Peroxisome Elevation Induces Stem Cell Differentiation and Intestinal Epithelial Repair
Peroxisome Elevation Induces Stem Cell Differentiation and Intestinal Epithelial Repair
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过氧化物酶体升高诱导干细胞分化和肠上皮修复
DOI：
10.1016/j.devcel.2020.03.002
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发表时间：
2020-04-20
影响因子：
11.8
通讯作者：
Chen, Haiyang
中科院分区：
文献类型：
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作者：
Du, Gang;Xiong, Lishou;Chen, Haiyang
上皮修复依赖性粘膜愈合（MH）与炎症性肠病（IBD）患者更有利的预后相关。MH通过肠上皮的修复和再生来完成。然而，MH的潜在机制是不明确的。我们发现炎症性肠病患者受损的隐窝中过氧化物酶体显著上调。通过增加果蝇中肠中过氧化物酶体水平，我们发现过氧化物酶体升高增强了RAB 7依赖的晚期内体成熟，然后通过调节Janus激酶（JAK）和信号转导和转录激活因子（STAT）-SOX 21 A信号传导促进干细胞和/或祖细胞分化。这反过来又增强了ISC介导的再生。重要的是，RAB 7和SOX 21在IBD患者的隐窝中上调。此外，增加过氧化物酶体水平的药物的施用逆转了葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎的症状。这项研究证明了过氧化物酶体介导的上皮修复机制，这为IBD患者MH的增强开辟了治疗途径。
Epithelial-repair-dependent mucosal healing (MH) is associated with a more favorable prognosis for patients with inflammatory bowel disease (IBD). MH is accomplished via repair and regeneration of the intestinal epithelium. However, the mechanism underlying MH is ill defined. We found a striking upregulation of peroxisomes in the injured crypts of IBD patients. By increasing peroxisome levels in Drosophila midguts, we found that peroxisome elevation enhanced RAB7-dependent late endosome maturation, which then promoted stem and/or progenitor-cell differentiation via modulation of Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT)-SOX21A signaling. This in turn enhanced ISC-mediated regeneration. Importantly, RAB7 and SOX21 were upregulated in the crypts of IBD patients. Moreover, administration of drugs that increased peroxisome levels reversed the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice. This study demonstrates a peroxisome-mediated epithelial repair mechanism, which opens a therapeutic avenue for the enhancement of MH in IBD patients.