Deletion of <i>Pten</i> Expands Lung Epithelial Progenitor Pools and Confers Resistance to Airway Injury

Tiozzo, Caterina; Langhe, Stijn De; Yu, Mingke; Londhe, Vedang A.; Carraro, Gianni; Li, Min; Li, Changgong; Xing, Yiming; Anderson, Stewart A.; Borok, Zea; Bellusci, Savério; Minoo, Parviz

doi:10.1164/rccm.200901-0100oc

Cited by 50 publications

(57 citation statements)

References 33 publications

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“…This staining is limited to the endodermally derived epithelial progenitor cells forming the primitive airways and the first branched structures of the embryonic lung ( Figure 1). Thereafter, LacZ can be found in all endodermally derived epithelial cells throughout lung development (18). In postnatal lung samples, LacZ staining is found in the epithelium of the bronchoalveolar duct junction (arrowheads in Figure 1K) as well as alveolar epithelial type II cells (arrows in Figure 1K).…”

Section: Epithelial Inactivation Of Tβrii By Nkx21-cre-driven Recombmentioning

confidence: 97%

Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis

Krishnaveni²,

Li³

et al. 2011

J. Clin. Invest.

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143

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Idiopathic pulmonary fibrosis (IPF) is a chronic fibroproliferative pulmonary disorder for which there are currently no treatments. Although the etiology of IPF is unknown, dysregulated TGF-β signaling has been implicated in its pathogenesis. Recent studies also suggest a central role for abnormal epithelial repair. In this study, we sought to elucidate the function of epithelial TGF-β signaling via TGF-β receptor II (TβRII) and its contribution to fibrosis by generating mice in which TβRII was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as TβRII Nkx2.1-cre mice, were used to determine the impact of TβRII inactivation on (a) embryonic lung morphogenesis in vivo; and (b) the epithelial cell response to TGF-β signaling in vitro and in a bleomycin-induced, TGF-β-mediated mouse model of pulmonary fibrosis. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, TβRII Nkx2.1-cre mice developed emphysema, suggesting a requirement for epithelial TβRII in alveolar homeostasis. Absence of TβRII increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic TGF-β. However, TβRII Nkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced pulmonary fibrosis. To our knowledge, these findings are the first to demonstrate a specific role for TGF-β signaling in the lung epithelium in the pathogenesis of pulmonary fibrosis.

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Section: Epithelial Inactivation Of Tβrii By Nkx21-cre-driven Recombmentioning

confidence: 97%

Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis

Krishnaveni²,

Li³

et al. 2011

J. Clin. Invest.

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200

143

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“…For the current study, we used Nkx-Cre mice to generate animals in which IFN-␤ promoter-controlled luciferase expression is restricted to lung epithelial cells (20). Further, we used LysM-Cre mice to generate reporter mice which express the luciferase gene in macrophages, granulocytes, and, at a low frequency, monocytes (19).…”

Section: Epithelial Cells and Macrophages Are The Main Producers Of Imentioning

confidence: 99%

Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1

Kallfass

Lienenklaus

Staeheli

2013

J Virol

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bThe innate host defense against influenza virus is largely dependent on the type I interferon (IFN) system. However, surprisingly little is known about the cellular source of IFN in the infected lung. To clarify this question, we employed a reporter mouse that contains the firefly luciferase gene in place of the IFN-␤-coding region. IFN-␤-producing cells were identified either by simultaneous immunostaining of lungs for luciferase and cellular markers or by generating conditional reporter mice that express luciferase exclusively in defined cell types. Two different strains of influenza A virus were employed that either do or do not code for nonstructural protein 1 (NS1), which strongly suppresses innate immune responses of infected cells. We found that epithelial cells and lung macrophages, which represent the prime host cells for influenza viruses, showed vigorous IFN-␤ responses which, however, were severely reduced and delayed if the infecting virus was able to produce NS1. Interestingly, CD11c؉ cell populations that were either expressing or lacking macrophage markers produced the bulk of IFN-␤ at 48 h after infection with wildtype influenza A virus. Our results demonstrate that the virus-encoded IFN-antagonistic factor NS1 disarms specifically epithelial cells and lung macrophages, which otherwise would serve as main mediators of the early response against infection by influenza virus.

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“…The tumor suppressor gene Pten, which is mutated in many human cancers, appears to be essential for the homeostasis of bronchioalveolar stem cells and hence for normal lung morphogenesis and the prevention of lung carcinogenesis (Yanagi et al, 2007). Deletion of this gene caused inhibition of the differentiation of various lung epithelial cell lines, with decreased numbers of terminally differentiated cells (Tiozzo et al, 2009). Another tumor suppressor gene, p63, related to the p53 gene, is present mainly in the basal layer of the developing trachea (and esophagus), but decreases towards the more superficial cells (Daniely et al, 2004); this gene appears in general to be involved in the development of stratified epithelia (Koster et al, 2004;Senoo et al, 2007).…”

Section: Gm Roomans Stem/progenitor Cells For Airway Repairmentioning

confidence: 99%

Tissue engineering and the use of stem/progenitor cells for airway epithelium repair

Roomans

2010

eCM

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Stem/progenitor cells can be used to repair defects in the airway wall, resulting from e.g., tumors, trauma, tissue reactions following long-time intubations, or diseases that are associated with epithelial damage. Several potential sources of cells for airway epithelium have been identified. These can be divided into two groups. The first group consists of endogenous progenitor cells present in the respiratory tract. This group can be subdivided according to location into (a) a ductal cell type in the submucosal glands of the proximal trachea, (b) basal cells in the intercartilaginous zones of the lower trachea and bronchi, (c) variant Clara cells (Clara v -cells) in the bronchioles and (d) at the junctions between the bronchioles and the alveolar ducts, and (e) alveolar type II cells. This classification of progenitor cell niches is, however, controversial. The second group consists of exogenous stem cells derived from other tissues in the body. This second group can be subdivided into: (a) embryonic stem (ES) cells, induced pluripotent stem (iPS) cells, or amniotic fluid stem cells, (b) side-population cells from bone marrow or epithelial stem cells present in bone marrow or circulation and (c) fat-derived mesenchymal cells. Airway epithelial cells can be co-cultured in a system that includes a basal lamina equivalent, extracellular factors from mesenchymal fibroblasts, and in an air-liquid interface system. Recently, spheroid-based culture systems have been developed. Several clinical applications have been suggested: cystic fibrosis, acute respiratory distress syndrome, chronic obstructive lung disease, pulmonary fibrosis, pulmonary edema, and pulmonary hypertension. Clinical applications so far are few, but include subglottic stenosis, tracheomalacia, bronchiomalacia, and emphysema.

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Deletion of Pten Expands Lung Epithelial Progenitor Pools and Confers Resistance to Airway Injury

Cited by 50 publications

References 33 publications

Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis

Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis

Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1

Tissue engineering and the use of stem/progenitor cells for airway epithelium repair

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