Age-related changes in the meibomian gland
Introduction
Meibomian glands are lipid excreting glands embedded in the tarsal plate of the eyelid. Lipids from the meibomian gland play an important role in the maintenance of the ocular surface tear film and form the most superficial layer that prevents evaporation and protects against excessive dehydration (Driver and Lemp, 1996). In meibomian gland dysfunction (MGD) there is thought to be abnormal lipid excretion either in quantity or quality that results in increased evaporation leading to blepharitis and evaporative dry eye syndrome (DES) (International Dry Eye WorkShop, 2007). During aging, several changes occur within the meibomian gland including acinar atrophy, basement membrane thickening, ductal hyperkeratinization and lipogranulomatous inflammation leading to a decreased volume and quality of meibomian gland excreta (Obata, 2002). There is also evidence showing an association between MGD and androgen deficiency that occurs in the elderly (Den et al., 2006, Steagall et al., 2002, Sullivan et al., 2002a, Sullivan et al., 2002b, Sullivan et al., 2002c, Sullivan et al., 2002d, Suzuki et al., 2002, Yamagami et al., 2002a, Yamagami et al., 2002b). Despite these findings, MGD is not a well characterized entity and further study is necessary to understand the pathogenesis of this disorder.
While the understanding of meibomian gland function is limited, there has been extensive research into the dynamic growth and differentiation of the sebaceous gland, a holocrine lipid excreting gland of the skin comprised of sebocytes. These studies indicate that sebocyte differentiation involves signaling by the peroxisome proliferator activator receptor (PPAR) in response to lipogenic factors that initiates lipogenesis and the accumulation of intracellular lipid droplets (sebum) (Tontonoz and Spiegelman, 2008). PPARs represent a family of transcription factors (α, β, σ, γ) that are activated by fatty acids for which PPARγ is the major isoform expressed in the sebaceous gland. As lipid droplets coalesce and fill the cytoplasm, the sebocyte then undergoes degeneration and releases lipid onto the hair shaft for lubrication and protection of the skin against bacterial infection (Fuchs, 2007). Replacement of disintegrated sebocytes is thought to involve sebocyte progenitor cells located within the ductal epithelium of sebaceous gland that express the transcriptional repressor, B-lymphocyte-induced maturation protein-1 (Blimp1). Studies suggest that Blimp1 suppresses c-myc, and that down-regulation of Blimp1 in progenitor cells allows for proliferation and differentiation of sebocytes.
Since aging has been associated with dysfunction of the meibomian gland and the sebaceous gland (Obata, 2002, Pochi et al., 1979, Zouboulis and Boschnakow, 2001), this study evaluated the effects of age on meibocyte differentiation and renewal by assessing the localization of PPARγ and Blimp1 in association with neutral lipid synthesis, cell cycling and meibomian gland size in the mouse. We report for the first time that there is a marked change from a cytoplasmic to nuclear localization of PPARγ during aging that is associated with significant decrease in meibocyte cell cycling and meibomian gland size. Furthermore, no isolated Blimp1 positive cells could be identified within the meibomian gland that were not CD45 positive indicating that some glands may be infiltrated by plasmacytoid cells, particularly in older mice.
Section snippets
Animals
A total of 49 C57Bl/6 mice were used in this study. Fifteen animals at 2 months, 13 animals at 6 months, 15 animals at 12 months and 6 animals at 24 months of age were humanely sacrificed by cervical neck dislocation after anesthesia using ketamine HCl (100 mg/kg body weight, Bioniche Pharma, Lake Forest, IL) and xylazine (20 mg/kg body weight, Lloyd Laboratories, Shenandoah, IO). All procedures were approved by the UCI IACUC and conducted in accordance with ARVO Statement for the Use of
Lipogenesis
The effect of age on meibocyte differentiation was first evaluated by identifying the location and expression of PPARγ within the meibomian gland acinar cells (Fig. 1). Immunofluorescent staining of eyelids from 2 month old and 6 month old mice showed perinuclear and cytoplasmic staining of meibocytes within the acini, which appeared more intense in basal cells of 2 month old mice and more vesicular in 6 month old mice (Fig. 1, A–D). This pattern of staining was noticeably changed in older mice
Discussion
We have identified distinct age-related changes in the mouse meibomian gland that appear to model changes in aging human meibomian glands (Obata, 2002) thought to underlie the development of age-related evaporative dry eye and meibomian gland dysfunction. In comparing young (2–6 month) to old (12–24 month) meibomian glands there was a distinct change from a cytoplasmic to a nuclear localization of the nuclear receptor PPARγ that plays an important role in controlling differentiation of the
Acknowledgments
Supported in part by NIH Infrastructure Grant EY016663; Support Grant from Research to Prevent Blindness, Inc, The Skirball Program in Molecular Ophthalmology, and a Research Gift from Alcon.
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Contributed equally to the paper.