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

Authors

Subhrajit Saha, Albert Einstein College of Medicine of Yeshiva University
Evelyn Aranda, Albert Einstein College of Medicine of Yeshiva University
Yoku Hayakawa, Columbia University Irving Medical Center
Payel Bhanja, Albert Einstein College of Medicine of Yeshiva University
Safinur Atay, University of Kansas Medical
N. Patrik Brodin, Albert Einstein College of Medicine of Yeshiva University
Jiufeng Li, Albert Einstein College of Medicine of Yeshiva University
Samuel Asfaha, Columbia University Irving Medical CenterFollow
Laibin Liu, Albert Einstein College of Medicine of Yeshiva University
Yagnesh Tailor, Columbia University Irving Medical Center
Jinghang Zhang, Albert Einstein College of Medicine of Yeshiva University
Andrew K. Godwin, University of Kansas Medical
Wolfgang A. Tome, Albert Einstein College of Medicine of Yeshiva University
Timothy C. Wang, Columbia University Irving Medical Center
Chandan Guha, Albert Einstein College of Medicine of Yeshiva University
Jeffrey W. Pollard, Albert Einstein College of Medicine of Yeshiva University

Document Type

Article

Publication Date

10-13-2016

Journal

Nature Communications

Volume

7

URL with Digital Object Identifier

10.1038/ncomms13096

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.