title: β1 integrin signaling maintains human epithelial progenitor cell survival in situ and controls proliferation, apoptosis and migration of their progeny.
abstract: β1 integrin regulates multiple epithelial cell functions by connecting cells with the extracellular matrix (ECM). While β1 integrin-mediated signaling in murine epithelial stem cells is well-studied, its role in human adult epithelial progenitor cells (ePCs) in situ remains to be defined. Using microdissected, organ-cultured human scalp hair follicles (HFs) as a clinically relevant model for studying human ePCs within their natural topobiological habitat, β1 integrin-mediated signaling in ePC biology was explored by β1 integrin siRNA silencing, specific β1 integrin-binding antibodies and pharmacological inhibition of integrin-linked kinase (ILK), a key component of the integrin-induced signaling cascade. β1 integrin knock down reduced keratin 15 (K15) expression as well as the proliferation of outer root sheath keratinocytes (ORSKs). Embedding of HF epithelium into an ECM rich in β1 integrin ligands that mimic the HF mesenchyme significantly enhanced proliferation and migration of ORSKs, while K15 and CD200 gene and protein expression were inhibited. Employing ECM-embedded β1 integrin-activating or -inhibiting antibodies allowed to identify functionally distinct human ePC subpopulations in different compartments of the HF epithelium. The β1 integrin-inhibitory antibody reduced β1 integrin expression in situ and selectively enhanced proliferation of bulge ePCs, while the β1 integrin-stimulating antibody decreased hair matrix keratinocyte apoptosis and enhanced transferrin receptor (CD71) immunoreactivity, a marker of transit amplifying cells, but did not affect bulge ePC proliferation. That the putative ILK inhibitor QLT0267 significantly reduced ORSK migration and proliferation and induced massive ORSK apoptosis suggests a key role for ILK in mediating the ß1 integrin effects. Taken together, these findings demonstrate that ePCs in human HFs require β1 integrin-mediated signaling for survival, adhesion, and migration, and that different human HF ePC subpopulations differ in their response to β1 integrin signaling. These insights may be exploited for cell-based regenerative medicine strategies that employ human HF-derived ePCs.
authors.affiliation: Department of Dermatology, University of Luebeck, Luebeck, Germany.
authors.forename: Nancy
authors.initials: N
authors.lastname: Ernst
authors.affiliation: Department of Histology and Embryology, University of Erciyes, Kayseri, Turkey.
authors.forename: Arzu
authors.initials: A
authors.lastname: Yay
authors.affiliation: DE-MTA ''Lendület'' Cellular Physiology Group, Department of Physiology, University of Debrecen, Debrecen, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Bíró
authors.affiliation: Institute of Experimental Immunology, Euroimmun AG, Luebeck, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Tiede
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Humphries
authors.affiliation: Department of Dermatology, University of Luebeck, Luebeck, Germany ; Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom.
authors.forename: Ralf
authors.initials: R
authors.lastname: Paus
authors.affiliation: Department of Dermatology, University of Luebeck, Luebeck, Germany.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Kloepper
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001391:Azo Compounds / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004247:DNA / Q000096:biosynthesis; D004847:Epithelial Cells / Q000166:cytology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D018859:Hair Follicle / Q000166:cytology; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D008024:Ligands; D008875:Middle Aged; D011720:Pyrazoles / Q000494:pharmacology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult
chemical_list: D001391:Azo Compounds; D019012:Integrin beta1; D008024:Ligands; D011720:Pyrazoles; C552362:QLT 0267; D004247:DNA