未分化肠道干细胞（ISC）对于维持体内平衡和解决损伤至关重要。隐窝基底中的 Lgr5 细胞不断分裂，将子细胞沿着隐窝轴向上推动，在那里它们分化成特殊的细胞类型。复杂转录程序的协调执行对于维持未分化的干细胞是必要的，同时允许体内平衡所需的各种肠道细胞的分化。此前，骨髓易位基因（MTG）家族的成员已被确定为转录共阻遏物，可调节包括肠道在内的多个器官系统中的干细胞维持和分化程序。 MTG 家族成员之一，髓样易位基因相关 1 (MTGR1)，已被认为是分泌细胞分化和损伤反应的关键调节因子。然而，MTGR1是否有助于ISC的功能尚未得到检验。在这里，我们使用 Mtgr1-/- 小鼠评估了 MTGR1 缺失对 ISC 生物学的影响。有趣的是，MTGR1 的缺失增加了表达 Lgr5（循环 ISC 的典型标记）的细胞总数，表明干细胞总数更高。然而，扩展的转录组和功能分析揭示了 Mtgr1-null ISC 的缺陷，包括失调的 ISC 相关转录程序。在离体实验中，Mtgr1缺失小鼠建立的肠道类器官由于异常分化以及干细胞和增殖细胞的丢失而无法存活和扩增。总之，这些结果表明 MTGR1 在肠道分化中的作用可能是干细胞固有的，并确定了 MTGR1 在维持 ISC 功能中的新作用。© 2024。作者。

Undifferentiated intestinal stem cells (ISCs) are crucial for maintaining homeostasis and resolving injury. Lgr5+ cells in the crypt base constantly divide, pushing daughter cells upward along the crypt axis where they differentiate into specialized cell types. Coordinated execution of complex transcriptional programs is necessary to allow for the maintenance of undifferentiated stem cells while permitting differentiation of the wide array of intestinal cells necessary for homeostasis. Previously, members of the myeloid translocation gene (MTG) family have been identified as transcriptional co-repressors that regulate stem cell maintenance and differentiation programs in multiple organ systems, including the intestine. One MTG family member, myeloid translocation gene related 1 (MTGR1), has been recognized as a crucial regulator of secretory cell differentiation and response to injury. However, whether MTGR1 contributes to the function of ISCs has not yet been examined. Here, using Mtgr1-/- mice, we have assessed the effects of MTGR1 loss specifically in ISC biology. Interestingly, loss of MTGR1 increased the total number of cells expressing Lgr5, the canonical marker of cycling ISCs, suggesting higher overall stem cell numbers. However, expanded transcriptomic and functional analyses revealed deficiencies in Mtgr1-null ISCs, including deregulated ISC-associated transcriptional programs. Ex vivo, intestinal organoids established from Mtgr1-null mice were unable to survive and expand due to aberrant differentiation and loss of stem and proliferative cells. Together, these results indicate that the role of MTGR1 in intestinal differentiation is likely stem cell intrinsic and identify a novel role for MTGR1 in maintaining ISC function.© 2024. The Author(s).