Date of Award

1-1-2019

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biological Sciences

Content Description

1 online resource (xii, 138 pages) : illustrations (chiefly color)

Dissertation/Thesis Chair

Melinda Larsen

Committee Members

Paolo Forni, Prashanth Rangan, Susan Laflamme

Keywords

Salivary glands, Rho-associated protein kinases, Stem cells, Sjogren's syndrome

Subject Categories

Cell Biology

Abstract

Salivary glands are crucial organs that are responsible for secreting saliva which is important for the breakdown of carbohydrates, providing lubrication of the mouth, and maintenance of oral health. Patients diagnosed with Sjögren's Syndrome or receiving treatment for head and neck cancer, can permanently lose salivary gland function, which is referred to as salivary hypofunction. As a result, these patients develop Xerostomia, or the feeling of dry mouth, and suffer from an overall decreased quality of life. To combat the negative effects of salivary hypofunction, stem cell therapy is an attractive option, as implantation of specific cell populations can rescue salivary gland function. Cells expressing the tyrosine kinase, Kit, have previously been shown to restore function in irradiated murine salivary glands. For clinical transplantation, expansion of stem/progenitor cells is a limiting factor. Expansion of salivary progenitor cells has previously been accomplished through floating 3D cultures known as salispheres. However, further characterizing the cellular composition of salispheres could improve their regenerative capabilities, as these salispheres could be grown under conditions that enrich for cells expressing progenitor markers that replenish the acinar lineage. As the Rho-associated Kinase (ROCK) inhibitor, Y27632, has been used to promote survival of stem/progenitor cells grown ex vivo, we investigated whether application of Y27632 treatment in salisphere formation in different cell media contexts could be used to modulate the composition of adult epithelial progenitor cells in salispheres. In a simple serum-containing medium, addition of Y27632 increased the number of proliferative basal progenitor cells expressing Keratin 5. Salispheres cultured for three days in specialized Salisphere (or Sali) medium in the presence of Y27632, showed an increased number of proliferating Kit+ cells and Mist1+ acinar cells, demonstrating that inhibition of ROCK signaling can modulate the expansion and survival of different progenitor cell populations, which is modified by other signals.

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