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Summary: The cross-talk between mesenchymal stem and stromal cells (MSCs) and macrophages is critical for the restoration of tissue homeostasis after injury. Here, we demonstrate a pathway through which MSCs instruct macrophages to resolve inflammation and preserve tissue-specific stem cells, leading to homeostasis in mice with autoimmune uveoretinitis and sterile-injury-induced corneal epithelial stem cell deficiency. Distinct from their conventional role in macrophage reprogramming to anti-inflammatory phenotype by a PGE2-dependent mechanism, MSCs enhance the phagocytic activity of macrophages, which partly depends on the uptake of MSC mitochondria-containing extracellular vesicles. The MSC-primed macrophages increase the secretion of amphiregulin (AREG) in a phagocytosis-dependent manner. AREG is essential for MSC-primed macrophages to suppress immune responses through regulatory T (Treg) cells and to protect corneal epithelial stem cells via apoptosis inhibition and proliferation promotion. Hence, the data reveal that MSCs harness macrophage-derived AREG to maintain tissue homeostasis after injury and provide a therapeutic target in immune-mediated disease and regenerative medicine. : Ko et al. demonstrate that amphiregulin (AREG) is an important growth factor that mediates the cross-talk between immune cells and epithelial cells for inflammation resolution and tissue regeneration, leading to homeostasis after injury. Mesenchymal stem and stromal cells (MSCs) activate this cross-talk by inducing transcription and secretion of AREG in macrophages. Keywords: amphiregulin, autoimmune uveoretinitis, corneal epithelial stem cell, homeostasis, extracellular vesicle, mesenchymal stem and stromal cell, macrophage, phagocytosis, prostaglandin E2, regulatory T cell