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Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium

BACKGROUND: The esophagus is known to be derived from the foregut. However, the mechanisms regulating this process remain unclear. In particular, the details of the human esophagus itself have been poorly researched. In this decade, studies using human induced pluripotent stem cells (hiPSCs) have pr...

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Autores principales: Koterazawa, Yasufumi, Koyanagi-Aoi, Michiyo, Uehara, Keiichiro, Kakeji, Yoshihiro, Aoi, Takashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Singapore 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376085/
https://www.ncbi.nlm.nih.gov/pubmed/32556644
http://dx.doi.org/10.1007/s00535-020-01695-7
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author Koterazawa, Yasufumi
Koyanagi-Aoi, Michiyo
Uehara, Keiichiro
Kakeji, Yoshihiro
Aoi, Takashi
author_facet Koterazawa, Yasufumi
Koyanagi-Aoi, Michiyo
Uehara, Keiichiro
Kakeji, Yoshihiro
Aoi, Takashi
author_sort Koterazawa, Yasufumi
collection PubMed
description BACKGROUND: The esophagus is known to be derived from the foregut. However, the mechanisms regulating this process remain unclear. In particular, the details of the human esophagus itself have been poorly researched. In this decade, studies using human induced pluripotent stem cells (hiPSCs) have proven powerful tools for clarifying the developmental biology of various human organs. Several studies using hiPSCs have demonstrated that retinoic acid (RA) signaling promotes the differentiation of foregut into tissues such as lung and pancreas. However, the effect of RA signaling on the differentiation of foregut into esophagus remains unclear. METHODS: We established a novel stepwise protocol with transwell culture and an air–liquid interface system for esophageal epithelial cell (EEC) differentiation from hiPSCs. We then evaluated the effect of all-trans retinoic acid (ATRA), which is a retinoic acid receptor (RAR)α, RARβ and RARγ agonist, on the differentiation from the hiPSC-derived foregut. Finally, to identify which RAR subtype was involved in the differentiation, we used synthetic agonists and antagonists of RARα and RARγ, which are known to be expressed in esophagus. RESULTS: We successfully generated stratified layers of cells expressing EEC marker genes that were positive for lugol staining. The enhancing effect of ATRA on EEC differentiation was clearly demonstrated with quantitative reverse transcription polymerase chain reaction, immunohistology, lugol-staining and RNA sequencing analyses. RARγ agonist and antagonist enhanced and suppressed EEC differentiation, respectively. RARα agonist had no effect on the differentiation. CONCLUSION: We revealed that RARγ activation promotes the differentiation of hiPSCs-derived foregut into EECs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00535-020-01695-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-73760852020-07-27 Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium Koterazawa, Yasufumi Koyanagi-Aoi, Michiyo Uehara, Keiichiro Kakeji, Yoshihiro Aoi, Takashi J Gastroenterol Original Article—Alimentary Tract BACKGROUND: The esophagus is known to be derived from the foregut. However, the mechanisms regulating this process remain unclear. In particular, the details of the human esophagus itself have been poorly researched. In this decade, studies using human induced pluripotent stem cells (hiPSCs) have proven powerful tools for clarifying the developmental biology of various human organs. Several studies using hiPSCs have demonstrated that retinoic acid (RA) signaling promotes the differentiation of foregut into tissues such as lung and pancreas. However, the effect of RA signaling on the differentiation of foregut into esophagus remains unclear. METHODS: We established a novel stepwise protocol with transwell culture and an air–liquid interface system for esophageal epithelial cell (EEC) differentiation from hiPSCs. We then evaluated the effect of all-trans retinoic acid (ATRA), which is a retinoic acid receptor (RAR)α, RARβ and RARγ agonist, on the differentiation from the hiPSC-derived foregut. Finally, to identify which RAR subtype was involved in the differentiation, we used synthetic agonists and antagonists of RARα and RARγ, which are known to be expressed in esophagus. RESULTS: We successfully generated stratified layers of cells expressing EEC marker genes that were positive for lugol staining. The enhancing effect of ATRA on EEC differentiation was clearly demonstrated with quantitative reverse transcription polymerase chain reaction, immunohistology, lugol-staining and RNA sequencing analyses. RARγ agonist and antagonist enhanced and suppressed EEC differentiation, respectively. RARα agonist had no effect on the differentiation. CONCLUSION: We revealed that RARγ activation promotes the differentiation of hiPSCs-derived foregut into EECs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00535-020-01695-7) contains supplementary material, which is available to authorized users. Springer Singapore 2020-06-16 2020 /pmc/articles/PMC7376085/ /pubmed/32556644 http://dx.doi.org/10.1007/s00535-020-01695-7 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Article—Alimentary Tract
Koterazawa, Yasufumi
Koyanagi-Aoi, Michiyo
Uehara, Keiichiro
Kakeji, Yoshihiro
Aoi, Takashi
Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium
title Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium
title_full Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium
title_fullStr Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium
title_full_unstemmed Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium
title_short Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium
title_sort retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium
topic Original Article—Alimentary Tract
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376085/
https://www.ncbi.nlm.nih.gov/pubmed/32556644
http://dx.doi.org/10.1007/s00535-020-01695-7
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