Identification of bone morphogenetic protein 7 (BMP7) as an instructive factor for human epidermal Langerhans cell differentiation

J Exp Med. 2013 Nov 18;210(12):2597-610. doi: 10.1084/jem.20130275. Epub 2013 Nov 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 7 / deficiency
  • Bone Morphogenetic Protein 7 / genetics
  • Bone Morphogenetic Protein 7 / metabolism*
  • Bone Morphogenetic Protein Receptors, Type I / metabolism
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Epidermal Cells
  • Epidermis / embryology
  • Epidermis / metabolism
  • Gene Expression
  • Humans
  • Langerhans Cells / cytology*
  • Langerhans Cells / immunology
  • Langerhans Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Signal Transduction
  • Smad Proteins / metabolism
  • Transforming Growth Factor beta1 / physiology


  • BMP7 protein, human
  • Bone Morphogenetic Protein 7
  • Cytokines
  • Smad Proteins
  • Transforming Growth Factor beta1
  • bmp7 protein, mouse
  • BMPR1A protein, human
  • Bone Morphogenetic Protein Receptors, Type I