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Effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through TGF-β-Smad3 signaling

BACKGROUND: This study aimed to investigate how aging alters the homeostasis of the colonic intestinal epithelium and regeneration after tissue injury using organoid models and to identify its underlying molecular mechanism. METHODS: To investigate aging-related changes in the colonic intestinal epi...

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Autores principales: Jo, Min Kyoung, Moon, Chang Mo, Jeon, Hyeon-Jeong, Han, Yerim, Lee, Eun Sook, Kwon, Ji-Hee, Yang, Kyung-Min, Ahn, Young-Ho, Kim, Seong-Eun, Jung, Sung-Ae, Kim, Tae Il
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339613/
https://www.ncbi.nlm.nih.gov/pubmed/37438837
http://dx.doi.org/10.1186/s41232-023-00282-6
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author Jo, Min Kyoung
Moon, Chang Mo
Jeon, Hyeon-Jeong
Han, Yerim
Lee, Eun Sook
Kwon, Ji-Hee
Yang, Kyung-Min
Ahn, Young-Ho
Kim, Seong-Eun
Jung, Sung-Ae
Kim, Tae Il
author_facet Jo, Min Kyoung
Moon, Chang Mo
Jeon, Hyeon-Jeong
Han, Yerim
Lee, Eun Sook
Kwon, Ji-Hee
Yang, Kyung-Min
Ahn, Young-Ho
Kim, Seong-Eun
Jung, Sung-Ae
Kim, Tae Il
author_sort Jo, Min Kyoung
collection PubMed
description BACKGROUND: This study aimed to investigate how aging alters the homeostasis of the colonic intestinal epithelium and regeneration after tissue injury using organoid models and to identify its underlying molecular mechanism. METHODS: To investigate aging-related changes in the colonic intestinal epithelium, we conducted organoid cultures from old (older than 80 weeks) and young (6–10 weeks) mice and compared the number and size of organoids at day 5 of passage 0 and the growth rate of organoids between the two groups. RESULTS: The number and size of organoids from old mice was significantly lower than that from young mice (p < 0.0001) at day 5 of passage 0. The growth rate of old-mouse organoids from day 4 to 5 of passage 0 was significantly slower than that of young-mouse organoids (2.21 times vs. 1.16 times, p < 0.001). RNA sequencing showed that TGF-β- and cell cycle-associated genes were associated with the aging effect. With regard to mRNA and protein levels, Smad3 and p-Smad3 in the old-mouse organoids were markedly increased compared with those in the young-mouse organoids. Decreased expression of ID1, increased expression of p16(INK4a), and increased cell cycle arrest were observed in the old mouse-organoids. Treatment with SB431542, a type I TGF-β receptor inhibitor, significantly increased the formation and growth of old-mouse organoids, and TGF-β1 treatment markedly suppressed the formation of young-mouse organoids. In the acute dextran sulfate sodium-colitis model and its organoid experiments, the colonic epithelial regeneration after tissue injury in old mice was significantly decreased compared with young mice. CONCLUSIONS: Aging reduced the formation ability and growth rate of colonic epithelial organoids by increasing cell cycle arrest through TGF-β-Smad3-p16(INK4a) signaling. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41232-023-00282-6.
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spelling pubmed-103396132023-07-14 Effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through TGF-β-Smad3 signaling Jo, Min Kyoung Moon, Chang Mo Jeon, Hyeon-Jeong Han, Yerim Lee, Eun Sook Kwon, Ji-Hee Yang, Kyung-Min Ahn, Young-Ho Kim, Seong-Eun Jung, Sung-Ae Kim, Tae Il Inflamm Regen Research Article BACKGROUND: This study aimed to investigate how aging alters the homeostasis of the colonic intestinal epithelium and regeneration after tissue injury using organoid models and to identify its underlying molecular mechanism. METHODS: To investigate aging-related changes in the colonic intestinal epithelium, we conducted organoid cultures from old (older than 80 weeks) and young (6–10 weeks) mice and compared the number and size of organoids at day 5 of passage 0 and the growth rate of organoids between the two groups. RESULTS: The number and size of organoids from old mice was significantly lower than that from young mice (p < 0.0001) at day 5 of passage 0. The growth rate of old-mouse organoids from day 4 to 5 of passage 0 was significantly slower than that of young-mouse organoids (2.21 times vs. 1.16 times, p < 0.001). RNA sequencing showed that TGF-β- and cell cycle-associated genes were associated with the aging effect. With regard to mRNA and protein levels, Smad3 and p-Smad3 in the old-mouse organoids were markedly increased compared with those in the young-mouse organoids. Decreased expression of ID1, increased expression of p16(INK4a), and increased cell cycle arrest were observed in the old mouse-organoids. Treatment with SB431542, a type I TGF-β receptor inhibitor, significantly increased the formation and growth of old-mouse organoids, and TGF-β1 treatment markedly suppressed the formation of young-mouse organoids. In the acute dextran sulfate sodium-colitis model and its organoid experiments, the colonic epithelial regeneration after tissue injury in old mice was significantly decreased compared with young mice. CONCLUSIONS: Aging reduced the formation ability and growth rate of colonic epithelial organoids by increasing cell cycle arrest through TGF-β-Smad3-p16(INK4a) signaling. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41232-023-00282-6. BioMed Central 2023-07-13 /pmc/articles/PMC10339613/ /pubmed/37438837 http://dx.doi.org/10.1186/s41232-023-00282-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Jo, Min Kyoung
Moon, Chang Mo
Jeon, Hyeon-Jeong
Han, Yerim
Lee, Eun Sook
Kwon, Ji-Hee
Yang, Kyung-Min
Ahn, Young-Ho
Kim, Seong-Eun
Jung, Sung-Ae
Kim, Tae Il
Effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through TGF-β-Smad3 signaling
title Effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through TGF-β-Smad3 signaling
title_full Effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through TGF-β-Smad3 signaling
title_fullStr Effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through TGF-β-Smad3 signaling
title_full_unstemmed Effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through TGF-β-Smad3 signaling
title_short Effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through TGF-β-Smad3 signaling
title_sort effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through tgf-β-smad3 signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339613/
https://www.ncbi.nlm.nih.gov/pubmed/37438837
http://dx.doi.org/10.1186/s41232-023-00282-6
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