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Epithelial stem cell homeostasis in Meibomian gland development, dysfunction, and dry eye disease
Edem Tchegnon1,2, Chung-Ping Liao1,3, Elnaz Ghotbi1
1Department of Dermatology and.
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.
Insights
Krox20 identifies stem cells crucial for Meibomian gland development and function. Loss of Krox20 leads to Meibomian gland dysfunction and dry eye disease, offering new models for research.
Area of Science:
- Ophthalmology
- Developmental Biology
- Stem Cell Biology
Background:
- Dry eye disease impacts over 16 million US adults, frequently caused by Meibomian gland dysfunction (MGD).
- The specific stem cells responsible for Meibomian gland development and maintenance remain poorly understood.
Purpose of the Study:
- To identify the stem cells involved in Meibomian gland development and homeostasis.
- To investigate the role of the transcription factor Krox20 in Meibomian gland biology.
- To establish novel mouse models for studying MGD-related dry eye disease.
Main Methods:
- Utilized genetic mouse models with Krox20 loss or deletion of KROX20-expressing cells.
- Performed lineage-tracing and gene expression analyses.
- Assessed Meibomian gland formation, homeostasis, and dry eye phenotypes.
Main Results:
- Loss of Krox20 or KROX20-expressing cells disrupted Meibomian gland formation and homeostasis, causing dry eye disease.
- Ablation of Krox20-lineage cells in adult mice also induced dry eye disease, indicating Krox20's role in mature gland maintenance.
- Krox20 expression is restricted to ductal areas, but Krox20-lineage cells generate the entire mature Meibomian gland, suggesting Krox20 marks a key progenitor population.
Conclusions:
- Krox20 marks a stem/progenitor cell population essential for Meibomian gland development and homeostasis.
- Krox20-deficient mouse models effectively replicate MGD-related dry eye disease and are suitable for therapeutic screening.
- This study elucidates the identity of critical stem cells for Meibomian gland function, advancing our understanding of dry eye disease.
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