MicroRNA-200 Loaded Lipid Nanoparticles Promote Intestinal Epithelium Regeneration in Canonical MicroRNA-Deficient Mice.
MicroRNA-200 Loaded Lipid Nanoparticles Promote Intestinal Epithelium Regeneration in Canonical MicroRNA-Deficient Mice.
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DOI：
10.1021/acsnano.3c08030
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发表时间：
2023-11-28
期刊：
影响因子：
17.1
通讯作者：
Chen YG
中科院分区：
文献类型：
--
作者：
Wei X;Yu S;Zhang T;Liu L;Wang X;Wang X;Chan YS;Wang Y;Meng S;Chen YG
肠上皮在损伤后经历再生，并且该过程的中断可导致炎性肠病和肿瘤发生。肠干细胞（ISCs）居住在隐窝是至关重要的，以维持肠上皮的稳态和促进再生损伤后。然而，DGCR 8（microRNA（miRNA）生物合成的关键组分）在肠道再生中的确切作用仍然知之甚少。在这项研究中，我们提供了令人信服的证据，证明上皮miRNA在5-FU或辐射诱导损伤的小鼠肠再生中不可或缺的作用。通过对Dgcr 8缺陷型类器官中miRNA功能的全面汇总筛选，我们观察到miR-200家族的缺失导致p53通路的过度活化，从而减少ISC并损害上皮再生。值得注意的是，miR-200家族的下调和p53通路的过度活化在来自患有活动性溃疡性结肠炎（UC）的患者的结肠组织中得到证实。最重要的是，通过口服递送携带miR-200的脂质纳米颗粒（LNP）瞬时供应miR-200恢复了小鼠急性损伤后的ISC并促进肠再生。我们的研究表明，miR-200/p53通路是miR-200家族水平降低的活动性UC患者有希望的治疗靶点。此外，我们的研究结果表明，LNP-miRNAs的临床应用可以提高肠道疾病现有治疗方式的有效性，安全性和可接受性。
Intestinal epithelium undergoes regeneration after injuries, and the disruption of this process can lead to inflammatory bowel disease and tumorigenesis. Intestinal stem cells (ISCs) residing in the crypts are crucial for maintaining the intestinal epithelium’s homeostasis and promoting regeneration upon injury. However, the precise role of DGCR8, a critical component in microRNA (miRNA) biogenesis, in intestinal regeneration remains poorly understood. In this study, we provide compelling evidence demonstrating the indispensable role of epithelial miRNAs in the regeneration of the intestine in mice subjected to 5-FU or irradiation-induced injury. Through a comprehensive pooled screen of miRNA function in Dgcr8-deficient organoids, we observe that the loss of the miR-200 family leads to the hyperactivation of the p53 pathway, thereby reducing ISCs and impairing epithelial regeneration. Notably, downregulation of the miR-200 family and hyperactivation of the p53 pathway are verified in colonic tissues from patients with active ulcerative colitis (UC). Most importantly, the transient supply of miR-200 through the oral delivery of lipid nanoparticles (LNPs) carrying miR-200 restores ISCs and promotes intestinal regeneration in mice following acute injury. Our study implies the miR-200/p53 pathway as a promising therapeutic target for active UC patients with diminished levels of the miR-200 family. Furthermore, our findings suggest that the clinical application of LNP-miRNAs could enhance the efficacy, safety, and acceptability of existing therapeutic modalities for intestinal diseases.
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