title: Wilms' tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis.
abstract: Pleural mesothelial cells (PMCs), which are derived from the mesoderm, exhibit an extraordinary capacity to undergo phenotypic changes during development and disease. PMC transformation and trafficking has a newly defined role in idiopathic pulmonary fibrosis (IPF); however, the contribution of Wilms' tumor 1 (Wt1)-positive PMCs to the generation of pathognomonic myofibroblasts remains unclear. PMCs were obtained from IPF lung explants and healthy donor lungs that were not used for transplantation. Short hairpin Wt1-knockdown PMCs (sh Wt1) were generated with Wt1 shRNA, and morphologic and functional assays were performed in vitro. Loss of Wt1 abrogated the PMC phenotype and showed evidence of mesothelial-to-mesenchymal transition (MMT), with a reduced expression of E-cadherin and an increase in the profibrotic markers α-smooth muscle actin (α-SMA) and fibronectin, along with increased migration and contractility, compared with that of the control. Migration of PMCs in response to active transforming growth factor (TGF)-β1 was assessed by live-cell imaging with 2-photon microscopy and 3D imaging, of Wt1-EGFP transgenic mice. Lineage-tracing experiments to map the fate of Wt1(+) PMCs in mouse lung in response to TGF-β1 were also performed by using a Cre-loxP system. Our results, for the first time, demonstrate that Wt1 is necessary for the morphologic integrity of pleural membrane and that loss of Wt1 contributes to IPF via MMT of PMCs into a myofibroblast phenotype.
authors.affiliation: 2Department of Medicine, University of Alabama at Birmingham, AL 35294, USA; vantony@uab.edu.
authors.forename: Suman
authors.initials: S
authors.lastname: Karki
authors.forename: Ranu
authors.initials: R
authors.lastname: Surolia
authors.forename: Thomas David
authors.initials: TD
authors.lastname: Hock
authors.forename: Purusotham
authors.initials: P
authors.lastname: Guroji
authors.forename: Jason S
authors.initials: JS
authors.lastname: Zolak
authors.forename: Ryan
authors.initials: R
authors.lastname: Duggal
authors.forename: Tong
authors.initials: T
authors.lastname: Ye
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.forename: Veena B
authors.initials: VB
authors.lastname: Antony
mesh_terms: D001483:Base Sequence; D002454:Cell Differentiation; D019070:Cell Lineage; D003094:Collagen / Q000378:metabolism; D017931:DNA Primers; D004848:Epithelium / Q000473:pathology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology*; D058628:Myofibroblasts / Q000473:pathology*; D010994:Pleura / Q000473:pathology*; D016133:Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D009396:Wilms Tumor / Q000235:genetics*
chemical_list: D017931:DNA Primers; D053773:Transforming Growth Factor beta1; D003094:Collagen
keywords: matrix remodeling; mesothelial-to-mesenchymal transition; smooth muscle actin