Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, Guangdong, China; Laboratory for Stem Cell and anti-Aging Research, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
Dev Cell. 2020 Apr 20;53(2):169-184.e11. doi: 10.1016/j.devcel.2020.03.002. Epub 2020 Apr 2.
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.
上皮修复依赖性黏膜愈合（MH）与炎症性肠病（IBD）患者的预后更有利相关。MH 通过肠上皮的修复和再生来实现。然而，MH 的机制尚未明确。我们发现在 IBD 患者受损的隐窝中过氧化物酶体明显上调。通过增加果蝇中肠的过氧化物酶体水平，我们发现过氧化物酶体的升高增强了 RAB7 依赖性晚期内体成熟，进而通过调节 Janus 激酶（JAK）和信号转导及转录激活因子（STAT）-SOX21A 信号促进干细胞和/或祖细胞分化。这反过来又增强了 ISC 介导的再生。重要的是，RAB7 和 SOX21 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给药逆转了 DSS 诱导的小鼠结肠炎的症状。这项研究表明了一种过氧化物酶体介导的上皮修复机制，为增强 IBD 患者的 MH 开辟了治疗途径。
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