Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury.
Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury.
复制标题
DOI：
10.1038/ncomms13096
复制
发表时间：
2016-10-13
影响因子：
16.6
通讯作者：
Pollard, Jeffrey W.
中科院分区：
文献类型：
--
作者：
Saha, Subhrajit;Aranda, Evelyn;Hayakawa, Yoku;Bhanja, Payel;Atay, Safinur;Brodin, N. Patrik;Li, Jiufeng;Asfaha, Samuel;Liu, Laibin;Tailor, Yagnesh;Zhang, Jinghang;Godwin, Andrew K.;Tome, Wolfgang A.;Wang, Timothy C.;Guha, Chandan;Pollard, Jeffrey W.
WNT/β-catenin信号传导对肠道内稳态至关重要。肠上皮和间质是WNT配体的主要来源，但它们的来源和在肠干细胞（ISC）和上皮修复中的作用仍不清楚。巨噬细胞是肠基质的主要成分。在这里，我们分析了巨噬细胞衍生的WNT在小鼠肠道修复中的作用，通过使用巨噬细胞限制性消融豪猪，WNT合成所必需的基因来抑制它们的释放。这种Porcn耗尽的小鼠具有正常的肠形态，但与野生型（WT）同窝出生的小鼠相比，对肠中的辐射损伤过敏。通过用WT而不是Porcn缺失的骨髓巨噬细胞条件培养基（CM）处理，将Porcn缺失的小鼠从辐射致死中拯救出来。从巨噬细胞CM消耗细胞外囊泡（EV）去除WNT功能及其从辐射致死中拯救ISC的能力。因此，巨噬细胞来源的EV包装的WNT对于肠道对辐射的再生反应是必不可少的。肠间质分泌WNT配体，但WNT在肠修复中的作用尚不清楚。在这里，作者表明，当从间质巨噬细胞中消除WNT合成时，肠形态正常，但对辐射损伤过敏，暗示巨噬细胞衍生的WNT参与肠修复。
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. The intestinal stroma secretes WNT ligands but the role of WNT in intestinal repair is unclear. Here, the authors show that when WNT synthesis is ablated from stromal macrophages, the intestine morphology is normal but hypersensitive to radiation injury, implicating macrophage-derived WNT in intestinal repair.
登录
查看更多内容
影响因子：
24.5
作者：
Hayakawa Y;Jin G;Wang H;Chen X;Westphalen CB;Asfaha S;Renz BW;Ariyama H;Dubeykovskaya ZA;Takemoto Y;Lee Y;Muley A;Tailor Y;Chen D;Muthupalani S;Fox JG;Shulkes A;Worthley DL;Takaishi S;Wang TC
通讯作者：
Wang TC
影响因子：
16.6
作者：
Leibowitz, Brian J.;Wei, Liang;Zhang, Lin;Ping, Xiaochun;Epperly, Michael;Greenberger, Joel;Cheng, Tao;Yu, Jian
通讯作者：
Yu, Jian
影响因子：
64.8
作者：
Buczacki, Simon J. A.;Zecchini, Heather Ireland;Winton, Douglas J.
通讯作者：
Winton, Douglas J.
影响因子：
8
作者：
Coombs, G. S.;Schmitt, A. A.;Canning, C. A.;Alok, A.;Low, I. C. C.;Banerjee, N.;Kaur, S.;Utomo, V.;Jones, C. M.;Pervaiz, S.;Toone, E. J.;Virshup, D. M.
通讯作者：
Virshup, D. M.
影响因子：
82.9
作者：
通讯作者：
--