Epithelial stem cell homeostasis in Meibomian gland development, dysfunction, and dry eye disease.

Edem Tchegnon,Lu Q Le,Elnaz Ghotbi,Tracey Shipman,Chung-Ping Liao,Yong Wang,Renee M Mckay

doi:10.1172/jci.insight.151078

Abstract

Dry eye disease affects over 16 million adults in the US, and the majority of cases are due to Meibomian gland dysfunction. Unfortunately, the identity of the stem cells involved in Meibomian gland development and homeostasis is not well elucidated. Here, we report that loss of Krox20, a zinc finger transcription factor involved in the development of ectoderm-derived tissues, or deletion of KROX20-expressing epithelial cells disrupted Meibomian gland formation and homeostasis, leading to dry eye disease secondary to Meibomian gland dysfunction. Ablation of Krox20-lineage cells in adult mice also resulted in dry eye disease, implicating Krox20 in homeostasis of the mature Meibomian gland. Lineage-tracing and expression analyses revealed a restricted KROX20 expression pattern in the ductal areas of the Meibomian gland, although Krox20-lineage cells generate the full, mature Meibomian gland. This suggests that KROX20 marks a stem/progenitor cell population that differentiates to generate the entire Meibomian gland. Our Krox20 mouse models provide a powerful system that delineated the identity of stem cells required for Meibomian gland development and homeostasis and can be used to investigate the factors underlying these processes. They are also robust models of Meibomian gland dysfunction–related dry eye disease, with a potential for use in preclinical therapeutic screening.

Highlights

Dry eye disease is one of the most common ocular surface issues, affecting over 16 million adults in the US, and its prevalence continues to increase [1]
We report that loss of Krox20, a zinc finger transcription factor involved in the development of ectoderm-derived tissues, or deletion of KROX20-expressing epithelial cells disrupted Meibomian gland formation and homeostasis, leading to dry eye disease secondary to Meibomian gland dysfunction
Immunofluorescence staining revealed complete absence of the corneal epithelial marker K12 in the scabrous area of the cornea (Figure 1F), while stratified epidermal markers (K15, K1, and loricrin) were present (Figure 1, G–I). These results indicate that elimination of KROX20 expression in the K14 lineage results in squamous metaplasia of the cornea, a manifestation of severe dry eye

Summary

Introduction

Dry eye disease is one of the most common ocular surface issues, affecting over 16 million adults in the US, and its prevalence continues to increase [1]. Meibomian glands are holocrine sebaceous glands located in the tarsal plate of both the upper and lower eyelids. They consist of several acini organized around a central duct; the acini contain epithelial cells called meibocytes that secrete meibum; after meibocytes mature and terminally differentiate, they rupture to release their lipid content [4, 5]. Meibum secreted from the Meibomian glands functions to maintain moisture on the ocular surface by protecting the aqueous layer from evaporation, while protecting the eye from environmental threats and infections [7, 8]. When meibum production is compromised by Meibomian gland dysfunction, the tear film is destabilized, resulting in evaporative dry eye disease, the most common type of dry eye disease [9]

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Results

Conclusion