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Sox17 promotes cell cycle progression and inhibits TGF-beta/Smad3 signaling to initiate progenitor cell behavior in the respiratory epithelium.

Lange AW, Keiser AR, Wells JM, Zorn AM, Whitsett JA - PLoS ONE (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

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.

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Prolonged expression of Sox17 results in formation of bronchiolar-like structures in the alveoli.Adult CCSPrtTA/tetO-Sox17 transgenic mice were maintained on Dox for 12 months. (A) H&E staining shows the presence of bronchiolar-like sheets of cells in the peripheral lung. Arrowhead indicates the pleural surface. (B–D) Immunostaining for Sox17 (B), Foxj1 (C), and CCSP (D) was performed on lung sections. The Sox17-induced bronchiolar-like structures contained cells expressing proximal airway markers CCSP and Foxj1. (E–H) Immunofluorescent staining for CCSP (E), proSP-C (F), and Sca-1 (G). The bronchiolar-like structures (dotted outline) contained cells that express Sca-1 and subsets of cells expressing CCSP or proSP-C. Arrowheads demark CCSP-expressing cells in the bronchiolar epithelium and the arrow indicates normal proSP-C expression in a type II cell. Nuclei are stained with DAPI (H; blue) Scale bars, 50 µm.
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pone-0005711-g002: Prolonged expression of Sox17 results in formation of bronchiolar-like structures in the alveoli.Adult CCSPrtTA/tetO-Sox17 transgenic mice were maintained on Dox for 12 months. (A) H&E staining shows the presence of bronchiolar-like sheets of cells in the peripheral lung. Arrowhead indicates the pleural surface. (B–D) Immunostaining for Sox17 (B), Foxj1 (C), and CCSP (D) was performed on lung sections. The Sox17-induced bronchiolar-like structures contained cells expressing proximal airway markers CCSP and Foxj1. (E–H) Immunofluorescent staining for CCSP (E), proSP-C (F), and Sca-1 (G). The bronchiolar-like structures (dotted outline) contained cells that express Sca-1 and subsets of cells expressing CCSP or proSP-C. Arrowheads demark CCSP-expressing cells in the bronchiolar epithelium and the arrow indicates normal proSP-C expression in a type II cell. Nuclei are stained with DAPI (H; blue) Scale bars, 50 µm.

Mentions: To determine the effects of prolonged expression of Sox17 in respiratory epithelial cells, adult CCSPrtTA/tetO-Sox17 mice were maintained on Dox for 12 months. Long-term expression of Sox17 caused the formation of organized sheets of epithelial cells in the peripheral lung with morphological similarities to the bronchiolar epithelium (Fig. 2). The bronchiolar-like structures expressed Sox17 (Fig. 2B) and contained subsets of cells that expressed proximal airway epithelial markers CCSP and Foxj1 (Fig. 2C–D), consistent with bronchiolar cell differentiation. While CCSP+ cells were detected in most of the bronchiolar-like structures, Foxj1+ cells were less frequently observed. Since the ability of Sox17 to reprogram mature alveolar type II cells suggests the induction of progenitor cell behavior, we examined the bronchiolar-like structures for coexpression of CCSP, proSP-C, and Sca-1, a property attributed to bronchoalveolar stem cells (BASCs), a potential lung stem/progenitor population [32]. Expression of Sca-1, a progenitor cell marker in several tissues, was detected in cells within the bronchiolar-like structures and colocalized with CCSP-expressing cells (Fig. 2E–H). While a rare subset of bronchiolar-like lesions contained cells that co-expressed CCSP and proSP-C (data not shown), CCSP+/proSP-C+/Sca-1+ cells were never observed. Thus, the Sox17-induced bronchiolar-like structures contained a mixed population of cells that expressed CCSP, Foxj1, Sca-1, CCSP+/Sca-1+, and CCSP+/proSP-C+, consistent with reprogramming of progenitor cells along several differentiated pathways. Such bronchiolar-like epithelial sheets were never detected in lungs from CCSPrtTA control mice maintained on Dox for 12 months (data not shown). Together these data show that prolonged expression of Sox17 in the adult mouse lung dramatically influences respiratory epithelial cell differentiation, generating ectopic structures in the peripheral lung with characteristics of the more proximal bronchiolar epithelium.


