Abstract
BackgroundType 2 alveolar epithelial cells (AT2s) behave as stem cells and show clonal proliferation upon alveolar injury followed by trans-differentiation (TD) into Type 1 alveolar epithelial cells (AT1s). In the present study we identified signaling pathways involved in the physiological AT2-to-AT1 TD process.MethodsAT2 cells can be isolated from human lungs and cultured in vitro where they undergo TD into AT1s. In the present study we identified signaling pathways involved in the physiological AT2-to-AT1 TD process using Affymetrix microarray, qRT-PCR, fluorescence microscopy, and an in vitro lung aggregate culture.ResultsAffymetrix microarray revealed Wnt signaling to play a crucial role in the TD process. Wnt7a was identified as a ligand regulating the AT1 marker, Aquaporin 5 (AQP5). Artificial Neural Network (ANN) analysis of the Affymetrix data exposed ITGAV: Integrin alpha V (ITGAV), thrombospondin 1 (THBS1) and epithelial membrane protein 2 (EMP2) as Wnt signaling targets.ConclusionsWnt signaling targets that can serve as potential alveolar epithelial repair targets in future therapies of the gas exchange surface after injury. As ITGAV is significantly increases during TD and is regulated by Wnt signaling, ITGAV might be a potential target to speed up the alveolar healing process.
Highlights
Type 2 alveolar epithelial cells (AT2s) behave as stem cells and show clonal proliferation upon alveolar injury followed by trans-differentiation (TD) into Type 1 alveolar epithelial cells (AT1s)
Wnt signaling pathways are the most active during AT2to-Alveolar Type 1 Cell (AT1) TD in vitro Freshly isolated primary human Alveolar Type 2 Cell (AT2) cells were cultured in vitro for 2, 3 and 6 days, mRNA was isolated and the generated cDNA was used in Affymetrix analysis
The AT1 marker Aquaporin 5 (AQP5) (Fig. 1a) and AT2 marker surfactant protein C (SPC) (Fig. 1b) were tested at each time points to confirm the initiation of the TD process
Summary
Type 2 alveolar epithelial cells (AT2s) behave as stem cells and show clonal proliferation upon alveolar injury followed by trans-differentiation (TD) into Type 1 alveolar epithelial cells (AT1s). In the present study we identified signaling pathways involved in the physiological AT2-to-AT1 TD process. The enormous alveolar surface of the lung has a significant and physiological regeneration capacity [4, 5]. Type 2 alveolar epithelial cells (AT2s) have been suspected to act as progenitor cells in the alveoli and recent genetic fate-tracking experiments in transgenic mice provided evidence that AT2s are function as stem cells and show clonal proliferation in response to injury [6]. About 95% of the alveolar surface area is covered by flat and thin Type 1 alveolar epithelial cells (AT1) that die by apoptosis upon injury leaving a denuded alveolar basement membrane behind.
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