In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations

Hong, Kyung U.; Reynolds, Susan D.; Watkins, Simon C.; Fuchs, Elaine; Stripp, Barry R.

doi:10.1152/ajplung.00155.2003

Cited by 325 publications

(312 citation statements)

References 26 publications

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“…Cx26 was not detected in CK8-positive cells, which represent early progenitors of SC and CC lineages (Rock et al, 2011), but is present in a population of CK14-positive HAECs. An early report in the rat tracheal epithelium and later mouse geneticlineage tracing studies showed that the proportion of CK14-expressing BCs transiently increased following epithelial damage, suggesting that CK14 is up-regulated when BCs are activated (Hong et al, 2004;Ghosh et al, 2010). Thus, our results suggest that Cx26 expression is induced in BCs activated for proliferation during the repair process; Cx26 expression, however, is strongly repressed with differentiation.…”

Section: Discussionsupporting

confidence: 45%

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: 45%

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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“…Therefore, our aim was to determine whether the CXCR4/CXCL12 biological axis is important in recruiting the circulating progenitor epithelial cells. We thus performed passive immunization experiments with either neutralizing anti-CXCL12 or control F(AbЈ) 2 Abs in male GFP ϩ mice that had received a female wild-type trachea by using a modification as described previously (13). Based on the fact that complete regeneration of pseudostratified epithelium was noted by day 21 post-tracheal transplantation, we used this time point to assess the effect of neutralizing Abs on circulating progenitor epithelial cells during the regeneration of the tracheal epithelium.…”

Section: Cxcr4/cxcl12 Biological Axis Mediates Recruitment Of Circulamentioning

confidence: 99%

“…Basal resident progenitor epithelial cells are located in the submucosal glands and ducts and have been shown to be capable of differentiating into all airway epithelial cell types (1)(2)(3). They possess the capacity for self-renewal, divide slowly, retain a BrdU label, and express markers of early epithelial differentiation (i.e., cytokeratin 5(CK5 3 and CK14) (1)(2)(3)(4)(5)(6). CK5 and CK14 are type I and type II intermediate filament proteins that are expressed together in basal regenerating cells of complicated epithelia.…”

mentioning

confidence: 99%

“…CK5 and CK14 are type I and type II intermediate filament proteins that are expressed together in basal regenerating cells of complicated epithelia. Injury to the airway results in an initial increase in the number of CK5 ϩ CK14 ϩ basal cells, with a return to normal CK5 ϩ CK14 ϩ resident progenitor cell numbers once the airway is repaired, suggesting a negative feedback mechanism (2).…”

mentioning

confidence: 99%

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Circulating Progenitor Epithelial Cells Traffic via CXCR4/CXCL12 in Response to Airway Injury

Gomperts

Belperio²,

Rao

et al. 2006

The Journal of Immunology

132

120

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Recipient airway epithelial cells are found in human sex-mismatched lung transplants, implying that circulating progenitor epithelial cells contribute to the repair of the airway epithelium. Markers of circulating progenitor epithelial cells and mechanisms for their trafficking remain to be elucidated. We demonstrate that a population of progenitor epithelial cells exists in the bone marrow and the circulation of mice that is positive for the early epithelial marker cytokeratin 5 (CK5) and the chemokine receptor CXCR4. We used a mouse model of sex-mismatched tracheal transplantation and found that CK5+ circulating progenitor epithelial cells contribute to re-epithelialization of the airway and re-establishment of the pseudostratified epithelium. The presence of CXCL12 in tracheal transplants provided a mechanism for CXCR4+ circulating progenitor epithelial cell recruitment to the airway. Depletion of CXCL12 resulted in the epithelium defaulting to squamous metaplasia, which was derived solely from the resident tissue progenitor epithelial cells. Our findings demonstrate that CK5+CXCR4+ cells are markers of circulating progenitor epithelial cells in the bone marrow and circulation and that CXCR4/CXCL12-mediated recruitment of circulating progenitor epithelial cells is necessary for the re-establishment of a normal pseudostratified epithelium after airway injury. These findings support a novel paradigm for the development of squamous metaplasia of the airway epithelium and for developing therapeutic strategies for circulating progenitor epithelial cells in airway diseases.

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“…16,17 Several other progenitors and niches have been described as potential contributors to the post-naphthalene reconstitution of Clara cells. [18][19][20][21] For example, in the trachea and larger airways basal cells have the ability to proliferate and might contribute to the recovery process after naphthalene-induced Clara cell ablation. 19,21 In addition, distinct from the NEB microenvironment, naphthalene-resistant Clara cells at the terminal bronchioalveolar duct junctions represent another potential contributor to the restoration of the injured epithelium.…”

mentioning

confidence: 99%

Loss of GFI1 impairs pulmonary neuroendorine cell proliferation, but the neuroendocrine phenotype has limited impact on post-naphthalene airway repair

Linnoila

Jensen-Taubman

Kazanjian

et al. 2007

Laboratory Investigation

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Naphthalene exposure kills lung airway epithelial (Clara) cells, but is rapidly followed by Clara cell reconstitution coincident with proliferation of pulmonary neuroendocrine cells (PNEC). Although a role for mature PNEC in the reconstitution process has been excluded, the reconstituting progenitor cells have been suggested to enter a transient neuroendocrine (NE) differentiation phase before differentiating to Clara cells. Furthermore, these progenitors were suggested to be the target population for transformation to a NE tumor; small cell lung cancer (SCLC). Although the NE phenotype is central to SCLC oncogenesis, the relevance of NE differentiation to post naphthalene reconstitution remains to be determined. The Growth factor independent-1 (Gfi1) transcription factor is expressed in SCLC and is required for the NE differentiation of PNEC. Gfi1 À/À mice display a 70% reduction in airway cells that express NE markers, and cells that stain for NE markers show weak expression of some markers. Therefore, to determine the relevance of the NE phenotype to post-naphthalene reconstitution, we examined post-naphthalene reconstitution in Gfi1 À/À mice. Our analyses indicate that the post-naphthalene regeneration process includes both airway epithelial proliferation and apoptosis. Gfi1 deletion lowered both airway epithelial proliferation and apoptosis; however, the post-naphthalene rate of increase in growth and apoptosis was not significantly different between Gfi1 À/À mice and wild-type littermates. Moreover, the timing and extent of CC10 þ cell regeneration was unaffected by Gfi1 deletion. These data suggest that neither Gfi1 nor the NE phenotype play a dominant role in the regeneration process. However, the few Gfi1 À/À cells capable of NE differentiation show a significant reduction in post-naphthalene proliferation. The modest proliferation seen in Gfi1 À/À NE cells is consistent with the previously proposed role for Gfi1 in controlling neuroendocrine cancer growth.

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In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations

Abstract: . In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations.

Cited by 325 publications

References 26 publications

Cx26 regulates proliferation of repairing basal airway epithelial cells

Cx26 regulates proliferation of repairing basal airway epithelial cells

Circulating Progenitor Epithelial Cells Traffic via CXCR4/CXCL12 in Response to Airway Injury

Loss of GFI1 impairs pulmonary neuroendorine cell proliferation, but the neuroendocrine phenotype has limited impact on post-naphthalene airway repair

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