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Enolase 1 and protein disulfide isomerase associated 3 regulate Wnt/β-catenin driven trans-differentiation of murine alveolar epithelial cells.
Dis. Model. Mech. 8, 877-890 (2015)
The alveolar epithelium represents a major site of tissue destruction during lung injury. It consists of alveolar epithelial type I (ATI) and type II (ATII) cells. ATII cells are capable of self-renewal and exert progenitor function for ATI cells upon alveolar epithelial injury. Cell differentiation pathways enabling this plasticity and allowing for proper repair, however, are poorly understood. Here, we applied proteomics, expression analysis, and functional studies in primary murine ATII cells to identify novel proteins and molecular mechanisms involved in alveolar epithelial plasticity. Mass spectrometry of cultured ATII cells revealed a reduction of carbonyl reductase 2 (CBR2) and an increase in enolase 1 (ENO1) and protein disulfide isomerase associated 3 (PDIA3) protein expression during ATII to ATI cell trans-differentiation. This was accompanied by increased Wnt/β-catenin signaling, as analyzed by qRT-PCR and immunoblotting. Notably, ENO1 and PDIA3, along with T1α, exhibited decreased protein expression upon pharmacological and molecular Wnt/β-catenin inhibition in cultured ATII cells, while CBR2 levels were stabilized. Moreover, we analyzed primary ATII cells from bleomycin-induced lung injury, a model exhibiting activated Wnt/β-catenin signaling in vivo. We observed reduced CBR2 significantly correlating with SFTPC, whereas ENO1 and PDIA3 along with T1α were increased in injured ATII cells. Finally, siRNA-mediated knockdown of ENO1, as well as PDIA3, in primary ATII cells led to reduced T1α expression, indicating diminished cell trans-differentiation. Our data thus identified novel proteins involved in ATII to ATI cell trans-differentiation and suggest a Wnt/β-catenin-driven functional role of ENO1 and PDIA3 in alveolar epithelial cell plasticity in lung injury and repair.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Alveolar Epithelial Cells ; Differentiation ; Lung Injury And Repair ; Beta-catenin ; Wnt Pathway ; Fibrosis; Idiopathic Pulmonary-fibrosis; I Cells; Molecular-mechanisms; Distal Lung; Stem-cells; Tgf-beta; Primary Culture; Adult Lung; Pathway; Expression
ISSN (print) / ISBN
1754-8403
e-ISSN
1754-8411
Journal
Disease Models and Mechanisms
Quellenangaben
Volume: 8,
Issue: 8,
Pages: 877-890
Publisher
Company of Biologists
Publishing Place
Cambridge
Non-patent literature
Publications
Reviewing status
Peer reviewed