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

文献类型： 外文期刊

作者： Ding, Siyuan 1 ; Song, Yanhua 2 ; Brulois, Kevin F. 2 ; Pan, Junliang 2 ; Co, Julia Y. 4 ; Ren, Lili 8 ; Feng, Ningguo 2 ;

作者机构： 1.Washington Univ, Sch Med, Dept Mol Microbiol, 660 S Euclid Ave,Rm 9220, St Louis, MO 63110 USA

2.VA Palo Alto Hlth Care Syst, Palo Alto Vet Inst Res, Palo Alto, CA USA

3.Stanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA

4.Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA

5.Jiangsu Acad Agr Sci, Inst Vet Med, Nanjing, Peoples R China

6.Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

7.Stanford Univ, Dept Pediat, Stanford, CA 94305 USA

8.Nanjing Tech Univ, Sch Pharmaceut Sci, Nanjing, Peoples R China

9.Stanford Univ, Dept Med, Div Hematol, Stanford, CA 94305 USA

关键词： Mucosal Immunity; Intestinal Enteroids; Rotavirus

期刊名称：GASTROENTEROLOGY （ 影响因子：22.682； 五年影响因子：23.936 ）

ISSN： 0016-5085

年卷期： 2020 年 159 卷 1 期

页码：

收录情况： SCI

摘要： 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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