Number and Proliferation of Clara Cells in Normal Human Airway Epithelium

Boers, James E.; Ambergen, A.W.; Thunnissen, F.B.J.M.

doi:10.1164/ajrccm.159.5.9806044

Cited by 266 publications

(250 citation statements)

References 19 publications

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“…As in proximal airways, the CFTR immunostaining signal was clear and consistent in the apical PM of every ciliated cell of the bronchiolar epithelium (7 normal subjects, Figure 6A). CFTR was not detected in Clara cells (note, Clara cells were absent in the human proximal bronchioles as previously reported by Boers et al 1999), nor in the PM of goblet cells identified with MUC5AC antibodies ( Figure 6B). …”

Section: Cftr Immunolocalization In Small Airwayssupporting

confidence: 80%

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

Kreda

Mall

Mengos

et al. 2005

MBoC

234

210

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Previous studies in native tissues have produced conflicting data on the localization and metabolic fate of WT and ⌬F508 cystic fibrosis transmembrane regulator (CFTR) in the lung. Combining immunocytochemical and biochemical studies utilizing new high-affinity CFTR mAbs with ion transport assays, we examined both 1) the cell type and region specific expression of CFTR in normal airways and 2) the metabolic fate of ⌬F508 CFTR and associated ERM proteins in the cystic fibrosis lung. Studies of lungs from a large number of normal subjects revealed that WT CFTR protein localized to the apical membrane of ciliated cells within the superficial epithelium and gland ducts. In contrast, other cell types in the superficial, gland acinar, and alveolar epithelia expressed little WT CFTR protein. No ⌬F508 CFTR mature protein or function could be detected in airway specimens freshly excised from a large number of ⌬F508 homozygous subjects, despite an intact ERM complex. In sum, our data demonstrate that WT CFTR is predominantly expressed in ciliated cells, and ⌬F508 CFTR pathogenesis in native tissues, like heterologous cells, reflects loss of normal protein processing.

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Section: Cftr Immunolocalization In Small Airwayssupporting

confidence: 80%

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

Kreda

Mall

Mengos

et al. 2005

MBoC

234

210

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“…Function of the respiratory epithelium also relies upon Clara and goblet cells to secrete proteins that maintain the function of the periciliary layer (46,47). Goblet cells are glandular columnar cells more localized in bronchi that secrete mucin; MUC5A/C is the gene that encodes Mucin 5AC and is associated with goblet cells in the respiratory epithelium (48).…”

Section: Resultsmentioning

confidence: 99%

“…5C). The relative distribution of these Clara cells is representative of in vivo airways where they represent 0.4% of cells in the trachea, increasing up to 22% in the bronchioles (46). Goblet-cell distribution is <2% in the large airways of mice but is often higher in human airways, dependent upon exposure to environmental factors.…”

Section: Resultsmentioning

confidence: 99%

Generation of multiciliated cells in functional airway epithelia from human induced pluripotent stem cells

Firth

Dargitz

Qualls

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

221

214

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Despite a significant improvement in the availability of therapeutic options to treat lung diseases, pulmonary disease still remains a major cause of morbidity and mortality around the world. Currently there are limited opportunities to study human lung disease either in vivo and in vitro. Using induced pluripotent stem cells (iPSC) we have generated a reproducible differentiation protocol to make mature post‐mitotic multiciliated cells in a functional airway epithelium. iPSC were generated from human skin biopsies and differentiated via FOXA2+SOX17+ definitive endoderm (>90% efficiency) to FOXA2+NKx2.1+ anterior foregut endoderm, FOXA2+NKx2.1+SOX2+ (~50% efficiency) pulmonary endoderm and then matured in an air liquid interface. Robust multiciliogenesis occurred when Notch signaling was inhibited and was confirmed by; i) the assembly of multiple pericentrin stained centrioles at the apical surface, ii) expression of transcription factor FOXJ1 and iii) presence of multiple acetylated tubulin labeled cilia projections in individual cells. The presence of NKx2.1+CC10+ Clara cells, MUC5A/C+ goblet cells and FOXA2+p63+ basal cells was also confirmed showing we are generating a complete polarized epithelial cell layer comprised of all relevant cell types. Functional cAMP activated and CFTRinh‐172 sensitive CFTR currents were recorded in isolated epithelial cells by whole cell patch clamp technique. Furthermore, we have corrected the deltaF508 mutation in the CFTR gene (>80% of all cases of CF) using a combination of CRISPR‐Cas9 endonuclease‐mediated genome editing and piggyBac transposase technologies, in the CF patient‐derived iPSC. The generation of mature multiciliated cells in a human iPSC differentiated respiratory epithelium and the ability to correct disease causing mutations provides a significant advancement toward modeling a number of human respiratory diseases in vitro. Grant Funding Source: Supported in part by CIRM and the Berger Foundation

