%0 Journal Article
%T RAR¦Á and RAR¦Ã reciprocally control K5+ progenitor cell expansion in developing salivary glands
%A Adam R. Stabell
%A Danielle C. Spitzer
%A Deirdre A. Nelson
%A Kara A. DeSantis
%A Kevin J. O'Keefe
%A Melinda Larsen
%J Archive of "Organogenesis".
%D 2017
%R 10.1080/15476278.2017.1358336
%X Understanding the mechanisms of controlled expansion and differentiation of basal progenitor cell populations during organogenesis is essential for developing targeted regenerative therapies. Since the cytokeratin 5-positive (K5+) basal epithelial cell population in the salivary gland is regulated by retinoic acid signaling, we interrogated how isoform-specific retinoic acid receptor (RAR) signaling impacts the K5+ cell population during salivary gland organogenesis to identify RAR isoform-specific mechanisms that could be exploited in future regenerative therapies. In this study, we utilized RAR isoform-specific inhibitors and agonists with murine submandibular salivary gland organ explants. We determined that RAR¦Á and RAR¦Ã have opposing effects on K5+ cell cycle progression and cell distribution. RAR¦Á negatively regulates K5+ cells in both whole organ explants and in isolated epithelial rudiments. In contrast, RAR¦Ã is necessary but not sufficient to positively maintain K5+ cells, as agonism of RAR¦Ã alone failed to significantly expand the population. Although retinoids are known to stimulate differentiation, K5 levels were not inversely correlated with differentiated ductal cytokeratins. Instead, RAR¦Á agonism and RAR¦Ã inhibition, corresponding with reduced K5, resulted in premature lumenization, as marked by prominin-1. With lineage tracing, we demonstrated that K5+ cells have the capacity to become prominin-1+ cells. We conclude that RAR¦Á and RAR¦Ã reciprocally control K5+ progenitor cells endogenously in the developing submandibular salivary epithelium, in a cell cycle-dependent manner, controlling lumenization independently of keratinizing differentiation. Based on these data, isoform-specific targeting RAR¦Á may be more effective than pan-RAR inhibitors for regenerative therapies that seek to expand the K5+ progenitor cell pool. Summary statement: RAR¦Á and RAR¦Ã reciprocally control K5+ progenitor cell proliferation and distribution in the developing submandibular salivary epithelium in a cell cycle-dependent manner while regulating lumenization independently of keratinizing differentiation
%K atR
%K Abranching morphogenesis
%K cytokeratin 5
%K RAR¦Á
%K RAR¦Ã
%K salivary gland
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669212/