Lu Q. Le, MD, PhD
Research from the lab of Lu Q. Le, MD, PhD, has identified a stem cell population required for the development and continuous renewal of tiny glands in the eyelids, called meibomian glands, that are critical for tear film maintenance. Meibomian gland dysfunction results in evaporative dry eye disease, marked by stinging, itchy, and red eyes. If left untreated, more serious problems can develop, including corneal abrasions, ulcers, and hyperkeratinization, which can cause vision loss.
Meibomian gland dysfunction accounts for approximately 90% of dry eye disease cases worldwide. Dr. Le, the Kenneth E. Greer, MD Professor and chair of the Department of Dermatology at the School of Medicine, and his team published their findings in Nature Communications.
Understanding Dry Eyes and Dry Skin
Meibomian glands (MGs) are located in the upper and lower eyelids and contain meibocytes: terminally differentiated, specialized cells that produce meibum. Meibocytes eventually rupture to release the meibum into the ductules of the MG, where it then enters the central duct and is secreted into the lid margin. Meibum is an oily substance produced by the MGs that coats the ocular surface after blinking to create the outermost layer of the tear film, stabilizing the tear film and preventing excessive evaporation of the watery component, thus keeping the eye surface healthy. Because meibocytes rupture when they release meibum they must be continually replenished throughout life.
The equivalent of the MG in the skin is the sebaceous gland, which secretes an oily substance called sebum that provides a protective coating to help the skin retain moisture. Dr. Le’s group has previously reported that the transcription factor KROX20 marks an epidermal stem cell population that gives rise to both hair and skin.
Dr. Le, lead author Yumeng Zhang, PhD, and colleagues now report that the transcription factor KROX20 marks a stem cell population in the MG that gives rise to the whole MGs and are also required for MG renewal. They found that deletion of the Krox20 gene or Krox20-expressing cells resulted in atrophied MGs leading to reduced tear volume and DED. Overexpression of Krox20 resulted in enlarged MGs. Thus, the KROX20-positive “skin” stem cell that gives rise to hair and skin also gives rise to the MG and its loss in MG causes DED, while its loss in skin causes dry skin.
Immunofluorescent stain of the Meibomian glands in the eyelids. Green cells are meibocytes and yellow/red cells are Krox20-expressing stem cells that give rise to the whole Meibomian gland.
Sequencing studies identified the Notch pathway as a downstream signaling pathway directly regulated by KROX20. The researchers found that genetic ablation of the Notch1 gene in Krox20-expressing cells leads to MG atrophy, tear volume loss, and dry eye with corneal hyperkeratinization similar to the phenotype seen with Krox20 deletion. Interestingly, over-expression of Notch was able to partially rescue the MG atrophy in mice with Krox20 deletion. Similarly, pharmacological activation of the Notch signaling pathway using a small molecule drug rescued the MG atrophy and DED suggesting that this could be a possible new treatment for dry eye disease.
These findings identify a Krox20-Notch1 network that transcriptionally regulates MG stem cells for MG development and renewal, and suggest that activation of Notch1 signaling may offer a novel therapeutic approach for preventing and/or treating dry eye diseas, one of the most common ocular conditions in the United States.
Findings Published
The UVA scientists have published their findings in the scientific journal Nature Communications. The research team consisted of Yumeng Zhang, Edem Tchegnon, Elnaz Ghotbi, Zhiguo Chen, Stefanie L. Moye, Yi He, Renee M. McKay, and corresponding author Lu Q. Le. None of the scientists has a financial interest in the work.
The research was supported by National Institutes of Health grant numbers R01 EY033344 and R01 CA166593
Learn more about Le Lab research by visiting their website: https://med.virginia.edu/le-lab/
Filed Under: Research