• Open Access

Age-related dystrophic changes in corneal endothelium from DNA repair–deficient mice

Authors

  • Danny S. Roh,

    1. Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Search for more papers by this author
  • Yiqin Du,

    1. Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Search for more papers by this author
  • Michelle L. Gabriele,

    1. Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Search for more papers by this author
  • Andria R. Robinson,

    1. Department of Human Genetics, University of Pittsburgh School of Public Health, Pittsburgh, PA 15261, USA
    2. University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA
    Search for more papers by this author
  • Laura J. Niedernhofer,

    1. University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA
    2. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA
    Current affiliation:
    1. Department of Metabolism and Aging, Scripps Florida, Jupiter, FL 33458, USA
    Search for more papers by this author
  • James L. Funderburgh

    Corresponding author
    1. Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    • Correspondence

      James L. Funderburgh, Department of Ophthalmology, University of Pittsburgh, 203 Lothrop St., Pittsburgh, PA 15213, USA. Tel.: +1 412 647 3853; fax: +1 412 647 5880; e-mail: jlfunder@pitt.edu

    Search for more papers by this author

Summary

The corneal endothelium (CE) is a single layer of cells lining the posterior face of the cornea providing metabolic functions essential for maintenance of corneal transparency. Adult CE cells lack regenerative potential, and the number of CE cells decreases throughout life. To determine whether endogenous DNA damage contributes to the age-related spontaneous loss of CE, we characterized CE in Ercc1−/Δ mice, which have impaired capacity to repair DNA damage and age prematurely. Eyes from 4.5- to 6-month-old Ercc1−/Δ mice, age-matched wild-type (WT) littermates, and old WT mice (24- to 34-month-old) were compared by spectral domain optical coherence tomography and corneal confocal microscopy. Histopathological changes in CE were further identified in paraffin tissue sections, whole-mount immunostaining, and scanning electron and transmission electron microscopy. The CE of old WT mice displayed polymorphism and polymegathism, polyploidy, decreased cell density, increased cell size, increases in Descemet's thickness, and the presence of posterior projections originating from the CE toward the anterior chamber, similar to changes documented for aging human corneas. Similar changes were observed in young adult Ercc1−/Δ mice CE, demonstrating spontaneous premature aging of the CE of these DNA repair–deficient mice. CD45+ immune cells were associated with the posterior surface of CE from Ercc1−/Δ mice and the tissue expressed increased IL-1α, Cxcl2, and TNFα, pro-inflammatory proteins associated with senescence-associated secretory phenotype. These data provide strong experimental evidence that DNA damage can promote aging of the CE and that Ercc1−/Δ mice offer a rapid and accurate model to study CE pathogenesis and therapy.

Ancillary