biostudies-literatureMinutti CMEuropean UnionMedical Research CouncilWellcome Trust645-654.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC6436929biostudies-literatureUnknown50(3)The epidermal growth factor receptor ligand Amphiregulin has a well-documented role in the restoration of tissue homeostasis after injury; however, the mechanism by which Amphiregulin contributes to wound repair remains unknown. Here we show that Amphiregulin functioned by releasing bioactive transforming growth factor beta (TGF-β) from latent complexes via integrin-α_V activation. Using acute injury models in two different tissues, we found that by inducing TGF-β activation on mesenchymal stromal cells (pericytes), Amphiregulin induced their differentiation into myofibroblasts, thereby selectively contributing to the restoration of vascular barrier function within injured tissue. Furthermore, we identified macrophages as a critical source of Amphiregulin, revealing a direct effector mechanism by which these cells contribute to tissue restoration after acute injury. Combined, these observations expose a so far under-appreciated mechanism of how cells of the immune system selectively control the differentiation of tissue progenitor cells during tissue repair and inflammation.ImmunityA Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation.PMC6436929103749/Z/14/Z103749095898/Z/11/Z'106122/A/14/ZMR/M011755/1095898/Z/11/ZMC_PC_18048095898/Z/11/Z'CIG-631413Blair NModak RVDobie RMinutti CMSmyth DJLi FHenderson NCGiampazolias EKopf MMaizels RMGriggs DWDorward DAMuir AMacdonald FKendall TJHusovsky CZaiss DMfalseA Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation.The epidermal growth factor receptor ligand Amphiregulin has a well-documented role in the restoration of tissue homeostasis after injury; however, the mechanism by which Amphiregulin contributes to wound repair remains unknown. Here we show that Amphiregulin functioned by releasing bioactive transforming growth factor beta (TGF-β) from latent complexes via integrin-α_V activation. Using acute injury models in two different tissues, we found that by inducing TGF-β activation on mesenchymal stromal cells (pericytes), Amphiregulin induced their differentiation into myofibroblasts, thereby selectively contributing to the restoration of vascular barrier function within injured tissue. Furthermore, we identified macrophages as a critical source of Amphiregulin, revealing a direct effector mechanism by which these cells contribute to tissue restoration after acute injury. Combined, these observations expose a so far under-appreciated mechanism of how cells of the immune system selectively control the differentiation of tissue progenitor cells during tissue repair and inflammation.2019-01-01T00:00:00Z2019 Mar2026-05-07T03:25:36.925Z2026-04-07T22:34:15.917ZS-EPMC64369293077025010.1016/j.immuni.2019.01.008