Mesenchymal Stem and Stromal Cells Harness Macrophage-Derived Amphiregulin to Maintain Tissue Homeostasis

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. [Display omitted] •MSCs enhance macrophage phagocytosis through MSC mitochondria-containing vesicles•MSCs elicit secretion and transcription of amphiregulin in macrophages•Amphiregulin secretion depends on macrophage phagocytosis and MSC vesicle uptake•Macrophage amphiregulin increases Treg cells and preserves epithelial stem cells 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.