Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell–skewed organoid cultures. We found that lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 enzymatically represses genes that are normally expressed only in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium toward a reparative state.

肠道上皮稳态由成体肠道干细胞维持，这些细胞与潘氏细胞一起出现在新生儿出生后。我们旨在通过在潘氏细胞倾斜的类器官培养物中测试一个小型的表观遗传修饰抑制剂库来确定新生儿肠上皮发育的调节因子。我们发现赖氨酸特异性去甲基化酶 1A ( Kdm1a/Lsd1 ) 是潘氏细胞分化所必需的。LSD1-缺乏潘氏细胞的隐窝仍然能够形成类器官，而不需要外源性或内源性 Wnt。从机制上讲，我们发现 LSD1 酶促抑制通常仅在胎儿和新生儿上皮细胞中表达的基因。该基因谱与修复上皮细胞相似，我们发现Lsd1 缺陷的上皮细胞在辐射损伤后具有出色的再生能力。总之，我们发现了一个重要的新生儿肠道发育调节因子，并确定了一个可将肠道上皮重新编程为修复状态的药物靶点。