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“…Third, in pathogen-free rats, the total number of airway epithelial cells remains constant during TGF-␣-induced goblet cell production, whereas the number of Clara cells decreases, suggesting that goblet cells form via differentiation of Clara cells (61). Indeed, some Clara cells can serve as stem cells (16,22), and some airway epithelial cells express both Clara cell secretory protein and mucin (5,14,25), suggesting that Clara cells are goblet cell precursors. However, whether goblet cells arise via cell differentiation has been questioned recently.…”

Section: Discussionmentioning

confidence: 98%

“…This evidence derives from several sources. First, goblet cells show no evidence of DNA synthesis (5,18,66) and contain unphosphorylated retinoblastoma protein and decreased levels of cyclin D 1 and cyclin-dependent kinase 2 (10), consistent with cell cycle arrest in the G1 phase. Second, in the endotoxin-treated rat nose, goblet cell production proceeds in the presence of metaphase blockade, indicating that goblet cell metaplasia can occur in the absence of cell proliferation (53).…”

Section: Discussionmentioning

confidence: 99%

E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC mucin expression in cultured human airway epithelial cells

Kim¹,

Schein²,

Nadel³

2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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Kim, Suil, Aaron J. Schein, and Jay A. Nadel. E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC mucin expression in cultured human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 289: L1049 -L1060, 2005. First published July 29, 2005; doi:10.1152/ajplung.00388.2004In previous work, we showed that epidermal growth factor receptor (EGFR) activation causes mucin expression in airway epithelium in vivo and in human NCI-H292 airway epithelial cells and normal human bronchial epithelial (NHBE) cells in vitro. Here we show that the cell surface adhesion molecule, E-cadherin, promotes EGFR-mediated mucin production in NCI-H292 cells in a cell density-and cell cycle-dependent fashion. The addition of the EGFR ligand, transforming growth factor (TGF)-␣, increased MUC5AC protein expression markedly in dense, but not in sparse, cultures. MUC5AC-positive cells in dense cultures contained 2 N DNA content and did not incorporate bromodeoxyuridine, suggesting that they develop via cell differentiation and that a surface molecule involved in cell-cell contact is important for EGFRmediated mucin production. In support of this hypothesis, in dense cultures of NCI-H292 cells and in NHBE cells at air-liquid interface, blockade of E-cadherin-mediated cell-cell contacts decreased EGFRdependent mucin production. E-cadherin blockade also increased EGFR-dependent cell proliferation and TGF-␣-induced EGFR tyrosine phosphorylation in dense cultures of NCI-H292 cells, suggesting that E-cadherin promotes EGFR-dependent mucin production and inhibits EGFR-dependent cell proliferation via modulation of EGFR phosphotyrosine levels. Furthermore, in dense cultures, E-cadherin blockade decreased the rate of EGFR tyrosine dephosphorylation, implicating an E-cadherin-dependent protein tyrosine phosphatase in EGFR dephosphorylation. Thus E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC production, and our results suggest that this occurs via a pathway involving protein tyrosine phosphatase-dependent EGFR dephosphorylation. epidermal growth factor receptor; airway epithelium THE PRODUCTION OF MUCIN-CONTAINING goblet cells in the airways is an important feature in diseases of mucus hypersecretion such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, nasal polyps, and bronchiectasis (reviewed in Ref. 38). Several years ago, Takeyama et al. (61) showed that epidermal growth factor receptor (EGFR) activation causes mucin production in airway epithelial cells in vivo and in human NCI-H292 airway epithelial cells in vitro. Subsequent studies have implicated EGFR activation in mucin upregulation (44) by many stimuli (7, 24, 26, 31, 32, 50 -52, 60, 62), suggesting that the EGFR cascade is a convergent pathway for mucin production by airway epithelial (goblet) cells.Biological responses to EGFR signaling are pleiotropic and include proliferation, differentiation, and apoptosis (reviewed in Ref. 19). In multicellular organisms, cell neighbors influence cell growth and differentiation. When normal e...

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Number and Proliferation of Clara Cells in Normal Human Airway Epithelium

Cited by 266 publications

References 19 publications

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

Generation of multiciliated cells in functional airway epithelia from human induced pluripotent stem cells

E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC mucin expression in cultured human airway epithelial cells

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