title: Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine &Montefiore Medical Center, Bronx, New York 10461, USA.
authors.forename: Subhrajit
authors.initials: S
authors.lastname: Saha
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Aranda
authors.affiliation: Department of Medicine, Division of Digestive and Liver Diseases, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA.
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine &Montefiore Medical Center, Bronx, New York 10461, USA.
authors.forename: Payel
authors.initials: P
authors.lastname: Bhanja
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Safinur
authors.initials: S
authors.lastname: Atay
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine &Montefiore Medical Center, Bronx, New York 10461, USA.
authors.forename: N Patrik
authors.initials: NP
authors.lastname: Brodin
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Jiufeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Digestive and Liver Diseases, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Asfaha
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine &Montefiore Medical Center, Bronx, New York 10461, USA.
authors.forename: Laibin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Digestive and Liver Diseases, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA.
authors.forename: Yagnesh
authors.initials: Y
authors.lastname: Tailor
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, 10461, USA.
authors.forename: Jinghang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine &Montefiore Medical Center, Bronx, New York 10461, USA.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Tome
authors.affiliation: Department of Medicine, Division of Digestive and Liver Diseases, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine &Montefiore Medical Center, Bronx, New York 10461, USA.|Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Chandan
authors.initials: C
authors.lastname: Guha
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.|MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pollard
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D000067128:Extracellular Vesicles / Q000378:metabolism*; D005260:Female; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011832:Radiation Injuries / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D008565:Membrane Proteins; D051153:Wnt Proteins; D000217:Acyltransferases; C491187:Porcn protein, mouse