MicroRNA-184 Regulates Corneal Lymphangiogenesis

The lymphatic network penetrates most tissues and its dysfunction is associated with a broad spectrum of disorders, such as cancer metastasis, inflammation, transplant rejection, hypertension, obesity, and lymphedema.1,2 After being neglected for centuries due to historical reasons and technical limitations, lymphatic research has gained significant attention and great progress in recent years. However, to date, few effective treatments are available for lymphatic disorders. Therefore, it is imperative to identify new regulators of lymphangiogenesis (LG; the formation of lymphatic vessels) in the hope of developing novel therapeutic strategies. The cornea offers an ideal site for LG research. Due to its accessible location, transparent nature, and alymphatic feature under normal condition, this tissue provides a favorable model to study inducible lymphatic growth without having to distinguish from preexisting or background vessels.2 Corneal LG can be induced by a number of pathologic insults, such as inflammation, infection, trauma, and chemical burns, and it is a primary mediator of transplant rejection.2–4 MicroRNAs are a class of small noncoding RNAs that regulate gene expression by RNA silencing and posttranscriptional regulation,5,6 Their specific roles in the eye and eye-related diseases remain largely unknown. A recent study using microRNA arrays to compare mouse cornea to epithelial-rich footpads has identified microRNA-184 (mir-184) as the most abundantly expressed microRNA in the mouse cornea.7 The restrictive expression profile of mir-184 in the normal and alymphatic cornea7,8 has prompted us to evaluate its potential role in corneal LG and whether it can be used as an antilymphangiogenic factor. We report the novel finding that mir-184 is significantly downregulated in corneal inflammatory LG and, accordingly, its synthetic mimic inhibits corneal lymphatic growth in vivo. Moreover, mir-184 overexpression in human lymphatic endothelial cells (LECs) in vitro suppresses their functions of adhesion, migration, and tube formation. These results together reveal that mir-184 is a negative regulator of the lymphangiogenic process. Further investigation on this natural regulator holds the great promise for developing new and effective treatment for LG-related diseases in the body.