Huang Yujun, Tu Siyu, Xu Zhenni, Xu Lu, Wang Xi, Tian Hefei, He Qican, Huang Lingxiao, Lei Xudan, Wang Shubin, Qu Mingyue, Liu Dengqun
School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, PR China.
Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, PR China.
J Pathol. 2025 Feb;265(2):132-145. doi: 10.1002/path.6360. Epub 2025 Jan 3.
Intestinal stem cells (ISCs) and Paneth cells (PCs) reside at the bottom of the crypts of Lieberkühn in the small intestine. Recent studies have shown that the transcription factor Mist1, also named BHLHA15, plays an important role in the maturation of PCs. Since there is an intimate interaction between PCs and ISCs, we speculated that the loss of Mist1 could impact these two neighboring cell types. Here, we report that mice lacking Mist1 had fewer but larger PCs with shrunken secretory granules, accompanied by an increase in goblet cells and tuft cells. Mist1 loss significantly decreased the number of proliferative crypt cells, especially columnar basal cells (CBCs). In addition, Mist1-deficient enteroids needed supplemental Wnt3a to support their growth. Results from RNA sequencing (RNA-seq) demonstrated an apparent deficiency of innate immunity in Mist1-knockout mice. Intriguingly, Mist1 loss increased the survival rate of mice subjected to whole abdominal irradiation (WAI). Moreover, radiation injury was ameliorated in Mist1-knockout mice compared with their wild-type littermates based on histological analysis and enteroid culture, which might be a consequence of increased contents of the endoplasmic reticulum (ER) and the increased activity of mTORC1 in Paneth cells. In summary, our data uncover that Mist1 plays an important functional role in PCs and regulates the maintenance of ISCs and their response to radiation injury. © 2025 The Pathological Society of Great Britain and Ireland.
肠道干细胞（ISCs）和潘氏细胞（PCs）位于小肠的利伯kühn隐窝底部。最近的研究表明，转录因子Mist1，也称为BHLHA15，在潘氏细胞的成熟过程中起重要作用。由于潘氏细胞和肠道干细胞之间存在密切的相互作用，我们推测Mist1的缺失可能会影响这两种相邻的细胞类型。在此，我们报告缺乏Mist1的小鼠的潘氏细胞数量减少但体积增大，分泌颗粒萎缩，同时杯状细胞和簇状细胞数量增加。Mist1的缺失显著减少了增殖性隐窝细胞的数量，尤其是柱状基底细胞（CBCs）。此外，缺乏Mist1的肠上皮细胞需要补充Wnt3a来支持其生长。RNA测序（RNA-seq）结果表明，Mist1基因敲除小鼠存在明显的先天免疫缺陷。有趣的是，Mist1的缺失提高了接受全腹照射（WAI）小鼠的存活率。此外，基于组织学分析和肠上皮细胞培养，与野生型同窝小鼠相比，Mist1基因敲除小鼠的辐射损伤有所改善，这可能是潘氏细胞内质网（ER）含量增加和mTORC1活性增强的结果。总之，我们的数据揭示了Mist1在潘氏细胞中发挥重要的功能作用，并调节肠道干细胞的维持及其对辐射损伤的反应。© 2025年英国和爱尔兰病理学会。
