Neuronal and Progenitor/Stem Cell Function During Salivary Gland Development

National Institute Of Dental & Craniofacial Research

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Abstract

This project has two parts, one investigating the communication between parasympathetic nerve development and SMG epithelial morphogenesis, and the second identifying mouse salivary gland stem/progenitor cell populations within the gland. The maintenance of progenitors as a reservoir of undifferentiated cells is required for organ development and regeneration. Parasympathetic nerves are a vital component of the progenitor niche during development. Injured adult organs do not regenerate after parasympathectomy, and there are few treatments to improve organ regeneration or prevent damage, particularly that caused by therapeutic irradiation. Restoring parasympathetic function with the neurotrophic factor neurturin increases epithelial organ regeneration after irradiation. We used SMG explant culture and injured the tissue with irradiation. The progenitors survived, parasympathetic function was diminished, and epithelial apoptosis reduced expression of neurturin, which consequently increased neuronal apoptosis. Treatment with neurturin reduced neuronal apoptosis, restored parasympathetic function, and increased epithelial regeneration. Furthermore adult human salivary glands damaged by irradiation also had reduced parasympathetic innervation but an increase in sympathetic innervation. We propose that neurturin will protect the parasympathetic nerves from damage and improve regeneration. We continue to use viral vectors that express neurotrophic factors to infect salivary glands of mice and minipigs in vivo to improve the function of surviving nerves in repairing the gland. Our goal is to characterize cells that express keratin 5 (K5) and Keratin 14 (K14) in salivary glands to identify markers that could be used to isolate specific subpopulations and to understand the relationships among these cells. We use mice that express transgenic reporters K5venus and K14rfp SMGs and single-cell genomic analyses. Our ongoing analysis will characterize the multiple cell populations and identify markers to isolate some of them by FACs. These cells may be useful to expand in vitro for use in regenerative therapy of irradiated salivary glands.