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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Singapore
2020
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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. |
format | Online Article Text |
id | pubmed-7376085 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer Singapore |
record_format | MEDLINE/PubMed |
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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