Collagen type I-mediated mechanotransduction controls epithelial cell fate conversion during intestinal inflammation.

IF 5 3区 医学 Q2 IMMUNOLOGY Inflammation and Regeneration Pub Date : 2022-11-28 DOI:10.1186/s41232-022-00237-3
Sakurako Kobayashi, Nobuhiko Ogasawara, Satoshi Watanabe, Yosuke Yoneyama, Sakura Kirino, Yui Hiraguri, Masami Inoue, Sayaka Nagata, Yoshimi Okamoto-Uchida, Satoshi Kofuji, Hiromichi Shimizu, Go Ito, Tomohiro Mizutani, Shinichi Yamauchi, Yusuke Kinugasa, Yoshihito Kano, Yasuhiro Nemoto, Mamoru Watanabe, Kiichiro Tsuchiya, Hiroshi Nishina, Ryuichi Okamoto, Shiro Yui
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引用次数: 2

Abstract

Background: The emerging concepts of fetal-like reprogramming following tissue injury have been well recognized as an important cue for resolving regenerative mechanisms of intestinal epithelium during inflammation. We previously revealed that the remodeling of mesenchyme with collagen fibril induces YAP/TAZ-dependent fate conversion of intestinal/colonic epithelial cells covering the wound bed towards fetal-like progenitors. To fully elucidate the mechanisms underlying the link between extracellular matrix (ECM) remodeling of mesenchyme and fetal-like reprogramming of epithelial cells, it is critical to understand how collagen type I influence the phenotype of epithelial cells. In this study, we utilize collagen sphere, which is the epithelial organoids cultured in purified collagen type I, to understand the mechanisms of the inflammatory associated reprogramming. Resolving the entire landscape of regulatory networks of the collagen sphere is useful to dissect the reprogrammed signature of the intestinal epithelium.

Methods: We performed microarray, RNA-seq, and ATAC-seq analyses of the murine collagen sphere in comparison with Matrigel organoid and fetal enterosphere (FEnS). We subsequently cultured human colon epithelium in collagen type I and performed RNA-seq analysis. The enriched genes were validated by gene expression comparison between published gene sets and immunofluorescence in pathological specimens of ulcerative colitis (UC).

Results: The murine collagen sphere was confirmed to have inflammatory and regenerative signatures from RNA-seq analysis. ATAC-seq analysis confirmed that the YAP/TAZ-TEAD axis plays a central role in the induction of the distinctive signature. Among them, TAZ has implied its relevant role in the process of reprogramming and the ATAC-based motif analysis demonstrated not only Tead proteins, but also Fra1 and Runx2, which are highly enriched in the collagen sphere. Additionally, the human collagen sphere also showed a highly significant enrichment of both inflammatory and fetal-like signatures. Immunofluorescence staining confirmed that the representative genes in the human collagen sphere were highly expressed in the inflammatory region of ulcerative colitis.

Conclusions: Collagen type I showed a significant influence in the acquisition of the reprogrammed inflammatory signature in both mice and humans. Dissection of the cell fate conversion and its mechanisms shown in this study can enhance our understanding of how the epithelial signature of inflammation is influenced by the ECM niche.

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i型胶原介导的机械转导控制肠道炎症期间上皮细胞命运的转化。
背景:组织损伤后胎儿样重编程的新概念已被公认为解决炎症期间肠上皮再生机制的重要线索。我们之前揭示了胶原原纤维间质重塑诱导覆盖在伤口床上的肠/结肠上皮细胞向胎儿样祖细胞的YAP/ taz依赖性命运转化。为了充分阐明间质细胞外基质(ECM)重塑与上皮细胞胎儿样重编程之间联系的机制,了解I型胶原如何影响上皮细胞的表型至关重要。在本研究中,我们利用胶原球,即纯化型胶原中培养的上皮类器官,来了解炎症相关重编程的机制。解决胶原球调控网络的整个景观有助于解剖肠上皮的重编程特征。方法:我们对小鼠胶原球进行微阵列、RNA-seq和ATAC-seq分析,并与Matrigel类器官和胎儿肠球(FEnS)进行比较。随后,我们用I型胶原培养人结肠上皮,并进行RNA-seq分析。通过已发表的基因集和溃疡性结肠炎(UC)病理标本的免疫荧光基因表达比较,证实了富集基因的有效性。结果:通过RNA-seq分析证实小鼠胶原球具有炎症和再生特征。ATAC-seq分析证实,YAP/TAZ-TEAD轴在诱导独特特征中起核心作用。其中,TAZ暗示了其在重编程过程中的相关作用,基于atac的基序分析不仅发现了Tead蛋白,还发现了在胶原球中高度富集的Fra1和Runx2蛋白。此外,人胶原球也显示出高度显著的炎症和胎儿样特征的富集。免疫荧光染色证实,人胶原球的代表性基因在溃疡性结肠炎炎症区高度表达。结论:I型胶原蛋白对小鼠和人类重编程炎症特征的获得有显著影响。本研究中对细胞命运转化及其机制的解剖可以增强我们对炎症的上皮特征如何受到ECM生态位的影响的理解。
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来源期刊
CiteScore
11.10
自引率
1.20%
发文量
45
审稿时长
11 weeks
期刊介绍: Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration (JSIR). This journal provides an open access forum which covers a wide range of scientific topics in the basic and clinical researches on inflammation and regenerative medicine. It also covers investigations of infectious diseases, including COVID-19 and other emerging infectious diseases, which involve the inflammatory responses. Inflammation and Regeneration publishes papers in the following categories: research article, note, rapid communication, case report, review and clinical drug evaluation.
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