Transcriptional network regulating meibomian gland resident stem cells during morphogenesis and homeostasis

Summary: The Meibomian Glands (MGs) are located in the eyelids and secrete meibum, an oily substance that prevents the tear film from evaporation. MGs are holocrine glands, meaning their cells –meibocytes – release meibum upon cell rupture. Thus, these cells must be replenished throughout life. Dysfunction of MGs results in one of the most common eye conditions, Dry Eye Disease, highlighting the importance of elucidating the molecular mechanisms underlying MG morphogenesis and homeostasis. In our studies, we found that loss of <i>Krox20</i> led to a significant reduction of MGs, whereas its overexpression resulted in enlarged MGs, indicating the critical role of <i>Krox20</i> in MG resident stem cells. Using <i>Krox20</i> lineage tracing and ablation studies, we investigated the processes that govern lineage commitment during MG morphogenesis and homeostasis. We found that <i>Krox20</i> marks MG stem/progenitor cell pools, and regulates cellular contributions to the glands. We also found that Notch1 signaling is regulated by <i>Krox20</i> and that ablation of the <i>Notch1</i> gene in <i>Krox20</i>-expressing cells leads to gland atrophy, while <i>Notch1</i> overexpression partially rescues MG atrophy caused by the loss of <i>Krox20</i>. Together, these results reveal a critical interaction between <i>Krox20</i> and the Notch1 pathway in MG resident stem cells. Activation of Notch1 signaling offers a potential novel approach to preventing and treating dry eye disease caused by the depletion of the MG stem cell pool that happens with normal aging and in some disease states. Yumeng Zhang¹, Edem Tchegnon², Elnaz Ghotbi², Yi He¹, Zhiguo Chen¹, Renee McKay¹, Lu Le¹ 1. Department of Dermatology, University of Virginia, Charlottesville, VA, United States. 2. Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, TX, United States. Stem Cell Biology, Tissue Regeneration and Wound Healing