title: Strain-induced differentiation of fetal type II epithelial cells is mediated via the integrin α6β1-ADAM17/tumor necrosis factor-α-converting enzyme (TACE) signaling pathway.
abstract: Mechanical forces are critical for normal fetal lung development. However, the mechanisms regulating this process are not well-characterized. We hypothesized that strain-induced release of HB-EGF and TGF-α is mediated via integrin-ADAM17/TACE interactions. Employing an in vitro system to simulate mechanical forces in fetal lung development, we showed that mechanical strain of fetal epithelial cells actives TACE, releases HB-EGF and TGF-α, and promotes differentiation. In contrast, in samples incubated with the TACE inhibitor IC-3 or in cells isolated from TACE knock-out mice, mechanical strain did not release ligands or promote cell differentiation, which were both rescued after transfection of ADAM17. Cell adhesion assay and co-immunoprecipitation experiments in wild-type and TACE knock-out cells using several TACE constructs demonstrated not only that integrins α6 and β1 bind to TACE via the disintegrin domain but also that mechanical strain enhances these interactions. Furthermore, force applied to these integrin receptors by magnetic beads activated TACE and shed HB-EGF and TGF-α. The contribution of integrins α6 and β1 to differentiation of fetal epithelial cells by strain was demonstrated by blocking their binding site with specific antibodies and by culturing the cells on membranes coated with anti-integrin α6 and β1 antibodies. In conclusion, mechanical strain releases HB-EGF and TGF-α and promotes fetal type II cell differentiation via α6β1 integrin-ADAM17/TACE signaling pathway. These investigations provide novel mechanistic information on how mechanical forces promote fetal lung development and specifically differentiation of epithelial cells. This information could be also relevant to other tissues exposed to mechanical forces.
authors.affiliation: From the Department of Pediatrics, Women & Infants Hospital of Rhode Island and the Warren Alpert Medical School, Brown University, Providence, Rhode Island 02905.
authors.forename: Yulian
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Pediatrics, Women & Infants Hospital of Rhode Island and the Warren Alpert Medical School, Brown University, Providence, Rhode Island 02905.
authors.forename: Zheping
authors.initials: Z
authors.lastname: Huang
authors.affiliation: From the Department of Pediatrics, Women & Infants Hospital of Rhode Island and the Warren Alpert Medical School, Brown University, Providence, Rhode Island 02905.
authors.forename: Pritha S
authors.initials: PS
authors.lastname: Nayak
authors.affiliation: the Vascular Biology Program, Departments of Medicine, Pathology, and Surgery, Harvard Medical School and Boston Children's Hospital, Boston, Massachusetts 02115, and.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Matthews
authors.affiliation: the Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027.
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.affiliation: the Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: From the Department of Pediatrics, Women & Infants Hospital of Rhode Island and the Warren Alpert Medical School, Brown University, Providence, Rhode Island 02905,. Electronic address: jsanchezesteban@wihri.org.
authors.forename: Juan
authors.initials: J
authors.lastname: Sanchez-Esteban
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D039121:Integrin alpha6beta1 / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D020545:Respiratory Mucosa / Q000166:cytology / Q000196:embryology*; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D039121:Integrin alpha6beta1; D036341:Intercellular Signaling Peptides and Proteins; D016211:Transforming Growth Factor alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: ADAM ADAMTS; Cell Differentiation; Cell Signaling; Cell Surface Receptor; Growth Factors; Integrins; Lung; Mechanotransduction