Controlling Autoimmune Inflammation and Promoting Salivary Gland Regeneration in Sjogren's Syndrome

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PROJECT SUMMARY Sjӧgren’s syndrome is an autoimmune disease that causes chronic inflammation and damage/dysfunction of salivary and lacrimal glands, with hyposalivation as one of the main clinical manifestations. The disease greatly compromises the oral and systemic health of 4 million Americans, mostly women, with no cure or effective biological therapy. Stem cell therapies hold great promise for Sjӧgren’s disease, but the chronic autoimmune inflammation greatly impedes the likelihood of success. There is a critical need for new strategies and methods for attenuation of autoimmune inflammation achieve effective and sustained regeneration of the damaged and dysfunctional salivary glands. The objective of this exploratory project to elucidate the impact of specialized pro- resolving mediators (SPMs) on the expansion, renewal and immune-regulatory activity of salivary gland stem cells both in vitro and in vivo. SPMs are pro-resolving lipid mediators that mediate active resolution of inflammation and have demonstrated abilities to enhance the immunomodulatory, pro-healing and regenerative properties of stem cells. Moreover, SPMs can also be produced by stem cells. Our preliminary studies provided compelling evidence that SPMs positively impact both the stem cell activity and the immune-regulatory property of mouse salivary gland stem cells. Our innovative central hypothesis is that SPMs can promote sustainable structural and functional restoration of damaged salivary glands in Sjӧgren’s disease setting by acting on both salivary gland stem cells and immune/inflammatory cells to simultaneously mitigate autoimmune inflammation and enhance tissue regeneration. In Aim 1, we will examine whether lipoxin A4 and maresin-1 can boost the renewal, expansion, salivary organoid formation, SPM production and immune-regulatory activity of salivary gland stem cells from normal C57BL/6 mice in Matrigel-based expansion and differentiation culture systems. In Aim 2, we will determine if these SPMs can promote the structural and functional restoration of damaged salivary glands in Sjӧgren’s disease condition in vivo. Specifically, we will assess whether lipoxin A4 and maresin-1 administered to Sjӧgren’s disease-afflicted mice transplanted with salivary gland stem cells can simultaneously attenuate inflammation and enhance tissue regeneration, thereby achieving sustainable structural and functional restoration of salivary glands. Major methodologies employed in this project include Matrigel culture, intra- salivary gland cell transfer, high-throughput RNA-sequencing and bioinformatics, flow cytometry, real-time qPCR, immunohistochemistry and Luminex assay. Completion of this innovative exploratory project will elucidate the actions of SPMs in salivary gland stem cell-mediated tissue regeneration in the Sjögren’s disease condition. It will advance the development of stem cell therapies that concomitantly attenuate autoimmune inflammation and enhance tissue regeneration to achieve sustainable and effective restoration of salivary glands for Sjögren’s syndrome patients as well as patients with other salivary gland injury/ inflammatory conditions.