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RAR? and RAR? reciprocally control K5+ progenitor cell expansion in developing salivary glands.

ABSTRACT: 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? and RAR? have opposing effects on K5+ cell cycle progression and cell distribution. RAR? negatively regulates K5+ cells in both whole organ explants and in isolated epithelial rudiments. In contrast, RAR? is necessary but not sufficient to positively maintain K5+ cells, as agonism of RAR? 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? agonism and RAR? 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? and RAR? 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? may be more effective than pan-RAR inhibitors for regenerative therapies that seek to expand the K5+ progenitor cell pool.RAR? and RAR? 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.

SUBMITTER: DeSantis KA

PROVIDER: S-EPMC5669212 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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RARα and RARγ reciprocally control K5+ progenitor cell expansion in developing salivary glands.

DeSantis Kara A KA Stabell Adam R AR Spitzer Danielle C DC O'Keefe Kevin J KJ Nelson Deirdre A DA Larsen Melinda M

Organogenesis 20170921 4

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 iden ...[more]

PMID: 28933645

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Project description:Branching organs, including the salivary and mammary glands, lung, and kidney, arise as epithelial buds that are morphologically very similar. However, the mesenchyme is known to guide epithelial morphogenesis and to help govern cell fate and eventual organ specificity. We performed single-cell transcriptome analyses of 14,441 cells from embryonic day 12 submandibular and parotid salivary glands to characterize their molecular identities during bud initiation. The mesenchymal cells were considerably more heterogeneous by clustering analysis than the epithelial cells. Nonetheless, distinct clusters were evident among even the epithelial cells, where unique molecular markers separated presumptive bud and duct cells. Mesenchymal cells formed separate, well-defined clusters specific to each gland. Neuronal and muscle cells of the 2 glands in particular showed different markers and localization patterns. Several gland-specific genes were characteristic of different rhombomeres. A muscle cluster was prominent in the parotid, which was not myoepithelial or vascular smooth muscle. Instead, the muscle cluster expressed genes that mediate skeletal muscle differentiation and function. Striated muscle was indeed found later in development surrounding the parotid gland. Distinct spatial localization patterns of neuronal and muscle cells in embryonic stages appear to foreshadow later differences in adult organ function. These findings demonstrate that the establishment of transcriptional identities emerges early in development, primarily in the mesenchyme of developing salivary glands. We present the first comprehensive description of molecular signatures that define specific cellular landmarks for the bud initiation stage, when the neural crest-derived ectomesenchyme predominates in the salivary mesenchyme that immediately surrounds the budding epithelium. We also provide the first transcriptome data for the largely understudied embryonic parotid gland as compared with the submandibular gland, focusing on the mesenchymal cell populations.

Dataset Information

RAR? and RAR? reciprocally control K5+ progenitor cell expansion in developing salivary glands.

Publications

RARα and RARγ reciprocally control K5<sup>+</sup> progenitor cell expansion in developing salivary glands.

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