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Activation, Epidermal Growth Factor Receptor leads to Occurrence, Transdifferentiation of ciliated epithelial cells
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
IL13 stimulates transdifferentiation of ciliated epithelial cells to goblet cells through EGFR activation (Tyner et al. 2006), MMP/ADAM (Yoshisue and Hasegawa 2004), p38 MAPK (Fujisawa, et al. 2008) and inhibition of FOXJ1 (Gomperts, et al. 2007). In addition to IL13, IL4 has been shown to act through shared receptor IL4RA to stimulate goblet cell differentiation and inhibit ciliogenesis (Laoukili, et al. 2001). IL4 and IL13 but not IL5 or IL9 have been shown to induce goblet cell metaplasia in mouse trachial epiethelial cells (Fujisawa, et al. 2008).
Evidence Supporting this KER
There is biological plausibility of ciliated cell transdifferentiation to goblet cells as a number of studies have shown a mix of features characteristic of each cell type within a cell (Tyner, et al. 2006, Laoukili, et al. 2001, Gomperts et al. 2007) or fluorescent labeling from ciliated cells detected in goblet cells after differentiation (Turner et al. 2011).
However, ciliated cell transdifferentiation remains controversial in terms of napthalene or sulfur dioxide-induced injury with conflicting reports for lack of transdifferentiation (Rawlins, et al. 2006) and evidence for transdifferentiation (Van Winkle, et al. 1995; Lawson, et al. 2002, Park, et al. 2006).
Uncertainties and Inconsistencies
IL13-induced goblet cell increase has been shown to be concentration-dependent in human bronchial epithelial cells with 1ng/ml inducing and 10ng/ml suppressing goblet cell increase (Atherton, et al. 2003), however multiple studies have shown that concentrations from 5-100ng/mL do induce goblet cell hyperplasia, including in human bronchial epithelial cells (Yoshisue 2004).
It has been shown that two weeks but not one week of human nasal epithelial cell differentiation and IL13 treatment showed a decrease in proportion of ciliated cells (shown by glutamylated tubulin protein expression) (Laouikili 2001), however other studies showed that IL13-induced ciliated to goblet cell differentiation were observed in as little as 3-5 days cultured human airway epithelium, mouse tracheal epithelial cells and a Sendai virus mouse model (Gomperts 2007, Fujisawa 2008, Tyner 2006). This difference may be due to the difference in cell types used in these experiments. Ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge for 48 hours which may be due to insufficient time for OVA-induced IL13 upregulation and subsequent effects (Pardo-Saganta 2013).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
There are many human studies demonstrating transdifferentiation from ciliated to goblet cells including in 3D human airway epithelial models (Gomperts et al. 2007), human bronchial or nasal epithelial cells in vitro (Yoshisue and Hasegawa 2004, Turner et al. 2011, Laoukili, et al. 2001) and in COPD patients (Tyner, et al. 2006).
Two mouse studies have demonstrated transdifferentiation and goblet metaplasia (Tyner, et al. 2006, Fujisawa, et al. 2008) while another mouse study has shown that ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge (Pardo-Saganta, et al. 2013), however this could be due to the short 48 hour time point which has been noted is not enough time for transdifferentiation (Laoukili, et al. 2001).
Rat studies have demonstrated IL-13 and/or EGFR involvement in goblet cell metaplasia/hyperplasia, however no rat studies have directly measured transdifferentiation of ciliated to goblet cells to our knowledge (Shim 2001, Takeyama 2008).