IFT140+/K14+ cells function as stem/progenitor cells in salivary glands

Abstract

Stem/progenitor cells are important for salivary gland development, homeostasis maintenance, and regeneration following injury. Keratin-14+ (K14+) cells have been recognized as bona fide salivary gland stem/progenitor cells. However, K14 is also expressed in terminally differentiated myoepithelial cells; therefore, more accurate molecular markers for identifying salivary stem/progenitor cells are required. The intraflagellar transport (IFT) protein IFT140 is a core component of the IFT system that functions in signaling transduction through the primary cilia. It is reportedly expressed in mesenchymal stem cells and plays a role in bone formation. In this study, we demonstrated that IFT140 was intensively expressed in K14+ stem/progenitor cells during the developmental period and early regeneration stage following ligation-induced injuries in murine submandibular glands. In addition, we demonstrated that IFT140+/ K14+ could self-renew and differentiate into granular duct cells at the developmental stage in vivo. The conditional deletion of Ift140 from K14+ cells caused abnormal epithelial structure and function during salivary gland development and inhibited regeneration. IFT140 partly coordinated the function of K14+ stem/progenitor cells by modulating ciliary membrane trafficking. Our investigation identified a combined marker, IFT140+/K14+, for salivary gland stem/progenitor cells and elucidated the essential role of IFT140 and cilia in regulating salivary stem/progenitor cell differentiation and gland regeneration.

Minor salivary gland stem cells: a comparative study of the biological properties under clinical-grade culture conditions

“…Keratin 14 is expressed in adult myoepithelial cells, but in addition, according to Adhikari et al, CKs 14 and 18 could also be found in acinar cells during acinar cell development (Adhikari et al 2018 ). We detected keratin 14 because Keratin-14 + (K14 + ) cells have gained increasing attention given that they are stem/progenitor cells that are actively involved in salivary gland development, homeostasis maintenance, and regeneration following injury (Zhang et al 2022 ). Furthermore, Kusama et al mentioned that CK18 was detected in the cytoplasm of acinar/ductal cells in normal human salivary glands (Kusama et al 2000 ).…”

Duct ligation/de-ligation model: exploring mechanisms for salivary gland injury and regeneration

“…May et al showed that CK14 + progenitor cells are fast-cycling cells that multiply in response to radiation-induced damage by persistent proliferation, and repopulate the granulated ducts by asymmetric division (May, et al, 2018). Zhang et al demonstrated that intra-flagellar transport (IFT + )/CK14 + stem/progenitor cells can promote gland regeneration by self-renewing and differentiating into granular ductal cells after duct de-ligation ( Zhang, et al, 2022 ). Hisatomi et al demonstrated that SMG duct ligation can induce the proliferation and expansion of Sca-1 + /c-Kit + stem cells to repair injury ( Hisatomi, et al, 2004 ).…”

Alterations in histology of the aging salivary gland and correlation with the glandular inflammatory microenvironment

“…A recent study identified a combined marker, the intraflagellar transport protein 140 (IFT140) and keratin-14, for salivary gland stem/progenitor cells. 6 The authors elucidated IFT140 was essential for regulating salivary stem/progenitor cell differentiation and gland regeneration. In contrast, another study combining genetic pulse-chase experiments with single-cell clonal analyses and lineage-tracing analyses has shown that salivary gland homeostasis is maintained through acinar cell self-renewal by self-duplicating without a significant input from stem/progenitor cells.…”