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.
Highlights
WNT/b-catenin signalling is crucial for intestinal homoeostasis
We have recently reported that the radiation-induced gastrointestinal syndrome (RIGS) results from a combination of radiation-induced loss of crypt progenitors and stromal cells along with aberrant signalling in the intestinal stem cell (ISC) niches[2]
Macrophage-specific deletion of Porcn was confirmed at the expression level by PCR of DNA isolated from BMMf, pulmonary and crypt epithelial cells and hepatocytes of Csf1r.iCre;Porcnfl/fl mice
Summary
WNT/b-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. Transplantation of the bone marrow-derived adherent stromal cell population depleted of all CD11b þ ve myeloid cells failed to rescue mice from lethal radiation injury[2]. In a mouse model of colitis, it has been shown TLR-mediated activation of colonic macrophages is critical for regeneration of colonic progenitors[4] While these earlier studies have outlined a role for macrophages in promoting intestinal regeneration, the effect of macrophages on survival and proliferation of ISCs and the nature of the signals that are transmitted has not been elucidated. Several reports, have demonstrated that Rspondin 1 (RSPO1), an ISC growth factor and LGR5 receptor agonist, activates WNT/bcatenin pathway to repair and regenerate the intestine following chemo-radiation-induced injury[9,10,11,12]. Systemic administration of DKK1, a negative regulator WNT/b-catenin pathway, impairs the RSPO1-induced intestinal regeneration[13]
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