Abstract
BackgroundThe origin of collagen-producing cells in lung fibrosis is unclear. The involvement of embryonic signaling pathways has been acknowledged and trans-differentiation of epithelial cells is discussed critically. The work presented here investigates the role of TGFB in cytoskeleton remodeling and the expression of Epithelial-Mesenchymal-Transition markers by Alveolar Epithelial Cells Type II and tests the hypothesis if human alveolar epithelial cells are capable of trans-differentiation and production of pro-fibrotic collagen.MethodsPrimary human alveolar epithelial cells type II were extracted from donor tissues and stimulated with TGFβ and a TGFβ-inhibitor. Transcriptome and pathway analyses as well as validation of results on protein level were conducted.ResultsA TGFβ-responsive fingerprint was found and investigated for mutual interactions. Interaction modules exhibited enrichment of genes that favor actin cytoskeleton remodeling, differentiation processes and collagen metabolism. Cross-validation of the TGFβ-responsive fingerprint in an independent IPF dataset revealed overlap of genes and supported the direction of regulated genes and TGFβ-specificity.ConclusionsPrimary human alveolar epithelial cells type II seem undergo a TGFβ-dependent phenotypic change, exhibit differential expression of EMT markers in vitro and acquire the potential to produce collagen.
Highlights
The origin of collagen-producing cells in lung fibrosis is unclear
We hypothesize that Transforming Growth Factor β (TGFβ) stimulation of primary human alveolar epithelial cells type II (AECII) will induce downstream processes that might result in phenotypic changes which lead to differential expression of EMT markers as well as possible production of collagens
Isolation of human alveolar epithelial cells type II Tumor-free lung tissues from surgical specimens of 28 different lung cancer patients who underwent pneumectomy or lobectomy with curative intent at the LungenClinic Grosshansdorf were used for extraction of primary cells
Summary
The origin of collagen-producing cells in lung fibrosis is unclear. The involvement of embryonic signaling pathways has been acknowledged and trans-differentiation of epithelial cells is discussed critically. The work presented here investigates the role of TGFB in cytoskeleton remodeling and the expression of Epithelial-Mesenchymal-Transition markers by Alveolar Epithelial Cells Type II and tests the hypothesis if human alveolar epithelial cells are capable of trans-differentiation and production of pro-fibrotic collagen. Despite studies using either rat or mouse AECII [13, 14] or immortalized cell lines [15] as well as isolated AECII from IPF patients [16], the direct mechanistic connection of the TGFβ pathway on trans-diffe rentiation and collagen metabolism in human, primary AECII remains to be elucidated. We hypothesize that TGFβ stimulation of primary human AECII (hAECII) will induce downstream processes that might result in phenotypic changes which lead to differential expression of EMT markers as well as possible production of collagens.
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