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

IF 5 3区 医学 Q2 IMMUNOLOGY Inflammation and Regeneration Pub Date : 2023-07-13 DOI:10.1186/s41232-023-00282-6
Min Kyoung Jo, Chang Mo Moon, Hyeon-Jeong Jeon, Yerim Han, Eun Sook Lee, Ji-Hee Kwon, Kyung-Min Yang, Young-Ho Ahn, Seong-Eun Kim, Sung-Ae Jung, Tae Il Kim
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Abstract

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 p16INK4a, 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-p16INK4a signaling.

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衰老通过TGF-β-Smad3信号通路改变细胞周期阻滞对结肠上皮类器官形成和生长的影响
背景:本研究旨在通过类器官模型研究衰老如何改变组织损伤后结肠肠上皮的稳态和再生,并确定其潜在的分子机制。方法:为研究老年(80周龄以上)小鼠和幼龄(6-10周龄)小鼠结肠上皮的衰老相关变化,分别进行类器官培养,比较两组小鼠第0代第5天类器官的数量、大小和生长速度。结果:老年小鼠类器官的数量和大小明显低于年轻小鼠(p INK4a),老年小鼠类器官的细胞周期阻滞增加。1型TGF-β受体抑制剂SB431542可显著促进老年小鼠类器官的形成和生长,TGF-β1可显著抑制年轻小鼠类器官的形成。在急性葡聚糖硫酸钠结肠炎模型及其类器官实验中,老龄小鼠组织损伤后的结肠上皮再生明显低于年轻小鼠。结论:衰老通过TGF-β-Smad3-p16INK4a信号通路增加细胞周期阻滞,从而降低结肠上皮类器官的形成能力和生长速度。
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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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