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Dlk1 Regulates Type II to Type I Cell Transition During Alveolar Repair Through Inhibition of Notch Signaling
Author(s) -
Finn Johanna,
Pajcini Kostandin,
Liu Yuru
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.60.5
Subject(s) - notch signaling pathway , microbiology and biotechnology , cell type , chemistry , progenitor cell , wild type , cell , cell culture , signal transduction , biology , stem cell , mutant , biochemistry , genetics , gene
Lung alveoli are lined with two types of epithelial cells: Type I cells and Type II cells. Type I cells are thin squamous cells covering ~95% of the surface area which are responsible for blood‐gas exchange. Type II cells have multiple functions including secretion of surfactant and are also able to act as progenitor cells, proliferating and subsequently converting to Type I cells after lung injury to restore the alveolar epithelial barrier. However, the signaling events responsible for inducing and regulation the Type II cell mediated repair remain poorly understood. Our data demonstrated that the non‐canonical Notch ligand Dlk1 (delta‐like 1 homolog) regulates Type II to Type I cell transition through regulation of Notch signaling. Through in vitro culture as well as by utilizing a mouse model of acute lung injury induced by Pseudomonas aeruginosa (PA) infection, we found a dynamic change in Dlk1 expression and Notch activity correlated with Type II to Type I cell transition. In a mouse model in which Dlk1 was specifically disrupted in Type II cells, we found that the mutant cells were unable to differentiate into Type I cells; instead, there is an accumulation of Type II cells expressing low levels of both Type II and Type I cell markers (Sp‐C low T1α low ) representing an intermediate cell type in between the Type II to Type I cell transition. Concurrently, Notch activity appeared to be abnormally elevated in these intermediate cells appearing during repair. Thus, we conclude that Dlk1 is required for the Type II to Type I cell transition during alveolar repair, and Dlk1 functions by inhibiting Notch signaling in a population of intermediate cells in between the transition of Type II to Type I cells to allow their full conversion into Type I cells. Further understanding of the involvement of Notch signaling and its regulation in the conversion process after Acute Lung Injury could help lead to novel clinical interventions in the treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome. Support or Funding Information NIH National Heart, Lung, and Blood Institute Training Grant in Lung Biology and Pathobiology (5T32HL007829) and R01HL105947