Project N2 ABCB5 & Pterygium

The role of ABCB5-expressing limbal epithelial stem cells in corneal lymphangiogenic privilege and pterygium pathogenesis

Summary as new project of second funding period:

Limbal epithelial stem cells (LESC) are localized at the junction between the avascular cornea and the heavily (lymph)vascularized conjunctiva. LESC maintain the integrity of the corneal epithelium and express ABCB5, which is a limbal stem cell gene required for corneal development and repair. Although it has been proven both clinically and experimentally that LESC destruction compromises corneal avascularity, the exact mechanisms behind this remain unclear. Exposure to UV irradiation is one mechanism known to compromise the LESC niche and is associated with pterygium, a non-cancerous tumour of the conjunctiva which grows onto the cornea and compromises corneal avascularity and vision. Our own preliminary data suggest that limbal epithelial stem cells become differentiated under UV exposure, thus leading to a pro-inflammatory and prolymphangiogenic micromillieu in the limbal stem cell niche. Furthermore, our own early data show damage to ABCB5+ LESC in human pterygium tissue. Our overall hypothesis is that while under normal circumstances, LESCs expressing ABCB5 contribute to corneal avascularity, following UV-induced damage they contribute to neovascularization and induction of pterygia. Therefore we aim to: 1. better understand the molecular mechanisms by which ABCB5-positive LESCs contribute to corneal avascularity and thereby identify novel regulators of corneal lymphangiogenic privilege and 2. unravel if and how UV light, known to be associated with pterygium pathogenesis, damages ABCB5-positive LESCs. Overall, a better understanding of the putative anti(lymph)angiogenic mechanisms exerted by ABCB5-positive limbal epithelial stem cells and their potential damage by UV light will eventually help to better understand the pathogenesis of blinding pterygium and to develop new treatment options against blinding neovascular corneal diseases.

Most recent publications of Project N2

Volatier T, Schumacher B, Meshko B, Hadrian K, Cursiefen C, Notara M. Short- Term UVB Irradiation Leads to Persistent DNA Damage in Limbal Epithelial Stem Cells, Partially Reversed by DNA Repairing Enzymes. Biology (Basel). 2023 Feb 7;12(2):265. doi: 10.3390/biology12020265. PMID: 36829542; PMCID: PMC9953128.

Domdey M, Kluth MA, Maßlo C, Ganss C, Frank MH, Frank NY, Coroneo MT, Cursiefen C, Notara M. Consecutive dosing of UVB irradiation induces loss of ABCB5 expression and activation of EMT and fibrosis proteins in limbal epithelial cells similar to pterygium epithelium. Stem Cell Res. 2022 Oct;64:102936. doi: 10.1016/j.scr.2022.102936. Epub 2022 Oct 5. PMID: 36242878; PMCID: PMC9582195.

Volatier T, Schumacher B, Cursiefen C, Notara M. UV Protection in the Cornea: Failure and Rescue. Biology (Basel). 2022 Feb 10;11(2):278. doi: 10.3390/biology11020278. PMID: 35205145; PMCID: PMC8868636.

Notara M, Lentzsch A, Clahsen T, Behboudifard S, Braun G, Cursiefen C. Bevacizumab Induces Upregulation of Keratin 3 and VEGFA in Human Limbal Epithelial Cells in Vitro. J Clin Med. 2019 Nov 9;8(11):1925. doi: 10.3390/jcm8111925. PMID: 31717500; PMCID: PMC6912829.

Notara M, Behboudifard S, Kluth MA, Maßlo C, Ganss C, Frank MH, Schumacher B, Cursiefen C (2018) UV light-blocking contact lenses protect against short-term UVB-induced limbal stem cell niche damage and inflammation. Scientific Reports 8(1):12564.

Notara M, Lentzsch A, Coroneo M, 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. doi: 10.1155/2018/8620172. eCollection 2018.

Selected Key Publications of Project N2

Volatier T, Schumacher B, Meshko B, Hadrian K, Cursiefen C, Notara M. Short- Term UVB Irradiation Leads to Persistent DNA Damage in Limbal Epithelial Stem Cells, Partially Reversed by DNA Repairing Enzymes. Biology (Basel). 2023 Feb 7;12(2):265. doi: 10.3390/biology12020265. PMID: 36829542; PMCID: PMC9953128.

Domdey M, Kluth MA, Maßlo C, Ganss C, Frank MH, Frank NY, Coroneo MT, Cursiefen C, Notara M. Consecutive dosing of UVB irradiation induces loss of ABCB5 expression and activation of EMT and fibrosis proteins in limbal epithelial cells similar to pterygium epithelium. Stem Cell Res. 2022 Oct;64:102936. doi: 10.1016/j.scr.2022.102936. Epub 2022 Oct 5. PMID: 36242878; PMCID: PMC9582195.

