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Nat Commun. 2016 Oct 13;7:13096. doi: 10.1038/ncomms13096.

Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury.

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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.
Department of Medicine, Division of Digestive and Liver Diseases, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA.
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, 10461, USA.
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh EH16 4TJ, UK.


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.

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