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

• Published in: Nature communications 2016-10, Vol.7 (1), p.13096-16, Article 13096
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: 13/100; 13/106; 13/31; 13/51; 14/19; 14/63; 631/532/2437; 631/80; 82; 82/51; Ablation; Acyltransferases - genetics; Acyltransferases - metabolism; Animals; Bone marrow; Cells, Cultured; Extracellular vesicles; Extracellular Vesicles - metabolism; Female; Growth factors; Humanities and Social Sciences; Intestinal Mucosa - cytology; Intestinal Mucosa - metabolism; Kaplan-Meier Estimate; Ligands; Macrophages - metabolism; Male; Medical schools; Medicine; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; multidisciplinary; Oncology; Radiation; Radiation Injuries - genetics; Radiation Injuries - metabolism; Science; Science (multidisciplinary); Stem cells; Stem Cells - metabolism; Wnt Proteins - metabolism; Wnt Signaling Pathway
• ISSN: 2041-1723; 2041-1723
• 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. 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.