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Helen P Makarenkova, Takeshi Umazume, Darlene A Dartt; Progenitor cell transplantation rescues lacrimal gland acinar structure in the thrombospondin-1 null (TSP-1-/-) mice. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3197.
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© ARVO (1962-2015); The Authors (2016-present)
In humans, the LG is the primary contributor to the aqueous layer of the tear film. Production of tears in insufficient quantity or of inadequate quality results in constant irritation of the ocular surface leading to aqueous deficiency dry eye (ADDE). Our novel therapeutic approach to treat dry eye is to enhance LG function by promoting regeneration via stem/progenitor cell transplantation.
Gene expression in murine LGs was examined by qRT-PCR and immunostaining. LacZ+ epithelial cell progenitors (EPCPs) were isolated by Fluorescence Activated Cell Sorting (FACS) and used in transplantation experiments to analyze donor cell engraftment and LG rescue. Analysis of transplanted cell engraftment was performed at 30, 60, and 90 days after transplantation using frozen and paraffin sections.
We analyzed the therapeutic potential of the LG epithelial progenitor cells (EPCPs), isolated from adult LacZ+ wild type LGs and transplanted into ‘diseased’ LGs of a new mouse model for Sjogrens Syndrome - the TSP-1-/- mice. TSP-1-/- mice are normal at birth, but progressively develop a chronic form of ocular surface disease, characterized by deterioration, inflammation, and secretory dysfunction of the lacrimal gland. Isolated donor EPCPs express pluripotency factors and markers of the epithelial cell lineage. Moreover, when transplanted into injured or diseased LGs, they restore acinar and ductal compartment of the LG. We compared structural changes in the LG of TSP-1-/- LG injected with EPCPs to the TSP-1-/- LGs injected with saline. We found that 20 days after cell injection EPCPs were mostly incorporated into LG ducts. At this early stage we also noticed decrease in density of infiltrating cells and general improvement of diseased LG structure, suggesting that injected EPCP cells may produce anti-inflammatory factors that reduce immune cell infiltration. Moreover, 60 and 90 days after injection, EPCPs were found in both ducts and secretory acini. EPCP-injected TSP-1-/- LGs showed progressive reduction of cell infiltration, differentiation of donor cells within secretory acini and substantial improvement of LG structural integrity.<br />
Our approach is the first proof for the use of progenitor cell transplantation to rescue LG deficiency. These findings are promising for development of stem cell therapies to treat LG diseases.
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