Article

Sox17 Promotes Cell Cycle Progression and Inhibits TGF-β/Smad3 Signaling to Initiate Progenitor Cell Behavior in the Respiratory Epithelium

Helmholtz Zentrum München/Ludwig-Maximilians-University Munich, Germany
PLoS ONE (Impact Factor: 3.53). 02/2009; 4(5):e5711. DOI: 10.1371/journal.pone.0005711
Source: PubMed

ABSTRACT The Sry-related high mobility group box transcription factor Sox17 is required for diverse developmental processes including endoderm formation, vascular development, and fetal hematopoietic stem cell maintenance. Expression of Sox17 in mature respiratory epithelial cells causes proliferation and lineage respecification, suggesting that Sox17 can alter adult lung progenitor cell fate. In this paper, we identify mechanisms by which Sox17 influences lung epithelial progenitor cell behavior and reprograms cell fate in the mature respiratory epithelium. Conditional expression of Sox17 in epithelial cells of the adult mouse lung demonstrated that cell cluster formation and respecification of alveolar progenitor cells toward proximal airway lineages were rapidly reversible processes. Prolonged expression of Sox17 caused the ectopic formation of bronchiolar-like structures with diverse respiratory epithelial cell characteristics in alveolar regions of lung. During initiation of progenitor cell behavior, Sox17 induced proliferation and increased the expression of the progenitor cell marker Sca-1 and genes involved in cell cycle progression. Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro. Sox17 decreased the expression of transforming growth factor-beta (TGF-beta)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-beta1-mediated transcriptional responses in vitro. Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity. Together, these data show that a subset of mature respiratory epithelial cells retains remarkable phenotypic plasticity and that Sox17, a gene required for early endoderm formation, activates the cell cycle and reinitiates multipotent progenitor cell behavior in mature lung cells.

0 Followers
 · 
102 Views
  • Source
    • "/ þ 63) of the mouse Cxcl5 promoter (NC_000071.5) was cloned using the following primers: 5 0 -CGACGCGTCGCCC ACTGTCAAATCCCTATCTGG-3 0 and 5 0 -CCGCTCGAGATGGTGTTCT CAAACCCACTGC-3 0 . SRE–luciferase construct was previously described (Lange et al, 2009). A549 or U2OS cells were transfected with CMV–Foxm1 (Kim et al, 2005) or CMV–empty plasmids as well as with luciferase constructs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alveolar epithelial cells (AECs) participate in the pathogenesis of pulmonary fibrosis, producing pro-inflammatory mediators and undergoing epithelial-to-mesenchymal transition (EMT). Herein, we demonstrated the critical role of Forkhead Box M1 (Foxm1) transcription factor in radiation-induced pulmonary fibrosis. Foxm1 was induced in AECs following lung irradiation. Transgenic expression of an activated Foxm1 transcript in AECs enhanced radiation-induced pneumonitis and pulmonary fibrosis, and increased the expression of IL-1β, Ccl2, Cxcl5, Snail1, Zeb1, Zeb2 and Foxf1. Conditional deletion of Foxm1 from respiratory epithelial cells decreased radiation-induced pulmonary fibrosis and prevented the increase in EMT-associated gene expression. siRNA-mediated inhibition of Foxm1 prevented TGF-β-induced EMT in vitro. Foxm1 bound to and increased promoter activity of the Snail1 gene, a critical transcriptional regulator of EMT. Expression of Snail1 restored TGF-β-induced loss of E-cadherin in Foxm1-deficient cells in vitro. Lineage-tracing studies demonstrated that Foxm1 increased EMT during radiation-induced pulmonary fibrosis in vivo. Foxm1 is required for radiation-induced pulmonary fibrosis by enhancing the expression of genes critical for lung inflammation and EMT.
    The EMBO Journal 01/2013; 32(2). DOI:10.1038/emboj.2012.336 · 10.75 Impact Factor
  • Source
    • "Several extracellular signals have been linked to the regulation of embryonic lung stem cells during development (Que et al, 2007; Lange et al, 2009; Morrisey and Hogan, 2010; Rock et al, 2011). However, the intracellular mechanisms involved in adult lung homeostasis and regeneration are still mostly unknown. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cellular and molecular mechanisms that control lung homeostasis and regeneration are still poorly understood. It has been proposed that a population of cells exists in the mouse lung with the potential to differentiate into all major lung bronchioalveolar epithelium cell types in homeostasis or in response to virus infection. A new population of E-Cad/Lgr6(+) putative stem cells has been isolated, and indefinitely expanded from human lungs, harbouring both, self-renewal capacity and the potency to differentiate in vitro and in vivo. Recently, a putative population of human lung stem cells has been proposed as being c-Kit(+). Unlike Integrin-α6(+) or c-Kit(+) cells, E-Cad/Lgr6(+) single-cell injections in the kidney capsule produce differentiated bronchioalveolar tissue, while retaining self-renewal, as they can undergo serial transplantations under the kidney capsule or in the lung. In addition, a signalling network involving the p38α pathway, the activation of p53 and the regulation of the miR-17-92 cluster has been identified. Disruption of the proper cross-regulation of this signalling axis might be involved in the promotion of human lung diseases.
    The EMBO Journal 07/2012; 31(16):3431-41. DOI:10.1038/emboj.2012.192 · 10.75 Impact Factor
  • Source
    • "These data suggest that Clara cells maintain their characteristics in the absence of promoting signals from lung mesenchyme, but type II AECs still require factors from distal lung mesenchyme to maintain their characteristics. An additional study demonstrates that ectopic expression of Sox17 in the distal airways of adult mice reprograms a subset of AECs into Clara and ciliated cells (Lange et al., 2009) suggesting that plasticity may be retained in at least a subset of respiratory cells into adulthood. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mammalian respiratory lineage, consisting of the trachea and lung, originates from the ventral foregut in an early embryo. Reciprocal signaling interactions between the foregut epithelium and its associated mesenchyme guide development of the respiratory endoderm, from a naive sheet of cells to multiple cell types that line a functional organ. This review synthesizes current understanding of the early events in respiratory system development, focusing on three main topics: (1) specification of the respiratory system as a distinct organ of the endoderm, (2) patterning and differentiation of the nascent respiratory epithelium along its proximal-distal axis, and (3) plasticity of the respiratory cells during the process of development. This review also highlights areas in need of further study, including determining how early endoderm cells rapidly switch their responses to the same signaling cues during development, and how the general proximal-distal pattern of the lung is converted to fine-scale organization of multiple cell types along this axis.
    Developmental Dynamics 03/2011; 240(3):477-85. DOI:10.1002/dvdy.22504 · 2.67 Impact Factor
Show more