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

doi:10.1038/ncomms13096

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

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186 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 language	English (US)
Article number	13096
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13096
State	Published - Oct 13 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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, Article 13096. https://doi.org/10.1038/ncomms13096

Saha, S, Aranda, E, Hayakawa, Y, Bhanja, P, Atay, S, Brodin, NP, Li, J, Asfaha, S, Liu, L, Tailor, Y, Zhang, J, Godwin, AK, Tome, WA, Wang, TC, Guha, C & Pollard, JW 2016, 'Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury', Nature communications, vol. 7, 13096. https://doi.org/10.1038/ncomms13096

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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.",

author = "Subhrajit Saha and Evelyn Aranda and Yoku Hayakawa and Payel Bhanja and Safinur Atay and Brodin, {N. Patrik} and Jiufeng Li and Samuel Asfaha and Laibin Liu and Yagnesh Tailor and Jinghang Zhang and Godwin, {Andrew K.} and Tome, {Wolfgang A.} and Wang, {Timothy C.} and Chandan Guha and Pollard, {Jeffrey W.}",

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AU - Atay, Safinur

AU - Brodin, N. Patrik

AU - Li, Jiufeng

AU - Asfaha, Samuel

AU - Liu, Laibin

AU - Tailor, Yagnesh

AU - Zhang, Jinghang

AU - Godwin, Andrew K.

AU - Tome, Wolfgang A.

AU - Wang, Timothy C.

AU - Guha, Chandan

AU - Pollard, Jeffrey W.

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N2 - 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.

AB - 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.

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

Abstract

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