Center for Molecular Medicine Cologne

Maria Notara - CAP 15

Effects of UV irradiation on corneal angiogenic privilege: pterygium as a UV-induced stem cell disease model: The limbal niche and corneal avascularity

The aim of this research group is to understand the mechanisms underlying the role of the limbal epithelial stem cells in corneal avascularity. Specifically, we are interested in the effect of UV irradiation on the limbal stem cell phenotype and pathological neovascularisation. 

Introduction

Vision is a key sensory function. Clear vision depends on transparency of the structures of the visual axis. Consequently, normal corneal tissue (the “windscreen of the eye”) is in an avascular and low inflammatory state. 

The limbal epithelial stem cells (LESC) maintain the integrity of the corneal epithelium thus preventing neovascularization, stromal scarring and conjunctivalisation. Although it has been proven both clinically and experimentally that LESCs destruction compromises corneal avascularity, the exact mechanisms by which this is achieved remain unidentified. 

Our group focuses on elucidating these mechanisms and aims to identify new LESC-related regulators of corneal neovascularisation which will lead to new therapeutic options (we are part of FOR2240, “(Lymph)angiogenesis and cellular immunity in inflammatory diseases of the eye”).

Exposure to UV irradiation compromises the LESC niche and induces corneal (lymph)angiogenesis. Pterygium, a non-cancerous tumour of the conjunctiva, is linked to UV-induced DNA and oxidative damage. The phenotype is associated with inflammation and neovascularisation causing discomfort and decrease of vision. 

Preliminary evidence links pterygium onset to limbal epithelial stem cell (LESC) deficiency and own data suggest that following short term UV irradiation LESC become differentiated. However, a direct involvement of LESC DNA damage in the disease is not fully explored.

Our hypothesis is, that following UV-induced damage the inability of LESCs to repair DNA damage contributes to induction of pterygia. In collaboration with the laboratory of Professor Björn Schumacher we will aim to investigate the possible links between UV damage and neovascularization using a nucleotide excision repair deficient mouse model. We will investigate the association of ERCC1 with pterygium and the possibility of using the ERCC deficient mouse as a model for UV-induced alterations relevant to pterygium. 

Also, we will explore the role of photolyase, a DNA repairing enzyme, as a therapeutic approach to prevent UV induced LESC damage leading to neovascularization, inflammation and thus pterygium. 

Perspectives

Pterygium has a higher prevalence in countries with elevated ultraviolet exposure. It is estimated that an expected 10% of all refugees who came to Germany from southern countries will most likely suffer from pterygium (i.e.>100000), resulting in a significant burden to the health system. Therefore, understanding the mechanisms underlying the disease will help developing more efficient prevention and treatment strategies.

Notara M, et al., UV light-blocking contact lenses protect against short-term UVB-induced limbal stem cell niche damage and inflammation, Sci Rep. 2018 Aug 22;8(1):12564

Notara M, et al.: The Role of Limbal Epithelial Stem Cells in Regulating Corneal (Lymph)angiogenic Privilege and the Micromilieu of the Limbal Niche following UV Exposure. Stem Cells International. (2018); 2018: 15.

Notara M, et al.: Short-Term Ultraviolet A Irradiation Leads to Dysfunction of the Limbal Niche Cells and an Antilymphangiogenic and Anti-inflammatory Micromilieu. Invest Ophthalmol Vis Sci. (2016); 57: 928-939.

Notara M, et al.: Short-term UVB-irradiation leads to putative limbal stem cell damage and niche cell-mediated upregulation of macrophage recruiting cytokines. Stem Cell Res. (2015); 15: 643-654.

Notara M, et al.: The impact of age on the physical and cellular properties of the human limbal stem cell niche. Age (Dordr). (2013); 35: 289-300.

Notara M, et al.: Characterization of the phenotype and functionality of corneal epithelial cells derived from mouse embryonic stem cells. Regen Med. (2012); 7: 167-178.

Notara M, et al.: The porcine limbal epithelial stem cell niche as a new model for the study of transplanted tissue-engineered human limbal epithelial cells. Tissue Eng Part A. (2011); 17: 741-750.

Notara M, et al.: IL6 and the human limbal stem cell niche: a mediator of epithelial-stromal interaction. Stem Cell Res. (2010); 5: 188-200.

Hos, D., Matthaei, M., Bock, F., Maruyama, K., Notara, M., Clahsen, T., Hou, Y., Le, V.N.H., Salabarria, A.C., Horstmann, J., Bachmann, B.O., and Cursiefen, C. (2019). Immune reactions after modern lamellar (DALK, DSAEK, DMEK) versus conventional penetrating corneal transplantation. Prog Retin Eye Res10.1016/j.preteyeres.2019.07.001.

Notara M, Behboudifard S, Kluth MA, Masslo C, Ganss C, Frank MH, Schumacher B, and Cursiefen C (2018). UV light-blocking contact lenses protect against short-term UVB-induced limbal stem cell niche damage and inflammation. Sci Rep 8, 12564.

Notara M, Lentzsch A, Coroneo M, and Cursiefen C (2018). The Role of Limbal Epithelial Stem Cells in Regulating Corneal (Lymph)angiogenic Privilege and the Micromilieu of the Limbal Niche following UV Exposure. Stem Cells Int 2018, 8620172.

Dr. Maria Notara CMMC Cologne
Dr. Maria Notara

Dept. of Ophthalmology

Principal Investigator CAP 15

+49 221 478 30621

+49 221 478 32785

Dept. of Ophthalmology

Kerpener Str. 62

50931 Köln

CMMC Profile Page

Publications - Maria Notara

Link to PubMed

Affiliations

FOR 2240

Group Members

Berbang Meshko (PhD Student)
Isabella Moshiri (GEROK Clinician Scientist)
Stephanie Brosig (Technician)
Marieke Dombey (Alumni - Master’s student)

Figure 1