Mucosal Macrophages Govern Intestinal Regeneration in Response to Injury

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BACKGROUND & AIMS: Radiation-induced enteritis develops in cancer patients treated with radiotherapy in the abdominal and pelvic cavity, a condition that impairs their quality of life. Radiation injury depletes proliferative intestinal stem cells; in response to this, the epithelium activates a regenerative program that facilitates the healing of the intestine. However, the mechanisms that induce the activation of the intestinal regenerative program are poorly characterized. METHODS: In this study, we induced radiation-induced enteritis in mice through abdominal irradiation, mimicking clinical scenarios. Through imaging and flow cytometric analysis, we investigated the recruitment of macrophages to the small intestine during injury and healing. Additionally, we developed a coculture system for mouse and human intestinal organoids and macrophages to explore the cross talk between these cells. Then by combining in vivo ablation of macrophages, fluorescent lineage tracing, imaging, bulk RNA-sequencing (RNA-seq), single-cell RNA-seq, human intestinal organoids, and cell trajectory analysis, we studied the macrophage induction of intestinal regeneration at the cellular and molecular level. RESULTS: Our findings revealed that macrophages are recruited around the intestinal stem cell compartment upon radiation injury, promoting a fetal-like reprogramming and proliferation of epithelial cells that drives the regeneration process. In contrast, macrophage ablation led to compromised regeneration. Moreover, our single-cell RNA-seq analysis identified key secreted molecules, neuregulin 1 and osteopontin, as pivotal players in regulating this process. Additionally, characterization of human macrophage/organoid cocultures and cell trajectory inference confirmed the conservation of macrophages' role in triggering the regenerative program in primary human cells. CONCLUSIONS: This study identifies macrophages as essential contributors to intestinal regeneration beyond their innate immune response. Targeting macrophages therapeutically may hold promise in enhancing regeneration and improving the quality of life for cancer survivors.

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