Conjunctival goblet cells: Ocular surface functions, disorders that affect them, and the potential for their regeneration

Abstract

Conjunctival goblet cells (CGCs) are specialized cells that produce and secrete soluble mucins to the tear film that bathes the ocular surface. CGC numbers and functions are affected in various ocular surface diseases including dry eye disease with diverse etiologies. In this review we will (i) summarize the important functions of CGCs in ocular surface health, (ii) describe the ocular surface diseases that affect CGC numbers and function, (iii) provide an update on recent research outcomes that elucidate CGC differentiation, gene expression and functions, and (iv) present evidence in support of the prediction that restoring CGC numbers and/or functions is a viable strategy for alleviating ocular surface disorders that impact the CGCs.

Keywords: Conjunctiva; Cornea; Goblet cells; Ocular surface; Tear film.

Figure 1.. Tear film lubricates, nourishes and protects the ocular surface.

A. The ocular surface (red) is a continuous epithelial surface that covers the cornea, conjunctiva and the ductal surfaces of the meibomian and lacrimal glands. Despite being comprised of different cell types, the ocular surface is a single functional unit whose functions are integrated by nervous, vascular, endocrine and immune systems. B. Structure and composition of tear film that covers the ocular surface. The superficial lipid layer derived from the meibomian glands, central aqueous layer derived mostly from the lacrimal glands with soluble mucins from CGCs, and the basal glycocalyx (mucus layer) of secreted gel-forming mucins (red squiggly lines) and membrane-bound mucins (green squiggly lines connected to the superficial epithelial cells) are shown. We believe that the glycocalyx layer gradually transitions into the aqueous layer with no distinct boundary in between. Thus, the gel-forming mucins may also be present in lower concentrations (in non-gel form) in the aqueous layer.

Figure 2.. Structure and functions of CGCs.

GCs are present in clusters or interspersed among stratified keratocytes and form leaky tight junctions with the neighboring cells. In the mouse conjunctiva, GCs unlike keratocytes, extend from the surface to the underlying extracellular matrix, where they interact with antigen presenting cell processes. Human GCs also are elongated and span the apical half of the conjunctiva. These cells are packed with multiple mucin granules which push the nucleus towards the base. Putative functions of CGCs are listed below, with the sites of these functions indicated in the schematic. GC-derived TGF-β2 drives dendritic cells toward an immature tolerogenic state. APC-P, Antigen presenting cell processes; NP, nerve processes; CALT, conjunctiva-associated lymphoid tissue; DC, dendritic cell; TSP1, thrombospondin-1; TGF-β, transforming growth factor-β.

Figure 3.. Gene regulatory network in GC differentiation.

Schematic shows key signal transduction pathways and genes known to influence CGC differentiation. The influence of IL-13, Notch, and Wnt signaling pathways on Spdef functions are inferred from studies on the lung and intestine GC fate determination. In pro-inflammatory conditions, TGF-β signaling suppresses Klf4 and Spdef affecting GC functions. NICD, Notch intracellular domain; Jak, