Biomechanical changes to Descemet's membrane precede endothelial cell loss in an early-onset murine model of Fuchs endothelial corneal dystrophy

Brian C. Leonard, Iman Jalilian, Vijay Krishna Raghunathan, Wei Wang, Albert Jun, Christopher J. Murphy, Sara M. Thomasy

Research output: Contribution to journalArticle

Abstract

Early-onset Fuchs endothelial corneal dystrophy (FECD) has been associated with nonsynonymous mutations in collagen VIII α2 (COL8A2), a key extracellular matrix (ECM) protein in Descemet's membrane (DM). Two knock-in strains of mice have been generated to each express a mutant COL8A2 protein (Col8a2L450W/L450W and Col8a2Q455K/Q455K) that recapitulate the clinical phenotype of early-onset FECD including endothelial cell loss, cellular polymegathism and pleomorphism, and guttae. Due to abnormalities in ECM protein composition and structure in FECD, the stiffness of DM in Col8a2 knock-in mice and wildtype (WT) controls was measured using atomic force microscopy at 5 and 10 months of age, coinciding with the onset of FECD phenotypic abnormalities. At 5 months, only sporadic guttae were identified via in vivo confocal microscopy (IVCM) in Col8a2Q455K/Q455K mice, otherwise both strains of Col8a2 transgenic mice were indistinguishable from WT controls in terms of endothelial cell density and size. By 10 months of age, Col8a2L450W/L450W and Col8a2Q455K/Q455K mice developed reduced corneal endothelial density, increased endothelial cell area and guttae, with the Col8a2Q455K/Q455K strain exhibiting a more severe phenotype. However, at 5 months of age, prior to the development endothelial cell abnormalities, Col8a2L450W/L450W and Col8a2Q455K/Q455K mice knock-in mice had reduced tissue stiffness of DM that was statistically significant in the Col8a2Q455K/Q455K mice when compared with wildtype controls. These data indicate that alterations in the tissue compliance of DM precede phenotypic changes in endothelial cell count and morphology, and may play a role in onset and progression of FECD.

LanguageEnglish (US)
Pages18-22
Number of pages5
JournalExperimental eye research
Volume180
DOIs
StatePublished - Mar 1 2019

Fingerprint

Fuchs' Endothelial Dystrophy
Descemet Membrane
Biomechanical Phenomena
Cornea
Endothelial Cells
Extracellular Matrix Proteins
Cell Count
Phenotype
Atomic Force Microscopy
Mutant Proteins
Cell Size
Confocal Microscopy
Transgenic Mice
Compliance
Collagen
Mutation

Keywords

  • Biomechanics
  • Cornea
  • Descemet's membrane
  • Endothelial
  • Fuchs

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Biomechanical changes to Descemet's membrane precede endothelial cell loss in an early-onset murine model of Fuchs endothelial corneal dystrophy. / Leonard, Brian C.; Jalilian, Iman; Raghunathan, Vijay Krishna; Wang, Wei; Jun, Albert; Murphy, Christopher J.; Thomasy, Sara M.

In: Experimental eye research, Vol. 180, 01.03.2019, p. 18-22.

Research output: Contribution to journalArticle

Leonard, Brian C. ; Jalilian, Iman ; Raghunathan, Vijay Krishna ; Wang, Wei ; Jun, Albert ; Murphy, Christopher J. ; Thomasy, Sara M. / Biomechanical changes to Descemet's membrane precede endothelial cell loss in an early-onset murine model of Fuchs endothelial corneal dystrophy. In: Experimental eye research. 2019 ; Vol. 180. pp. 18-22.
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