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体信号调节肠干细胞平衡和适应饮食

Chia-Wei Cheng¹, Moshe Biton², Adam L Haber³

¹Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.

|August 24, 2019

概括

体,如β-甲酸 (βOHB),对于肠干细胞 (ISC) 功能至关重要. 饮食影响βOHB水平,影响ISC自我更新和组织修复的分化.

科学领域:

代谢学
干细胞生物学
胃肠病学

背景情况:

代谢物在组织特异性干细胞功能和生理学调节中起着至关重要的作用.
关联代谢物与肠干细胞 (ISC) 行为的具体机制尚不清楚.

研究的目的:

研究3-基-3-甲基-CoA合成酶2 (Hmgcs2) 和它的产物β-基酸盐 (βOHB) 在哺乳动物小肠干细胞功能中的作用.
阐明βOHB如何影响ISC自我更新,分化和对饮食变化的反应.

主要方法:

在Lgr5+ISC中对Hmgcs2表达的分析与分化肠细胞的分析.
在Hmgcs2基因操纵后评估ISC中的βOHB水平.
使用外源βOHB和I类基因脱乙酶 (HDAC) 抑制剂的救援实验.
在不同的饮食条件下评估ISC功能和再生 (基因与葡萄糖补充).

主要成果:

Hmgcs2表达区分了自我更新的Lgr5+ISC与其他肠道细胞类型.
Hmgcs2的损失降低了ISC中的βOHB,导致分泌命运的差异化.
外源性βOHB和HDAC抑制剂可以挽救分化表型.
βOHB抑制了HDAC,加强了ISC自我更新和谱系决策的关键信号.
性饮食通过βOHB介导的Notch信号增强ISC功能和再生,而补充葡萄糖的饮食则具有相反的效果.

结论:

β-基酸盐 (βOHB) 是调节肠干细胞自我更新和分化的关键代谢物.
通过调节βOHB水平和相关信号通路,饮食摄入显著影响ISC功能和肠道再生.
针对βOHB激活的信号提供了一个调节干细胞适应肠道平衡和损伤的潜在策略.

关键词:

在HDAC Hmgcs2 其他肠道干细胞没有贝塔-基酸基因饮食体

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