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Helen P Makarenkova, Daren Lui, Driss Zoukhri, Robert L McKown, Gordon W Laurie; Lacritin Enhances Cell Proliferation in Mouse Lacrimal Gland. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5709. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Aqueous deficient dry eye (ADDE) is characterized by a lack of lacrimal gland (LG) tear secretion associated in some pathological conditions with targeting by immune cells, epithelial cell death and poor regenerative response. It is important therefore to find factors/treatments that promote LG epithelial cell proliferation and gland regeneration. Lacritin is a multifunctional tear protein expressed largely by LG's in humans, horses and canines, and likely in other species in which genomic alignment has detected the lacritin gene Lacrt. Despite the lack of an apparent Lacrt gene in the mouse and rat, the lacritin co-receptor/receptor, modifying enzyme and signaling machinery are conserved, thereby offering an opportunity to explore the potential of exogenous lacritin in LG regeneration or expansion – a putative treatment approach for severe dry eye.
LG explants from embryonic day 15-15.5 (E15-15.5) mice were treated with 4 µM human recombinant lacritin or inactive lacritin truncation mutant C-25 for 24 - 48 hours. Control explants were treated with 4 µM BSA. Explants were immunostained with monoclonal anti-phospho-Histone H3 (pSer28) antibody (Sigma-Aldrich) to assess mitotic G2 to M transition, and counterstained with a polyclonal antibody to laminin (Sigma-Aldrich) to visualize the basement membrane. RNA-seq and /or qRT PCR was used to assess changes in the lacritin co-receptor and modifying enzyme in an adult LG regeneration model.
Lacritin treated explants displayed a ~1.6 fold increase in LG acinar cells vs C-25 or control explants (p = 0.003 [Exp. 1], p = 0.006 [Exp. 2], p = 0.0001 [Exp. 3], respectively). No difference was observed between C-25 and BSA controls (p = 0.27, 0.57, 0.86, respectively). Regeneration of adult LG upregulates expression of lacritin co-receptor syndecan-1 (Sdc1) and the modifying enzyme heparanase (
Recombinant lacritin application triggered LG epithelial cell proliferation, an approach with potential application to severe dry eye with the lacritin co-receptor/modifying enzyme complex available and upregulated in adult LG regeneration. This activity coupled with topical lacritin's capacity to promote basal tearing and restore corneal ocular surface health in dry eye mice point to a potential role for lacritin not only in LG morphogenesis and regeneration, but also in maintaining ocular surface homeostasis.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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