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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-αV 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. Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.


Carlos M Minutti, Rucha V Modak, Felicity Macdonald, Fengqi Li, Danielle J Smyth, David A Dorward, Natalie Blair, Connor Husovsky, Andrew Muir, Evangelos Giampazolias, Ross Dobie, Rick M Maizels, Timothy J Kendall, David W Griggs, Manfred Kopf, Neil C Henderson, Dietmar M Zaiss. A Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation. Immunity. 2019 Mar 19;50(3):645-654.e6

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PMID: 30770250

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