcriptome, immunofluorescence, scanning electron microscope, and transcytosis experiments to validate the development of phenotypic and functional human M cells.

Results

A combination of retinoic acid and lymphotoxin induced differentiation of glycoprotein 2-positive human M cells, which lack apical microvilli structure. Upregulated expression of innate immune-related genes within M cells correlated with a lack of viral antigens after rotavirus infection. Human M cells, developed in the enteroid system, internalized and transported enteric viruses, such as rotavirus and reovirus, across the intestinal epithelium barrier in the enteroids.

Conclusions

We identified signaling pathways required for differentiation of intestinal M cells, and used this information to create a robust culture method to develop human M cells with capacity for internalization and transport of viruses. Studies of this model might increase our understanding of antigen presentation and the systemic entry of enteric pathogens in the human intestine.

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