Pneumologie 2012; 66 - A507
DOI: 10.1055/s-0032-1315514

Regulation and role of notch signaling in epithelial progenitor cell differentiation and proliferation in the normal and the fibrotic lung

K Piskulak 1, I Henneke 1, J Wilhelm 1, S Bellusci 1, W Seeger 1, 2, A Günther 1, 2, 3, C Ruppert 1
  • 1Universities of Gießen and Marburg Lung Center (UGMLC), Department of Internal Medicine, Justus-Liebig-University Gießen, Gießen
  • 2Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein
  • 3German Center for Lung Research

Introduction: Differenzial regulation of the TGF-ß, Wnt and Notch pathway was recently identified by transcriptome profiling of still normal appearing, microdissected alveolar septae from IPF lungs. The Notch signaling pathway is involved in cell fate decisions, differentiation and proliferation during development, but it may also play a key role in repair processes of the injured lung.

Methods: The cellular regulation of the Notch signaling pathway was investigated on mRNA, protein and immunohistochemical level (IPF vs. donor lungs; bleomycin-treated vs. control mice lungs). Proliferation and survival of an AECII and AECII-like cell line (MLE12) was investigated after in vitro transfection with Notch1 ICD, POFUT1 siRNA and DAPT (γ-secretase inhibitor) treatment.

Results: There were no significant changes in the expression of Notch receptors and ligands on mRNA level. On protein level, however, the receptor Notch1 (NICD) and the Notch ligand Delta1 were found to be upregulated in IPF lung and NICD1 in bleomycin lungs. Notch1 receptor was immunohistochemically detected in AECII of IPF lungs. MLE12 cells showed an increased proliferation when transfected with Notch ICD and reduced proliferation upon treatment with POFUT1 siRNA and DAPT. We also confirmed influence of Notch pathway on primary mouse alveolar type II cells (AECII) proliferation.

Discussion: Our findings suggest that the Notch system seems to be activated in IPF as well as in a murine fibrosis model. This may indicate a key role of Notch signaling pathway in the repair process of the alveolar epithelium in response to the chronic injury of AECII in IPF.