Notara M, Behboudifard S, Kluth MA, Maßlo C, Ganss C, Frank MH, Schumacher B, Cursiefen C (2018) UV light-blocking contact lenses protect against short-term UVB-induced limbal stem cell niche damage and inflammation. Scientific Reports 8(1):12564.

Notara M, Lentzsch A, Coroneo M, 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. doi: 10.1155/2018/8620172. eCollection 2018.

Notara M, Refaian N, Braun G, Steven P, Bock F, Cursiefen C (2016) Short-Term Ultraviolet A Irradiation Leads to Dysfunction of the Limbal Niche Cells and an Antilymphangiogenic and Anti-inflammatory Micromilieu. Investigative ophthalmology & visual science 57: 928-39

Notara M, Refaian N, Braun G, Steven P, Bock F, Cursiefen C (2015) Short-term uvb irradiation leads to putative limbal stem cell damage and niche cell-mediated upregulation of macrophage recruiting cytokines. Stem cell research 15: 643-654

Hos D, Bukowiecki A, Horstmann J, Bock F, Bucher F, Heindl LM, Siebelmann S, Steven P, Dana R, Eming SA, Cursiefen C (2017) Transient Ingrowth of Lymphatic Vessels into the Physiologically Avascular Cornea Regulates Corneal Edema and Transparency. Scientific reports 7: 7227

Hos D, Schlereth SL, Bock F, Heindl LM, Cursiefen C (2015) Antilymphangiogenic therapy to promote transplant survival and to reduce cancer metastasis: what can we learn from the eye? Seminars in cell & developmental biology 38: 117-30

Cursiefen C, Maruyama K, Bock F, Saban D, Sadrai Z, Lawler J, Dana R, Masli S (2011) Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. The Journal of experimental medicine 208: 1083-92

Ackermann L, Schell M, Pokrzywa W, Kevei E, Gartner A, Schumacher B#, Hoppe T# (2016) E4 ligase-specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis. Nature structural & molecular biology 23: 995-1002 (#cocorresponding authors)

Mueller MM, Castells-Roca L, Babu V, Ermolaeva MA, Muller RU, Frommolt P, Williams AB, Greiss S, Schneider JI, Benzing T, Schermer B, Schumacher B (2014) DAF-16/FOXO and EGL-27/GATA promote developmental growth in response to persistent somatic DNA damage. Nature cell biology 16: 1168-1179

Behrens A, van Deursen JM, Rudolph KL, Schumacher B (2014) Impact of genomic damage and ageing on stem cell function. Nature cell biology 16: 201-7

Ermolaeva MA, Segref A, Dakhovnik A, Ou HL, Schneider JI, Utermohlen O, Hoppe T, Schumacher B (2013) DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature 501: 416-20

More Publications of Project N2

Clahsen T, Hadrian K, Notara M, Schlereth SL, Howaldt A, Prokosch V, Volatier T, Hos D, Schroedl F, Kaser-Eichberger A, Heindl LM, Steven P, Bosch JJ, Steinkasserer A, Rokohl AC, Liu H, Mestanoglu M, Kashkar H, Schumacher B, Kiefer F, Schulte-Merker S, Matthaei M, Hou Y, Fassbender S, Jantsch J, Zhang W, Enders P, Bachmann B, Bock F, Cursiefen C. The novel role of lymphatic vessels in the pathogenesis of ocular diseases. Prog Retin Eye Res. 2023 Feb 7:101157. doi: 10.1016/j.preteyeres.2022.101157. Epub ahead of print. PMID: 36759312.

Heinen H, Notara M, Loreck N, Grajewski RS, Cursiefen C. Unklare bilaterale perilimbale Schwellung [Unclear bilateral perilimbal swelling]. Ophthalmologe. 2020 Oct;117(10):1045-1048. German. doi: 10.1007/s00347-020-01046-0. PMID: 32016510; PMCID: PMC7653811.

Schlereth SL, Hos D, Matthaei M, Hamrah P, Schmetterer L, O’Leary O, Ullmer C, Horstmann J, Bock F, Wacker K, Schröder H, Notara M, Haagdorens M, Nuijts RMMA, Dunker SL, Dickman MM, Fauser S, Scholl HPN, Wheeler-Schilling T, Cursiefen C. New Technologies in Clinical Trials in Corneal Diseases and Limbal Stem Cell Deficiency: Review from the European Vision Institute Special Interest Focus Group Meeting. Ophthalmic Res. 2021;64(2):145-167. doi: 10.1159/000509954. Epub 2020 Jul 7. PMID: 32634808.

Hos D, Matthaei M, Bock F, Maruyama K, Notara M, Clahsen T, Hou Y, Le VNH, Salabarria AC, Horstmann J, Bachmann BO, Cursiefen C. Immune reactions after modern lamellar (DALK, DSAEK, DMEK) versus conventional penetrating corneal transplantation. Prog Retin Eye Res. 2019 Nov;73:100768. doi: 10.1016/j.preteyeres.2019.07.001. Epub 2019 Jul 3. PMID: 31279005.