Autophagy in PDGFRA+ mesenchymal cells is required for intestinal homeostasis and mammalian survival.
Autophagy in PDGFRA+ mesenchymal cells is required for intestinal homeostasis and mammalian survival.
复制标题
PDGFRA 间充质细胞中的自噬是肠道稳态和哺乳动物生存所必需的。
DOI：
10.1080/15548627.2022.2090694
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发表时间：
2023
期刊：
影响因子：
13.3
通讯作者：
White,Eileen
中科院分区：
文献类型：
--
作者：
Yang,Yang;White,Eileen
巨自噬/自噬缺陷是炎症性肠病（IBD）的危险因素，但其机制尚不清楚。我们之前证明了成年小鼠（atg 7 Δ/Δ）中essentialAtg 7（自噬相关7）基因的条件性全身缺失会导致特定的组织损伤，并将寿命缩短至三个月，主要是由于神经变性，令人惊讶的是对肠道没有干扰作用。相比之下，我们最近发现，其他必需的自噬基因Atg 5或Rb 1cc 1/Fip 200（atg 5 Δ/Δ或rb 1cc 1 Δ/Δ）的条件性全身缺失，由于自噬的快速抑制，肠道干细胞的消除和回肠屏障功能的丧失，在5天内导致死亡。atg 5 Δ/Δ小鼠失去PDGFRA/PDGFRα+间充质细胞（PMC）和干细胞更新所必需的WNT信号。新型质谱成像（MALDI-MSI）显示，在tg 5 Δ/Δ回肠中天冬氨酸和核苷酸消耗，与潜在PMC损失的代谢功能不全一致。自噬基因敲除表型的差异可能是由于自噬丧失的不同动力学，因为逐渐的全身atg 5缺失延长了寿命，表型模仿Atg 7或Atg 12的缺失。因此，我们确定自噬是回肠PMC代谢、干细胞维持和哺乳动物存活所必需的。因此，由自噬缺陷引起的PMC损失可能有助于IBD。
Macroautophagy/autophagy defects are a risk factor for inflamatory bowel disease (IBD), but the mechanism remains unclear. We previously demonstrated that conditional whole-body deletion of the essentialAtg7(autophagy related 7) gene in adult mice (atg7Δ/Δ) causes specific tissue damage and shortens lifespan to three months primarily due to neurodegeneration with surprisingly no disturbing effects on the intestine. In contrast, we recently found that conditional whole-body deletion of other essential autophagy genes,Atg5orRb1cc1/Fip200(atg5Δ/Δor rb1cc1Δ/Δ), cause death within five days due to rapid inhibition of autophagy, elimination of intestinal stem cells, and loss of barrier function in the ileum.atg5Δ/Δmice lose PDGFRA/PDGFRα+mesenchymal cells (PMCs) and WNT signaling essential for stem cell renewal. Depletion of aspartate and nucleotides inatg5Δ/Δileum was revealed by novel mass-spectrometry imaging (MALDI-MSI), consistent with metabolic insufficiency underlying PMCs loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss because gradual whole-bodyatg5deletion extends lifespan, phenocopying deletion ofAtg7orAtg12. Therefore, we established that autophagy is required for ileum PMC metabolism, stem cell maintenance and mammalian survival. PMC loss caused by autophagy deficiency may therefore contribute to IBD.