Epiregulin is critical for the acinar cell regeneration of the submandibular gland in a mouse duct ligation model

Abstract

Acinar cell regeneration from tubular structures has been reported to occur in duct-deligated salivary glands. However, the detailed process of acinar cell regeneration has not been clarified. We have developed a mouse duct ligation model to clarify the mechanisms underlying acinar cell regeneration, and we analyzed the epidermal growth factor receptor (EGFR) and epidermal growth factor (EGF) ligands using the model. We studied these ligands expressions in the course of acinar cell regeneration using immunohistochemistry and RT-PCR methods. In the duct-ligated portion of the submandibular gland (SMG) that underwent atrophy, newly formed acinar cells were observed arising from the tubular structures after the release of the duct obstruction. The constitutive expression of EGFR was observed by immunohistochemistry in both the duct-ligated and duct-deligated animals as well as in normal controls. The EGFR phosphorylation detected on the tubular structures after duct ligation paralleled the acinar cell regeneration. RT-PCR showed an increase in the epiregulin and heparin-binding EGF levels from day 0 to day 3 after the release of the duct obstruction. The EGF level was increased only after day 7. In vitro, cultured cells isolated from ligated SMGs proliferated and produced EGF ligands following the addition of epiregulin to the culture medium. These findings suggest that the tubular structures localized in an atrophic gland are the source of acinar cell regeneration of the salivary gland. The induction of EGF ligands, in particular epiregulin, may play an important role in acinar cell regeneration in this model.

Expression of c-kit and Cytokeratin 5 in the Submandibular Gland after Release of Long-Term Ligation of the Main Excretory Duct in Mice

“…Expression of c-kit has been reported in some ducts in mature, healthy salivary glands [20, 24, 30], and in and around atrophied salivary glands and duct-like structures [9, 17]. While duct-like structures were initially thought to reflect only regressive changes in the acinar portion, they have since been reported to play a role in their regeneration [18, 22]. When rat submandibular glands were exposed to a laser, duct-like structures were observed to proliferate and to differentiate into an immature acinar portion during regeneration [26].…”

Alteration in cellular turnover and progenitor cell population in lacrimal glands from thrombospondin 1 −/− mice, a model of dry eye

“…Many reports have indicated that exocrine glands such as the salivary gland, exocrine pancreas, salivary, and mammary glands have the ability to regenerate (Chuong et al, 2014; Holmberg and Hoffman, 2014; Migliorini et al, 2014) (Arany et al, 2011; Burford-Mason et al, 1993; Nagai et al, 2014). The LG also exhibits repair mechanisms.…”

Switching to normal diet reverses kwashiorkor-induced salivary impairments via increased nitric oxide level and expression of aquaporin 5 in the submandibular glands of male Wistar rats

“…The observed reversal of impaired salivary parameters in the re-fed kwashiorkor rats could be associated with improvement in the body weight and salivary gland weights of the animals. Many studies have shown regeneration of salivary gland following atrophy due to duct ligation (Burgess and Dardick 1998;Takahashi et al 2004;Nagai et al 2014), or denervation (Zhang et al 2014) in rodents. Nagai et al (2014) reported that in the duct ligated portion of the submandibular gland in a mouse that underwent atrophy, newly formed acinar cells were observed arising from the tubular structures after the release of the duct obstruction.…”

“…Many studies have shown regeneration of salivary gland following atrophy due to duct ligation (Burgess and Dardick 1998;Takahashi et al 2004;Nagai et al 2014), or denervation (Zhang et al 2014) in rodents. Nagai et al (2014) reported that in the duct ligated portion of the submandibular gland in a mouse that underwent atrophy, newly formed acinar cells were observed arising from the tubular structures after the release of the duct obstruction. Thus, it was suggested that the tubular structures localized in an atrophic gland are the source of acinar cell regeneration of the salivary gland (Nagai et al 2014).…”

“…Nagai et al (2014) reported that in the duct ligated portion of the submandibular gland in a mouse that underwent atrophy, newly formed acinar cells were observed arising from the tubular structures after the release of the duct obstruction. Thus, it was suggested that the tubular structures localized in an atrophic gland are the source of acinar cell regeneration of the salivary gland (Nagai et al 2014).…”