Intestinal stem cells (ISCs) initiate intestinal epithelial regeneration and tumorigenesis, and they experience rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence. It is crucial to reveal the mechanism underlying such plasticity for intestinal health. Recent studies have found that metabolic pathways control stem cell fate in homeostasis, but the role of metabolism in the regeneration of ISCs after damage has not been clarified. Here, we find that in a human colorectal cancer dataset, miR-29a and b (miR-29a/b) are metabolic regulators highly associated with intestinal tumorigenesis and worse prognostic value of radiotherapy. We also show that these two microRNAs are required for intestinal stemness maintenance in mice, and their expression is induced in regenerated ISCs after irradiation injury, resulting in skewed ISC fate from differentiation towards self-renewal. This upregulation of miR-29a/b expression in ISCs leads to suppression of fatty acid oxidation (FAO) and depression of oxidative phosphorylation, which in turn controls the balance between self-renewal and differentiation of ISCs. Deletion of miR-29a/b prevents these effects and thus impairs ISC-mediated epithelial recovery. Finally, we filter the potential targets of miR-29a/b and identify Hnf4g, a transcription factor, that drives this metabolic reprogramming through regulating FAO-related enzymes. Our work discovers an important metabolic mechanism of ISC-mediated regeneration and potentially pave the way for more targeted and effective therapeutic strategies for intestinal repair as well as tumor treatment.

中文翻译：

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肠道干细胞的再生由 miR-29 诱导的代谢重编程驱动


肠道干细胞 （ISC） 启动肠上皮再生和肿瘤发生，它们在各种损伤后经历快速再充盈以进行上皮修复和肿瘤复发。揭示这种可塑性对肠道健康的潜在机制至关重要。最近的研究发现，代谢途径在体内平衡中控制干细胞的命运，但代谢在 ISCs 损伤后再生中的作用尚未阐明。在这里，我们发现在人类结直肠癌数据集中，miR-29a 和 b （miR-29a/b） 是与肠道肿瘤发生高度相关的代谢调节因子，放疗的预后价值较差。我们还表明，这两种 microRNA 是小鼠肠道干性维持所必需的，并且在照射损伤后在再生的 ISC 中诱导它们的表达，导致 ISC 命运从分化到自我更新的偏斜。ISC 中 miR-29a/b 表达的上调导致脂肪酸氧化 （FAO） 的抑制和氧化磷酸化的抑制，这反过来又控制了 ISC 自我更新和分化之间的平衡。miR-29a/b 的缺失会阻止这些作用，从而损害 ISC 介导的上皮恢复。最后，我们过滤 miR-29a/b 的潜在靶标并鉴定 Hnf4g，一种转录因子，通过调节 FAO 相关酶来驱动这种代谢重编程。我们的工作发现了 ISC 介导的再生的重要代谢机制，并可能为更针对性和更有效的肠道修复和肿瘤治疗策略铺平道路。