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Editors Selection IGR 11-3

Basic Science: Trabecular meshwork cell loss and regeneration

Comment by Terete Borras on:

56161 Outflow tract ablation using a conditionally cytotoxic feline immunodeficiency viral vector, Zhang Z; Dhaliwal AS; Tseng H et al., Investigative Ophthalmology and Visual Science, 2014; 55: 935-940

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It is well-accepted that trabecular meshwork (TM) cellularity decreases with age and POAG patients have lower TM cellularity than age-matched controls. Since Alvarado's first report in the early 1980s, cell loss mechanisms and their potential association with elevated IOP have been barely studied. The main reason for this lag was the lack of a model able to manipulate the TM cellular system.

Making use of their experience delivering transgenes to the TM using lentiviral vectors, Loewen's group put together a very clever idea to specifically ablate TM cells in living rats. The authors generated a lentiviral vector carrying the Herpes Simplex Virus thymidine kinase gene (HSVtk) and targeted it to the rat's TM. This gene product phosphorylates nucleotide analogs, such ganciclovir (GCV), which compete with normal nucleotides during DNA replication and lead cells to its death. The strategy is being extensively used in cancer to specifically destroy rapidly growing tumors. Its application to manipulate TM cellularity is clever and highly innovative. After showing proof of principle in culture, the authors injected HSVtkiG intracamerally followed by intraperitoneal GCV one week post-infection. IOPs went down one to two days post-GCV and recovered at 30 days. Histology showed TM cell depletion from two to seven days post-CGV and cell recovery at 30 days.

lthough some methods need polishing, their strategy and findings open a new research era on the role of TM cellularity

Although some methods need polishing (precise cell counting descriptions), their strategy and findings open a new research era on the role of TM cellularity. Discussion of the unexpected GCV effect on quiescent cells, correlation of TM cell loss with lower pressures rather than with glaucomatous signs, or the remarkable finding of cellular regeneration, would had been desirable. However, it is not expected to have all answers in a first study. What is truly important is that this innovative approach gives the field a much needed model to study loss/regeneration of TM cells in vivo.

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