Department of Radiation Oncology, Albert Einstein College of Medicine &Montefiore Medical Center, Bronx, New York 10461, USA.
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Nat Commun. 2016 Oct 13;7:13096. doi: 10.1038/ncomms13096.
WNT/β-catenin signalling is crucial for intestinal homoeostasis. The intestinal epithelium and stroma are the major source of WNT ligands but their origin and role in intestinal stem cell (ISC) and epithelial repair remains unknown. Macrophages are a major constituent of the intestinal stroma. Here, we analyse the role of macrophage-derived WNT in intestinal repair in mice by inhibiting their release using a macrophage-restricted ablation of Porcupine, a gene essential for WNT synthesis. Such Porcn-depleted mice have normal intestinal morphology but are hypersensitive to radiation injury in the intestine compared with wild-type (WT) littermates. Porcn-null mice are rescued from radiation lethality by treatment with WT but not Porcn-null bone marrow macrophage-conditioned medium (CM). Depletion of extracellular vesicles (EV) from the macrophage CM removes WNT function and its ability to rescue ISCs from radiation lethality. Therefore macrophage-derived EV-packaged WNTs are essential for regenerative response of intestine against radiation.
WNT/β-catenin 信号通路对于肠道内稳态至关重要。肠道上皮细胞和基质是 WNT 配体的主要来源，但它们在肠道干细胞（ISC）和上皮修复中的起源和作用尚不清楚。巨噬细胞是肠道基质的主要组成部分。在这里，我们通过使用 Porcupine 的巨噬细胞特异性消融来抑制其释放，分析了巨噬细胞衍生的 WNT 在小鼠肠道修复中的作用，Porcupine 是 WNT 合成所必需的基因。与野生型（WT）同窝仔相比，这种 Porcn 缺失的小鼠具有正常的肠道形态，但对肠道辐射损伤更为敏感。用 WT 而不是 Porcn 缺失的骨髓巨噬细胞条件培养基（CM）处理可使 Porcn 缺失的小鼠免于辐射致死。从巨噬细胞 CM 中耗尽细胞外囊泡（EV）会去除 WNT 的功能及其使 ISC 免于辐射致死的能力。因此，巨噬细胞衍生的 EV 包裹的 WNTs 对于肠道对辐射的再生反应是必需的。
