Article

Thy-1 signals through PPARγ to promote lipofibroblast differentiation in the developing lung.

Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 4.11). 01/2012; 46(6):765-72. DOI: 10.1165/rcmb.2011-0316OC
Source: PubMed

ABSTRACT Thy-1 is a glycosylphosphytidylinositol-linked cell-surface glycoprotein present on a subset of lung fibroblasts, which plays an important role in postnatal alveolarization. In the present study, we define the role of Thy-1 in pulmonary lipofibroblast differentiation and in the regulation of lipid homeostasis via peroxisome proliferator-activated receptor-γ (PPARγ). Thy-1 was associated with interstitial cells containing lipid droplets in vivo. The transfection of Thy-1 into Thy-1 (-) fibroblasts increased triglyceride content, fatty-acid uptake, and the expression of the lipofibroblast marker adipocyte differentiation-related protein. Thy-1 (+) fibroblasts exhibited 2.4-fold higher PPARγ activity, and the inhibition or activation of PPARγ reduced and increased triglyceride content, respectively. Thy-1 (-) fibroblasts were not responsive to either of the PPARγ agonists ciglitazone or prostaglandin J(2), supporting the importance of Thy-1 in signaling via PPARγ. Thy-1 (+) fibroblasts expressed significantly higher concentrations of fatty-acid transporter protein-3 mRNA, and demonstrated higher rates of fatty-acid uptake and increased triglyceride content. The inhibition of fatty-acid transporter protein function reduced Thy-1 (+) fibroblast lipid content. The expression of Thy-1 in C57BL/6 lung fibroblasts increased during the neonatal period, coinciding with the onset of alveolarization. Thy-1 promoted lipofibroblast differentiation via the expression of PPARγ, stimulated lipid accumulation via fatty-acid esterification, and enhanced the fatty-acid uptake mediated by fatty-acid transporter proteins. Thy-1 is important in the regulation of lipofibroblast differentiation in the developing lung.

Full-text

Available from: Brian M Varisco, Jun 14, 2015
1 Follower
 · 
115 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Each of the steps of respiratory system development relies on intricate interactions and coordinated development of the lung epithelium and mesenchyme. In the past, more attention has been paid to the epithelium than the mesenchyme. The mesenchyme is a source of specification and morphogenetic signals as well as a host of surprisingly complex cell lineages that are crucial for normal lung development and function. This review highlights recent research focusing on the mesenchyme that has revealed genetic and epigenetic mechanisms of its development in the context of other cell layers during respiratory lineage specification, branching morphogenesis, epithelial differentiation, lineage distinction, vascular development, and alveolar maturation. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Current opinion in genetics & development 06/2015; 32. DOI:10.1016/j.gde.2015.01.011 · 8.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The formation of discrete elastin bands at the tips of secondary alveolar septa is important for normal alveolar development, but the mechanisms regulating the lung elastogenic program are incompletely understood. JNK suppress elastin synthesis in the aorta and is important in a host of developmental processes. We sought to determine whether JNK suppresses pulmonary fibroblast elastogenesis during lung development. Alveolar size, elastin content, and mRNA of elastin-associated genes were quantitated in wild type and JNK-deficient mouse lungs, and expression profiles were validated in primary lung fibroblasts. Tropoelastin protein was quantitated by Western blot. Changes in lung JNK activity throughout development were quantitated, and pJNK was localized by confocal imaging and lineage tracing. By morphometry, alveolar diameters were increased by 7% and lung elastin content increased 2-fold in JNK-deficient mouse lungs compared to wild type. By Western blot, tropoelastin protein was increased 5-fold in JNK-deficient lungs. Postnatal day 14 (PND14) lung JNK activity was 11-fold higher and pJNK:JNK ratio 6-fold higher compared to PN 8 week lung. Lung tropoelastin, emilin-1, fibrillin-1, fibulin-5, and lysyl oxidase mRNAs inversely correlated with lung JNK activity during alveolar development. Phosphorylated JNK localized to pulmonary lipofibroblasts. PND14 JNK-deficient mouse lungs contained 7-fold more tropoelastin, 2,000-fold more emilin-1, 800-fold more fibrillin-1, and 60-fold more fibulin-5 than PND14 wild type lungs. Primarily lung fibroblasts from wild type and JNK-deficient mice showed similar differences in elastogenic mRNAs. JNK suppresses fibroblast elastogenesis during the alveolar stage of lung development.
    Respiratory research 03/2014; 15(1):34. DOI:10.1186/1465-9921-15-34 · 3.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although the pulmonary interstitial lipofibroblast (LF) has been widely recognized in rat and mouse lungs, their presence in human lungs remains controversial. In this issue of the Journal (xxx-xxx) Tahedl and associates address this controversy and provide the most detailed stereological analysis of LFs in mammals other than rodents. Strikingly, their observations demonstrate that LFs were only observed in rodents, which contrasts with earlier reports. This editorial reviews the anatomical, physiological, and biochemical characteristics of the LF to better understand the significance of LFs for lung development and disease. Although lipid droplets are a signature of the LF cell-type, it remains unclear whether lipid storage is the defining characteristic of LFs, or whether other less overt properties determine the importance of LFs. Are lipid droplets an adaptation to the neonatal environment, or are LFs a surrogate for other properties which promote alveolar development, and do lipid droplets modify physiology or disease in adults?
    AJP Lung Cellular and Molecular Physiology 09/2014; 307(8). DOI:10.1152/ajplung.00230.2014 · 4.04 Impact Factor