Basal-like Cells Constitute the Proliferating Cell Population in Cystic Fibrosis Airways

Voynow, Judith A.; Fischer, Bernard M.; Roberts, Bruce C.; Proia, Alan D.

doi:10.1164/rccm.200410-1398oc

Cited by 106 publications

(94 citation statements)

References 29 publications

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“…These results may relate to the hyper-proliferative state previously described in CF HAECs (Voynow et al, 2005;Hajj et al, 2007). The rapid onset of proliferation in CF HAECs could be explained, in part, by increased amount of progenitor cells in these cultures.…”

Section: Discussionsupporting

confidence: 55%

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Cx26 regulates proliferation of repairing basal airway epithelial cells

Crespin

Bacchetta

Saab

et al. 2014

The International Journal of Biochemistry & Cell Biology

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The recovery of an intact epithelium following injury is critical for restoration of lung homeostasis, a process that may be altered in cystic fibrosis (CF). In response to injury, progenitor cells in the undamaged areas migrate, proliferate and re-differentiate to regenerate an intact airway epithelium. The mechanisms regulating this regenerative response are, however, not well understood. In a model of circular wound injury of well-differentiated human airway epithelial cell (HAEC) cultures, we identified the gap junction protein Cx26 as an important regulator of cell proliferation. We report that induction of Cx26 in repairing HAECs is associated with cell proliferation. We also show that Cx26 is expressed in a population of CK14-positive basal-like cells. Cx26 silencing in immortalized cell lines using siRNA and in primary HAECs using lentiviral-transduced shRNA enhanced Ki67-labeling index and Ki67 mRNA, indicating that Cx26 acts a negative regulator of HAEC proliferation.Cx26 silencing also markedly decreased the transcription of KLF4 in immortalized HAECs.We further show that CF HAECs exhibited deregulated expression of KLF4, Ki67 and Cx26 as well enhanced rate of wound closure in the early response to injury. These results point to an altered repair process of CF HAECs characterized by rapid but desynchronized initiation of HAEC activation and proliferation.

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Section: Discussionsupporting

confidence: 55%

“…We also evaluated whether KLF4 regulates Cx26 expression in repairing HAECs. Because a hyperproliferative state has been described in CF HAECs (Voynow et al, 2005;Hajj et al, 2007), we investigated the expression of Cx26 and KLF4 in this disease as well.…”

Section: Introductionmentioning

confidence: 99%

Cx26 regulates proliferation of repairing basal airway epithelial cells

Crespin

Bacchetta

Saab

et al. 2014

The International Journal of Biochemistry & Cell Biology

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“…Histological changes include goblet cell hyperplasia, BC hyperplasia and airway wall tissue destruction that can lead to bronchiectasis (dilation of the airways). An informative study showed that hyperproliferative airway epithelial cells in patients with CF expressed KRT5, and/or KRT14 and epidermal growth factor receptor (EGFR), which are markers of BCs (Voynow et al, 2005).…”

Section: Cystic Fibrosismentioning

confidence: 99%

Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling

Rock

Randell

Hogan

2010

Disease Models &Amp; Mechanisms

640

683

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The small airways of the human lung undergo pathological changes in pulmonary disorders, such as chronic obstructive pulmonary disease (COPD), asthma, bronchiolitis obliterans and cystic fibrosis. These clinical problems impose huge personal and societal healthcare burdens. The changes, termed 'pathological airway remodeling' , affect the epithelium, the underlying mesenchyme and the reciprocal trophic interactions that occur between these tissues. Most of the normal human airway is lined by a pseudostratified epithelium of ciliated cells, secretory cells and 6-30% basal cells, the proportion of which varies along the proximal-distal axis. Epithelial abnormalities range from hypoplasia (failure to differentiate) to basal-and goblet-cell hyperplasia, squamous-and goblet-cell metaplasia, dysplasia and malignant transformation. Mesenchymal alterations include thickening of the basal lamina, smooth muscle hyperplasia, fibrosis and inflammatory cell accumulation. Paradoxically, given the prevalence and importance of airway remodeling in lung disease, its etiology is poorly understood. This is due, in part, to a lack of basic knowledge of the mechanisms that regulate the differentiation, maintenance and repair of the airway epithelium. Specifically, little is known about the proliferation and differentiation of basal cells, a multipotent stem cell population of the pseudostratified airway epithelium. This Perspective summarizes what we know, and what we need to know, about airway basal cells to evaluate their contributions to normal and abnormal airway remodeling. We contend that exploiting well-described model systems using both human airway epithelial cells and the pseudostratified epithelium of the genetically tractable mouse trachea will enable crucial discoveries regarding the pathogenesis of airway disease.

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“…Subsequent studies showed that EGFR activation is required for inducing mucous metaplasia in animal models and for up-regulation of mucin expression in human airway epithelial cells in response to allergens, viruses, neutrophils, and cigarette smoke (25,(53)(54)(55)(56). EGFR expression was also shown to be up-regulated in the airway epithelium of humans with asthma (57, 58), COPD (59), and CF (60). Thus, EGFR is another necessary signal for mucous metaplasia.…”

Section: Epidermal Growth Factor Receptormentioning

confidence: 99%

Advances in Mucous Cell Metaplasia

Curran

Cohn

2010

Am J Respir Cell Mol Biol

156

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Mucous cell metaplasia is induced in response to harmful insults and provides front-line protection to clear the airway of toxic substances and cellular debris. In chronic airway diseases mucous metaplasia persists and results in airway obstruction and contributes significantly to morbidity and mortality. Mucus hypersecretion involves increased expression of mucin genes, and increased mucin production and release. The past decade has seen significant advances in our understanding of the molecular mechanisms by which these events occur. Inflammation stimulates epidermal growth factor receptor activation and IL-13 to induce both Clara and ciliated cells to transition into goblet cells through the coordinated actions of FoxA2, TTF-1, SPDEF, and GABA A R. Ultimately, these steps lead to up-regulation of MUC5AC expression, and increased mucin in goblet cell granules that fuse to the plasma membrane through actions of MARCKS, SNAREs, and Munc proteins. Blockade of mucus in exacerbations of asthma and chronic obstructive pulmonary disease may affect morbidity. Development of new therapies to target mucus production and secretion are now possible given the advances in our understanding of molecular mechanisms of mucous metaplasia. We now have a greater incentive to focus on inhibition of mucus as a therapy for chronic airway diseases.

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Basal-like Cells Constitute the Proliferating Cell Population in Cystic Fibrosis Airways

Abstract: Our results suggest that basal-like cells, expressing the epidermal growth factor receptor, constitute the proliferating cell population in cystic fibrosis airways.

Cited by 106 publications

References 29 publications

Cx26 regulates proliferation of repairing basal airway epithelial cells

Cx26 regulates proliferation of repairing basal airway epithelial cells

Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling

Advances in Mucous Cell Metaplasia

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