Meibocyte differentiation and renewal: Insights into novel mechanisms of meibomian gland dysfunction (MGD)

Abstract

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.

Meibomian Gland Disease

“…13 Down regulation of PPARγ is thought to underlie the decreased meibocyte differentiation and lipid synthesis seen in aging, leading to gland atrophy and a hyposecretory state. 6,11 Interestingly, hyperkeratinization and gland obstruction were not found to play a role in the development of MGD in this mouse model. 6 …”

“…3–5 Newer studies have added to this paradigm and describe meibocyte abnormalities as a contributing mechanism in MGD. 6,7 Support for the role of the meibocyte in MGD comes from pathophysiologic studies evaluating intrinsic (e.g. aging) and extrinsic (e.g.…”

“…10 Likely underlying these changes, aged meibomian glands exhibit decreased meibocyte differentiation, decreased meibocyte cell renewal, decreased meibomian gland size, and increased inflammatory cell infiltration, as studied in human and mouse models. 6,11,12 These changes have been associated with decreased expression of peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ is a nuclear receptor protein involved in regulating meibocyte differentiation and lipid biosynthesis, contributing to the formation and function of meibomian glands.…”

Meibomian glands, meibum, and meibogenesis

“…A different approach was undertaken by Jester and colleagues who tested the role of PPARγ in modulating the lipid metabolism in cultured mouse meibocytes and mice (Hwang et al, 2017; Jester et al, 2016). It was observed that the amount of lipid produced by the cells was dependent on the serum levels in the culture media: low serum concentrations (0% to 2%) led to a marked reduction in the lipid production, as evidenced by HCS LipidTox staining.…”

Differentiation Patterns of Immortalized Human Meibomian Gland Epithelial Cells in Three-Dimensional Culture

“…It was recently proposed that renewal of meibocyte could rely on a limited number of progenitor meibocytes, whereas meibomian gland duct would be derived from multiple origins. 49,50 This can explain why HMGECs induced CK expression in a pattern closely resembling that of ductal cells in response to an air-rich environment. Even if appropriate progenitor populations are found in HMGECs, they may have been exhausted because HMGECs were established from donors ranging from 35 to 85 years.…”