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Myeloid Cell-Derived HB-EGF Drives Tissue Recovery After Pancreatitis

dc.contributor.authorWen, Hui-Ju
dc.contributor.authorGao, Shan
dc.contributor.authorWang, Yin
dc.contributor.authorRay, Michael
dc.contributor.authorMagnuson, Mark A.
dc.contributor.authorWright, Christopher V. E.
dc.contributor.authorDi Magliano, Marina Pasca
dc.contributor.authorFrankel, Timothy L.
dc.contributor.authorCrawford, Howard C.
dc.identifier.citationWen, H. J., Gao, S., Wang, Y., Ray, M., Magnuson, M. A., Wright, C., Di Magliano, M. P., Frankel, T. L., & Crawford, H. C. (2019). Myeloid Cell-Derived HB-EGF Drives Tissue Recovery After Pancreatitis. Cellular and molecular gastroenterology and hepatology, 8(2), 173–192.
dc.description.abstractBACKGROUND & AIMS: Pancreatitis is a major cause of morbidity and mortality and is a risk factor for pancreatic tumorigenesis. Upon tissue damage, an inflammatory response, made up largely of macrophages, provides multiple growth factors that promote repair. Here, we examine the molecular pathways initiated by macrophages to promote pancreas recovery from pancreatitis. METHODS: To induce organ damage, mice were subjected to cerulein-induced experimental pancreatitis and analyzed at various times of recovery. CD11b-DTR mice were used to deplete myeloid cells. Hbeg(f/f);LysM-Cre mice were used to ablate myeloid cell-derived heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF). To ablate EGFR specifically during recovery, pancreatitis was induced in Egfr(f/f);Ptf1a(Flp0/+);FSF-Rosa26(CAG-CreERT2 )mice followed by tamoxifen treatment. RESULTS: Macrophages infiltrating the pancreas in experimental pancreatitis make high levels of HB-EGF. Both depletion of myeloid cells and ablation of myeloid cell HB-EGF delayed recovery from experimental pancreatitis, resulting from a decrease in cell proliferation and an increase in apoptosis. Mechanistically, ablation of myeloid cell HB-EGF impaired epithelial cell DNA repair, ultimately leading to cell death. Soluble HB-EGF induced EGFR nuclear translocation and methylation of histone H4, facilitating resolution of DNA damage in pancreatic acinar cells in vitro. Consistent with its role as the primary receptor of HB-EGF, in vivo ablation of EGFR from pancreatic epithelium during recovery from pancreatitis resulted in accumulation of DNA damage. CONCLUSIONS: By using novel conditional knockout mouse models, we determined that HB-EGF derived exclusively from myeloid cells induces epithelial cell proliferation and EGFR-dependent DNA repair, facilitating pancreas healing after injury.en_US
dc.description.sponsorshipThis study was supported by National Institutes of Health grants R01CA159222 (H.C.C.), U01CA224145 (H.C.C. and M.P.d.M.), R01CA151588 and R01CA198074 (M.P.d.M.), UO1DK089570 (C.V.E.W.), U01DK072473 (to the Vanderbilt Transgenic/Embryonic Stem Cell Shared Resource core facility and Beta Cell Biology Consortium Mouse Embryonic Stem Cell Core), and CA68485, DK20593, DK58404, and DK59637 (for Vanderbilt Cell Imaging Shared Resource using imaging scholarships from the Vanderbilt University Medical Center Digestive Disease Research Center and Diabetes Research and Training Center and the Vanderbilt-Ingram Cancer Center); and National Cancer Institute grant K08CA201581 (T.L.F.), and Cancer Center Core grant P30CA46592 (Rogel Cancer Center, University of Michigan). Additional support was provided by the Sky Foundation (Detroit, MI) (H.C.C.).en_US
dc.publisherCellular and Molecular Gastroenterology and Hepatologyen_US
dc.rightsCopyright © 2019 The Authors This is an open access article under the CC BY-NC-ND license (
dc.subjectDNA Damageen_US
dc.titleMyeloid Cell-Derived HB-EGF Drives Tissue Recovery After Pancreatitisen_US

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