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, Jeffrey W. Pollard

Research output: Contribution to journalArticle

68 Scopus citations

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.

Original languageEnglish (US)
Article number13096
JournalNature communications
Volume7
DOIs
StatePublished - Oct 13 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Saha, S., Aranda, E., Hayakawa, Y., Bhanja, P., Atay, S., Brodin, N. P., Li, J., Asfaha, S., Liu, L., Tailor, Y., Zhang, J., Godwin, A. K., Tome, W. A., Wang, T. C., Guha, C., & Pollard, J. W. (2016). Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury. Nature communications, 7, [13096]. https://doi.org/10.1038/ncomms13096