This paper reviews our current understanding of age-related meibomian gland dysfunction (MGD) and the role of the nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ), in the regulation of meibomian gland function, meibocyte differentiation and lipid synthesis. The studies suggest that PPARγ is a master regulator of meibocyte differentiation and function, whose expression and nuclear signaling coupled with meibocyte renewal is altered during aging, potentially leading to atrophy of the meibomian gland as seen in clinical MGD. Study of meibomian gland stem cells also suggest that there is a limited number of precursor meibocytes that provide progeny to the acini, that may be susceptible to exhaustion as occurs during aging and other environmental factors. Further study of pathways regulating PPARγ expression and function as well as meibocyte stem cell maintenance may provide clues to establishing cellular and molecular mechanisms underlying MGD and the development of novel therapeutic strategies to treating this disease.
Purpose Mice exposed to standardized desiccating environmental stress to induce dry eye-like symptoms have been used as a model to study the underlying mechanisms of evaporative dry eye. While studies have shown marked inflammatory and immune changes, the effect of such stress on meibomian gland function remains largely unknown. We sought to evaluate the effects of desiccating stress on meibocyte proliferation and meibum quality. Methods Ten mice were treated with scopolamine and subjected to a drafty low humidity environment (30–35%). Five and ten days after treatment, eyelids were harvested and cryosections stained with Ki67 antibody to identify cycling cells. Sections were also imaged using stimulated Raman scattering (SRS) microscopy to characterize the gland compositional changes by detecting the vibrational signatures of methylene (lipid) and amide-I (protein). Results Desiccating stress caused a 3-fold increase in basal acinar cell proliferation from 18.3 ± 11.1% in untreated mice to 64.4 ± 19.9% and 66.6 ± 13.4% after 5 and 10 days exposure, respectively (P < .001). In addition, SRS analysis showed a wider variation in the protein-to-lipid ratio throughout the gland, suggesting alterations in meibocyte differentiation and lipid synthesis. Conclusions These data are consistent with a model that a desiccating environment may have a direct effect on meibomian gland function, leading to a significant increase in basal acinar cell proliferation, abnormal meibocyte differentiation, and altered lipid production.
Meibomian gland dysfunction (MGD) is the major cause of evaporative dry eye disease (EDED) and dysfunction is widely thought to mechanistically involve ductal hyperkeratinization, plugging and obstruction. This review re-evaluates the role of hyperkeratinization in MGD based on more recent findings from mouse models. In these studies, eyelids from normal young and old mice or mice exposed to desiccating stress were evaluated by immunofluorescent tomography and 3-dimensional reconstruction to evaluate gland volume, expression of hyperkeratinization markers and cell proliferation or stimulated Raman scattering (SRS) microscopy to assess lipid quality. Results indicate that aging mice show dropout of meibomian glands with loss of gland volume and a forward migration of the mucocutaneous junction anterior to the gland orifice; similar age-related changes that are detected in human subjects. Atrophic glands also showed evidence of epithelial plugging of the orifice without the presence of hyperkeratinization. Mice exposed to desiccating stress showed hyperproliferation of the meibomian gland and ductal dilation suggesting a marked increase in lipid synthesis. Lipid quality was also affected in EDED mice with an increase in the protein content of lipid within the duct of the gland. Overall, age-related changes in the mouse show similar structural and functional correlates with that observed in clinical MGD without evidence of hyperkeratinization suggesting that gland atrophy may be a major cause of EDED. The response of the meibomian gland to desiccating stress also suggest that environmental conditions may accelerate or potentiate age-related changes.
Meibomian gland dysfunction (MGD) is frequent with aging and is the primary cause of dry eye disease, the most prevalent ocular complaint. We used a novel 3-D reconstruction technique, immunofluorescent computed tomography (ICT), to characterize meibomian gland keratinization and cell proliferation in a mouse model of age-related meibomian gland dysfunction (ARMGD). To visualize the changes associated with ARMGD, 5-month and 2-year old mouse eyelids were 3-D reconstructed by ICT using antibodies to cytokeratin (CK) 1, 5 and 6 and the proliferation marker Ki67. We quantified total gland, ductal and lipid volume from the reconstructions, observing a dramatic decrease in old glands. In young glands, proliferative ductules suggest a potential site of acinar progenitors that were found to be largely absent in aged, atrophic glands. In the aged mouse, we observed an anterior migration of the mucocutaneous junction (MCJ) and an absence of hyper-keratinization with meibomian gland atrophy. Thus, we propose that changes in the MCJ and glandular atrophy through a loss of meibocyte progenitors are most likely responsible for ARMGD and not ductal hyper-keratinization and gland obstruction.
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