The Role of Limbal Epithelial Stem Cells in Regulating Corneal (Lymph)angiogenic Privilege and the Micromilieu of the Limbal Niche following UV Exposure

Abstract

The cornea is a clear structure, void of blood, and lymphatic vessels, functioning as our window to the world. Limbal epithelial stem cells, occupying the area between avascular cornea and vascularized conjunctiva, have been implicated in tissue border maintenance, preventing conjunctivalisation and propagation of blood and lymphatic vessels into the cornea. Defects in limbal epithelial stem cells are linked to corneal neovascularisation, including lymphangiogenesis, chronic inflammation, conjunctivalisation, epithelial abnormalities including the presence of goblet cells, breaks in Bowman's membrane, persistent epithelial defects and ulceration, ocular surface squamous neoplasia, lipid keratopathy, pain, discomfort, and compromised vision. It has been postulated that pterygium is an example of focal limbal deficiency. Previous reports showing changes occurring in limbal epithelium during pterygium pathogenesis suggest that there is a link to stem cell damage. In this light, pterygium can serve as a model disease of UV-induced stem cell damage also characterised by corneal blood and lymphangiogenesis. This review focuses on the role of corneal and limbal epithelial cells and the stem cell niche in maintaining corneal avascularity and corneal immune privilege and how this may be deregulated following UV exposure. We present an overview of the PUBMED literature in the field as well as recent work from our laboratories.

Inhibition of mTOR by Rapamycin Aggravates Corneal Epithelial Stem Cell Deficiency by Upregulating Inflammatory Response

“…At days 7, 14, 21, and 28 after injury, the cornea was serially observed for clinical signs of LSCD: corneal epithelial defects, vascularization, and opacification (Fig. A) . Rapamycin treatment significantly delayed corneal epithelial healing in a dose‐dependent manner (Fig.…”

“…Therefore, the failure of CESCs to regenerate corneal epithelial cells leads to corneal opacification and severe visual impairment, a condition called limbal stem cell deficiency (LSCD) . Although various diseases of the cornea can produce LSCD, the most severe form of LSCD is associated with sterile inflammation as in chemical burn or Stevens–Johnson syndrome, an indication that inflammatory damage underlies the loss of CESCs in LSCD . For this reason, the current treatment options for LSCD include anti‐inflammatory therapies such as corticosteroids or amniotic membrane transplantation in the acute phase of a disease.…”

Regulation of matrix metalloproteinases 2 and 9 in corneal neovascularization

“…Isoforms of VEGF-A have differences in the affinities for heparan sulfate proteoglycans (HSPGs) and VEGF receptors, which exert distinct influences on vessel growth. VEGF-A binds to two tyrosine kinases, vascular endothelial growth factor receptor-1 (VEGFR-1) and vascular endothelial growth factor receptor-2 (VEGFR-2) in high affinity, and receptors are abundant in vascular endothelial cells (Notara, Lentzsch, Coroneo, & Cursiefen, 2018). These effects like permeability, migration, and proliferation are achieved by signal pathways, such as MAPK, NO, and PI-3K-AKT/PKB (Penn et al, 2008).…”

Clinical Trials of Limbal Stem Cell Deficiency Treated with Oral Mucosal Epithelial Cells

“…Many studies reported that the limbal region functions as a barrier between the cornea and conjunctiva. The role of the barrier is to block the conjunctivalization and the neovascularization of the cornea [10][11][12][13]. Damage to this barrier leads to the development of limbal stem cell deficiency (LSCD).…”