title: Identification of bone morphogenetic protein 7 (BMP7) as an instructive factor for human epidermal Langerhans cell differentiation.
abstract: Human Langerhans cell (LC) precursors populate the epidermis early during prenatal development and thereafter undergo massive proliferation. The prototypic antiproliferative cytokine TGF-β1 is required for LC differentiation from human CD34(+) hematopoietic progenitor cells and blood monocytes in vitro. Similarly, TGF-β1 deficiency results in LC loss in vivo. However, immunohistology studies revealed that human LC niches in early prenatal epidermis and adult basal (germinal) keratinocyte layers lack detectable TGF-β1. Here we demonstrated that these LC niches express high levels of bone morphogenetic protein 7 (BMP7) and that Bmp7-deficient mice exhibit substantially diminished LC numbers, with the remaining cells appearing less dendritic. BMP7 induces LC differentiation and proliferation by activating the BMP type-I receptor ALK3 in the absence of canonical TGF-β1-ALK5 signaling. Conversely, TGF-β1-induced in vitro LC differentiation is mediated via ALK3; however, co-induction of ALK5 diminished TGF-β1-driven LC generation. Therefore, selective ALK3 signaling by BMP7 promotes high LC yields. Within epidermis, BMP7 shows an inverse expression pattern relative to TGF-β1, the latter induced in suprabasal layers and up-regulated in outer layers. We observed that TGF-β1 inhibits microbial activation of BMP7-generated LCs. Therefore, TGF-β1 in suprabasal/outer epidermal layers might inhibit LC activation, resulting in LC network maintenance.
authors.affiliation: Institute of Pathophysiology and Immunology, Center for Molecular Medicine and 2 Center for Medical Research, Medical University Graz, A-8036 Graz, Austria.
authors.forename: Nighat
authors.initials: N
authors.lastname: Yasmin
authors.forename: Thomas
authors.initials: T
authors.lastname: Bauer
authors.forename: Madhura
authors.initials: M
authors.lastname: Modak
authors.forename: Karin
authors.initials: K
authors.lastname: Wagner
authors.forename: Christopher
authors.initials: C
authors.lastname: Schuster
authors.forename: Rene
authors.initials: R
authors.lastname: Köffel
authors.forename: Maria
authors.initials: M
authors.lastname: Seyerl
authors.forename: Johannes
authors.initials: J
authors.lastname: Stöckl
authors.forename: Adelheid
authors.initials: A
authors.lastname: Elbe-Bürger
authors.forename: Daniel
authors.initials: D
authors.lastname: Graf
authors.forename: Herbert
authors.initials: H
authors.lastname: Strobl
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007801:Langerhans Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000502:physiology
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D016207:Cytokines; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C525820:bmp7 protein, mouse; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I