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Abstract
Corneal endothelium is the single layer of cells forming a boundary between the corneal
stroma and anterior chamber. The barrier and "pump" functions of the endothelium are
responsible for maintaining corneal transparency by regulating stromal hydration.
Morphological studies have demonstrated an age-related decrease in endothelial cell
density and indicate that the endothelium in vivo either does not proliferate at all
or proliferates at a rate that does not keep pace with the rate of cell loss. Lack
of a robust proliferative response to cell loss makes the endothelium, at best, a
fragile tissue. As a result of excessive cell loss due to accidental or surgical trauma,
dystrophy, or disease, the endothelium may no longer effectively act as a barrier
to fluid flow from the aqueous humor to the stroma. This loss of function can cause
corneal edema, decreased corneal clarity, and loss of visual acuity, thus requiring
corneal transplantation to restore normal vision. Studies from this and other laboratories
indicate that corneal endothelium in vivo DOES possess proliferative capacity, but
is arrested in G1-phase of the cell cycle. It appears that several intrinsic and extrinsic
factors together contribute to maintain the endothelium in a non-replicative state.
Ex vivo studies comparing cell cycle kinetics in wounded endothelium of young (< 30
years old) and older donors ( > 50 years old) provide evidence that cells from older
donors can enter and complete the cell cycle; however, the length of G1-phase appears
to be longer and the cells require stronger mitogenic stimulation than cells from
younger donors. In vivo conditions per se also contribute to maintenance of a non-replicative
monolayer. Endothelial cells are apparently unable to respond to autocrine or paracrine
stimulation even though they express mRNA and protein for a number of growth factors
and their receptors. Exogenous transforming growth factor-beta (TGF-beta) and TGF-beta
in aqueous humor suppress S-phase entry in cultured endothelial cells, suggesting
that this cytokine could inhibit proliferation in vivo. In addition, cell-cell contact
appears to inhibit endothelial cell proliferation during corneal development and to
help maintain the mature endothelial monolayer in a non-proliferative state, in part,
via the activity of p27kip1, a known G1-phase inhibitor. The fact that human corneal
endothelium retains proliferative capacity has led to recent efforts to induce division
and increase the density of these important cells. For example, recent studies have
demonstrated that adult human corneal endothelial cells can be induced to grow in
culture and then transplanted to recipient corneas ex vivo. The laboratory work that
has been conducted up to now opens an exciting new door to the future. The time is
right to apply the knowledge that has been gained regarding corneal endothelial cell
proliferative capacity and regulation of its cell cycle to develop new therapies to
treat patients at risk for vision loss due to low endothelial cells counts.