Ocular inflammatory stimuli, such as a corneal transplant, can trigger the sprouting of new lymphatic vessels in the limbal region—a process researchers have termed lymphangiogenesis. This is a significant risk factor for corneal transplant rejection, and it can lead to corneal scarring and reduced vision. Although the exact mechanisms governing lymphangiogenesis remain unknown, previous research shows hyaluronan (HA), which promotes inflammatory angiogenesis in other vascular beds, is also abundant in the limbal extracellular matrix and may play a key role in lymphangiogenesis.

To better understand this process, researchers used a mouse model to investigate the effects of injuries that induce lymphangiogenesis, as well as mice lacking the hyaluronan synthases. They found the mice without HA in the limbal stem cell niche could only form rudimentary lymphatic vessels in the corneal limbus—normal mice had a threefold increase in corneal lymphatic vessel branches compared with mice lacking HA synthases.

“The inability of these mice to synthesize HA might well explain their failure to form lymphatic vessels,” the study speculates. Using an induced alkali burn, they found mice able to increase HA production in response to the injury had a concurrent increase in lymphangiogenesis. Mice with blocked HA production did not, but a single injection of HA triggered lymphangiogenesis and subsequent corneal scarring. 

The researchers suggest therapeutic blockade of HA-mediated lymphangiogenesis might prevent the corneal scarring and rejection that frequently result from corneal transplantation.

“Understanding mechanisms that govern corneal lymphangiogenesis opens new research avenues for the development of specific strategies to limit lymphatic vessel growth,” the researchers wrote in their paper. Limiting HA expression after injury could limit corneal lymphangiogenesis, tumor growth and metastasis, all of which have serious visual consequences.

Sun M, Puri S, Mutoji KN, et al. Hyaluronan derived from the limbus is a key regulator of corneal lymphangiogenesis. Invest Ophthalmol Vis Sci. 2019;60(4):1050-62.