Lacrimal Gland Inflammation Deregulates Extracellular Matrix Remodeling and Alters Molecular Signature of Epithelial Stem/Progenitor Cells

Abstract

PURPOSE. The adult lacrimal gland (LG) is highly regenerative and is able to repair itself even after substantial damage; however, this ability to regenerate is lost with the development of dry eye conditions in chronically inflamed LGs.This study compares changes in the cell adhesion and cell matrix molecules and stem cell transcription factors in the LGs of healthy mice and of two mouse models of Sjögren's syndrome: nonobese diabetic (NOD) and MRLlpr/lpr (MRL/lpr) mice during the early stage of inflammation. METHODS. TheLGs from 12-to 13-week-old female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for quantitative (q) RT-PCR and qRT-PCR Arrays, histology, immunohistochemistry, and Western blotting. RESULTS. The extracellular matrix (ECM) and adhesion molecules RT2 -PCR array combined with protein expression data revealed changes in the expression of integrins, matrix metalloproteinases, and other molecules, which are associated largely with invasion, attachment, and expansion of the lymphocytic cells, whereas changes in the stem cell transcription factors revealed substantial decrease in expression of transcription factors associated with epithelial stem/progenitor cell lineage. CONCLUSIONS.We concluded that the expression of several important ECM components is significantly deregulated in the LG of two murine models of Sjögren's syndrome, suggesting an alteration of the epithelial stem/progenitor cell niche. This may result in profound effects on localization, activation, proliferation, and differentiation of the LG stem/progenitor cells and, therefore, LG regeneration.

Manipulation of Panx1 Activity Increases the Engraftment of Transplanted Lacrimal Gland Epithelial Progenitor Cells

“…Our previous 14 , 74 and current studies support the idea that persistent chronic LG inflammation mediates changes in the stem/progenitor cell survival/function that recovers when inflammation abates.…”

“… 14 Our experiments also suggested that endogenous stem cell function and engraftment of transplanted cells depends on LG inflammation level. 14 , 74 These data imply that using anti-inflammatory approaches may have important therapeutic implications in ongoing dry eye disease or as a therapy combined with stem/progenitor cell transplantation. The acute LG injury model reported previously 15 was useful to study cell engraftment.…”

Lacrimal Gland Repair Using Progenitor Cells

“…Importantly, we showed for the first time that intraglandular transplantation of EPCPs could restore structure and function of the chronically “diseased” TSP1 −/− LG. We recently showed that expression of important epithelial stem/progenitor cell markers is altered in the LGs of two mouse models of Sjögren's syndrome: nonobese diabetic and MRL‐lpr/lpr mice during LG inflammation . This finding suggests the importance of the LG state for stem progenitor cell function and the possible role of inflammation in suppressing regeneration.…”

Regeneration of Lacrimal Gland Function to Maintain the Health of the Ocular Surface

“…Stem cell microenvironment or ''niche'' has been recognized as very important in stem cell maintenance. Umazume et al 31 have shown that the expression of epithelial stem/ progenitor cell markers is altered in the LGs of those with Sjögren's syndrome (nonobese diabetic and MRL-lpr/lpr mice) during LG inflammation. Mishima et al 32 have sorted cells by the expression of the adenosine triphosphate-binding cassette superfamily G member 2 (ABCG2), a critical factor for the side population (SP) phenotype.…”