Abstract
Xerostomia and salivary hypofunction often result as a consequence of radiation therapy for head and neck cancers, which are diagnosed in roughly 60,000 individuals every year in the U.S. Due to the lack of effective treatments for radiation-induced salivary hypofunction, stem cell-based therapies have been suggested to regenerate the irradiated salivary glands. Pharmacologically, restoration of salivary gland function has been accomplished in mice by administering IGF-1 shortly after radiation treatment, but it is not known if salivary stem and progenitor cells play a role. We show that radiation inactivates aPKCζ and promotes nuclear redistribution of Yap in a population of label-retaining cells in the acinar compartment of the parotid gland (PG)– which comprises a heterogeneous pool of salivary progenitors. Administration of IGF-1 post-radiation maintains activation of aPKCζ and partially rescues Yap’s cellular localization in label retaining cells, while restoring salivary function. Finally, IGF-1 fails to restore saliva production in mice lacking aPKCζ, demonstrating the importance of the kinase as a potential therapeutic target.
Highlights
Regeneration was mediated by the protective effect of neurturin on parasympathetic nerves, which in turn promotes survival of Keratin-5 progenitors[14]
The Par3-aPKC complex, which is comprised of atypical protein kinase C zeta or iota, partitioning defective 3 (PAR3) and 6 (PAR6), and cell division control 42 (CDC42), is involved in appropriate formation of the apical-lateral membrane borders[27,28], as well as regulating cell division and cell fate in lower organisms and mammalian cells[21,29,30,31,32]
While administration of Insulin-like growth factor 1 (IGF-1) induces recovery of saliva in wild type animals at 30 days post-treatment, saliva output of IGF-treated Prkcz−/− mice is significantly lower compared to controls and similar to irradiated animals (Fig. 7C), indicating that aPKCζ is required for functional restoration of salivary glands with IGF-1. It has been a matter of debate whether salivary gland SPCs contribute to maintain homeostasis in the adult glands and whether they can be stimulated to promote repair following radiation injury
Summary
Regeneration was mediated by the protective effect of neurturin on parasympathetic nerves, which in turn promotes survival of Keratin-5 progenitors[14]. The Par3-aPKC complex, which is comprised of atypical protein kinase C zeta or iota (aPKCζ, aPKCι), partitioning defective 3 (PAR3) and 6 (PAR6), and cell division control 42 (CDC42), is involved in appropriate formation of the apical-lateral membrane borders[27,28], as well as regulating cell division and cell fate in lower organisms and mammalian cells[21,29,30,31,32] Disruption of this complex has been linked to deficient wound healing[30,31,33,34]. IGF-1, a growth factor previously shown to restore function of irradiated salivary glands in mice[7], has been shown to induce activation of aPKCζ38,39, and aPKCζ is a known negative regulator of Yap during tissue regeneration[40]. This restoration process involves maintenance of aPKCζ phosphorylation and modulation of nuclear translocation of Yap in acinar LRCs in an aPKCζ-dependent fashion
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