Sox17 promotes cell cycle progression and inhibits TGF-beta/Smad3 signaling to initiate progenitor cell behavior in the respiratory epithelium.

Lange AW, Keiser AR, Wells JM, Zorn AM, Whitsett JA - PLoS ONE (2009)

Prolonged expression of Sox17 results in formation of bronchiolar-like structures in the alveoli.Adult CCSPrtTA/tetO-Sox17 transgenic mice were maintained on Dox for 12 months. (A) H&E staining shows the presence of bronchiolar-like sheets of cells in the peripheral lung. Arrowhead indicates the pleural surface. (B–D) Immunostaining for Sox17 (B), Foxj1 (C), and CCSP (D) was performed on lung sections. The Sox17-induced bronchiolar-like structures contained cells expressing proximal airway markers CCSP and Foxj1. (E–H) Immunofluorescent staining for CCSP (E), proSP-C (F), and Sca-1 (G). The bronchiolar-like structures (dotted outline) contained cells that express Sca-1 and subsets of cells expressing CCSP or proSP-C. Arrowheads demark CCSP-expressing cells in the bronchiolar epithelium and the arrow indicates normal proSP-C expression in a type II cell. Nuclei are stained with DAPI (H; blue) Scale bars, 50 µm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2682659&req=5

pone-0005711-g002: Prolonged expression of Sox17 results in formation of bronchiolar-like structures in the alveoli.Adult CCSPrtTA/tetO-Sox17 transgenic mice were maintained on Dox for 12 months. (A) H&E staining shows the presence of bronchiolar-like sheets of cells in the peripheral lung. Arrowhead indicates the pleural surface. (B–D) Immunostaining for Sox17 (B), Foxj1 (C), and CCSP (D) was performed on lung sections. The Sox17-induced bronchiolar-like structures contained cells expressing proximal airway markers CCSP and Foxj1. (E–H) Immunofluorescent staining for CCSP (E), proSP-C (F), and Sca-1 (G). The bronchiolar-like structures (dotted outline) contained cells that express Sca-1 and subsets of cells expressing CCSP or proSP-C. Arrowheads demark CCSP-expressing cells in the bronchiolar epithelium and the arrow indicates normal proSP-C expression in a type II cell. Nuclei are stained with DAPI (H; blue) Scale bars, 50 µm.
Mentions: To determine the effects of prolonged expression of Sox17 in respiratory epithelial cells, adult CCSPrtTA/tetO-Sox17 mice were maintained on Dox for 12 months. Long-term expression of Sox17 caused the formation of organized sheets of epithelial cells in the peripheral lung with morphological similarities to the bronchiolar epithelium (Fig. 2). The bronchiolar-like structures expressed Sox17 (Fig. 2B) and contained subsets of cells that expressed proximal airway epithelial markers CCSP and Foxj1 (Fig. 2C–D), consistent with bronchiolar cell differentiation. While CCSP+ cells were detected in most of the bronchiolar-like structures, Foxj1+ cells were less frequently observed. Since the ability of Sox17 to reprogram mature alveolar type II cells suggests the induction of progenitor cell behavior, we examined the bronchiolar-like structures for coexpression of CCSP, proSP-C, and Sca-1, a property attributed to bronchoalveolar stem cells (BASCs), a potential lung stem/progenitor population [32]. Expression of Sca-1, a progenitor cell marker in several tissues, was detected in cells within the bronchiolar-like structures and colocalized with CCSP-expressing cells (Fig. 2E–H). While a rare subset of bronchiolar-like lesions contained cells that co-expressed CCSP and proSP-C (data not shown), CCSP+/proSP-C+/Sca-1+ cells were never observed. Thus, the Sox17-induced bronchiolar-like structures contained a mixed population of cells that expressed CCSP, Foxj1, Sca-1, CCSP+/Sca-1+, and CCSP+/proSP-C+, consistent with reprogramming of progenitor cells along several differentiated pathways. Such bronchiolar-like epithelial sheets were never detected in lungs from CCSPrtTA control mice maintained on Dox for 12 months (data not shown). Together these data show that prolonged expression of Sox17 in the adult mouse lung dramatically influences respiratory epithelial cell differentiation, generating ectopic structures in the peripheral lung with characteristics of the more proximal bronchiolar epithelium.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

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.

Show MeSH
Related in: MedlinePlus