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M.I. Rosenblatt, C.M. Nimigean, D.T. Azar; Modeling Corneal Cell Kinetics: Implications for Gene Transfer . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2591.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To develop a novel modeling scheme to characterize the theoretical kinetics of corneal cell layer maintenance and regeneration, allowing predictions of gene transfer behavior. Methods: For modeling, a cell layer was divided into three potential compartments. Compartment A contained stem cells capable of dividing or moving to compartment B or C. Compartment B represented dividing cells capable of either replicating or moving to compartment C. Compartment C contained cells which could not replicate, but which could be lost. Models contained rate constants for replication and transitions between compartments. The model for corneal epithelium contained all three compartments (A, stem cells; B, basal cells; and C, superficial cells) as well as rate constants for division and movement. For stromal cells, only a B compartment was modeled with a rate constant for cell division. The endothelial layer was modeled using a C compartment with a rate constant for cell loss. Gene transfer with retroviral vectors (stable infection of dividing cells only), lentiviral vectors (stable infection of both dividing and non–dividing cells), or adenoviral vectors (transient expression in all cells) was modeled for each cell layer. For adenoviral vectors a rate constant for vector degradation was added. Results: Epithelium: For retroviral infection, the initial percentage of expression in A was lower than in B. Over time the percentage of infection within B approached the initial percentage of A infection. Initial lentiviral infection was higher than for retrovirus. Again, the B compartment expression would over time approach the percentage of that seen in the A and overall expression would remain higher. For adenoviral infection all compartments would initially have high levels of expression, but the levels would eventually be zero. Stroma: The rate of infection would remain constant for retroviral and lentiviral infection, although the initial rate would be higher for the lentiviral vectors. Adenoviral infection would steadily decline. Endothelium: Retroviral infection was not possible. Lentiviral infection demonstrated a constant percentage of infected cells, albeit a steady decline in total cells infected. Adenoviral infection steadily declined. Conclusions: The variable mechanisms for regeneration and maintenance of the corneal cell layers pose challenges in choosing a gene transfer system. Using theoretical modeling, however, may provide guidance in choosing the appropriate vector system to alter specific corneal processes.
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