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

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

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13096

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