Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la recherche, 69000 Lyon, France.
Université de Strasbourg, Inserm, IRFAC/UMR-S1113, FMTS, 67200 Strasbourg, France.
Development. 2021 Apr 15;148(8). doi: 10.1242/dev.194357. Epub 2021 Apr 20.
The thyroid hormone T3 and its nuclear receptor TRα1 control gut development and homeostasis through the modulation of intestinal crypt cell proliferation. Despite increasing data, in-depth analysis on their specific action on intestinal stem cells is lacking. By using ex vivo 3D organoid cultures and molecular approaches, we observed early responses to T3 involving the T3-metabolizing enzyme Dio1 and the transporter Mct10, accompanied by a complex response of stem cell- and progenitor-enriched genes. Interestingly, specific TRα1 loss-of-function (inducible or constitutive) was responsible for low ex vivo organoid development and impaired stem cell activity. T3 treatment of animals in vivo not only confirmed the positive action of this hormone on crypt cell proliferation but also demonstrated its key action in modulating the number of stem cells, the expression of their specific markers and the commitment of progenitors into lineage-specific differentiation. In conclusion, T3 treatment or TRα1 modulation has a rapid and strong effect on intestinal stem cells, broadening our perspectives in the study of T3/TRα1-dependent signaling in these cells.
甲状腺激素 T3 和其核受体 TRα1 通过调节肠隐窝细胞增殖来控制肠道发育和稳态。尽管有越来越多的数据，但缺乏对其在肠道干细胞上的特定作用的深入分析。通过使用离体 3D 类器官培养和分子方法，我们观察到 T3 的早期反应涉及 T3 代谢酶 Dio1 和转运体 Mct10，同时伴随着干细胞和祖细胞富集基因的复杂反应。有趣的是，TRα1 的特定功能丧失（诱导型或组成型）导致离体类器官发育不良和干细胞活性受损。体内 T3 处理不仅证实了该激素对隐窝细胞增殖的积极作用，还证明了其在调节干细胞数量、其特异性标志物的表达以及祖细胞向谱系特异性分化的定向方面的关键作用。总之，T3 处理或 TRα1 调节对肠道干细胞有快速而强大的作用，拓宽了我们在这些细胞中研究 T3/TRα1 依赖性信号的视野。
