Insulin-like growth factor binding protein-7: A marker of conjunctivalization in an animal model of limbal stem cell deficiency

Mijeong Park; Jessica Mazalo; Nick Di Girolamo

doi:10.1016/j.jtos.2019.05.005

Insulin-like growth factor binding protein-7: A marker of conjunctivalization in an animal model of limbal stem cell deficiency

Ocul Surf. 2019 Jul;17(3):447-457. doi: 10.1016/j.jtos.2019.05.005. Epub 2019 May 21.

Authors

Mijeong Park¹, Jessica Mazalo¹, Nick Di Girolamo²

Affiliations

¹ Mechanisms of Disease and Translational Research, School of Medical Sciences, Faculty of Medicine, University of NSW, Sydney, NSW, 2052, Australia.
² Mechanisms of Disease and Translational Research, School of Medical Sciences, Faculty of Medicine, University of NSW, Sydney, NSW, 2052, Australia. Electronic address: n.digirolamo@unsw.edu.au.

PMID: 31125784
DOI: 10.1016/j.jtos.2019.05.005

Abstract

Purpose: Limbal stem cell deficiency (LSCD) is characterized by the loss of limbal epithelial stem cells, resulting in a pathological process termed 'conjunctivalization' which compromises corneal transparency, leading to blindness. Current diagnosis for LSCD is limited because reliable conjunctiva-specific biomarkers are lacking. This study sought to address this shortcoming through the serendipitous discovery of insulin-like growth factor binding protein (IGFBP)-7.

Methods: IGFBP-7 expression was determined in normal (n=83) and conjunctivalized (n=52) mouse corneas with experimentally-induced LSCD, and in cadaveric normal human corneas (n=7) and human pterygia (n=15); a disease characterized by the invasion of a conjunctivalized, fibrovascular pannus. Clinical assessments including slit-lamp microscopy, fluorescein staining and impression cytology, and biochemical, molecular and immunological assays were also conducted.

Results: Mass spectrometry of conditioned media from mouse limbal explant-derived cells revealed the presence of IGFBP-7. This factor was expressed in normal limbal and conjunctival epithelium and conjunctivalized corneas from mice with LSCD, and in human pterygium epithelium but not in normal mouse or human corneal epithelium. Four weeks after inducing LSCD, IGFBP-7 staining was increased by 2.9-fold in mouse corneas compared to steady-state, and by 1.6-fold in impression cytology specimens derived from the same mice. Notably, IGFBP-7 was detected approximately 2-weeks earlier than Muc5AC.

Conclusions: This study provides novel insights into the specificity of IGFBP-7 for the mammalian conjunctival epithelium in health and disease. A point-of-care test for IGFBP-7 could be developed to assist clinicians in early diagnosis, and in monitoring disease progression, severity and therapeutic outcomes in patients with LSCD.

Keywords: Conjunctivalization; Cornea; Epithelium; IGFBP-7; Impression cytology; Limbal stem cell deficiency; Limbal stem cells; Pterygium.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Animals
Biomarkers / metabolism
Blotting, Western
Conjunctiva / metabolism
Conjunctiva / pathology*
Corneal Diseases / metabolism*
Corneal Diseases / pathology
Disease Models, Animal
Female
Humans
Insulin-Like Growth Factor Binding Proteins / biosynthesis*
Limbus Corneae / metabolism*
Limbus Corneae / pathology
Male
Mice
Middle Aged
Stem Cells / pathology*

Substances

Biomarkers
Insulin-Like Growth Factor Binding Proteins
insulin-like growth factor binding protein-related protein 1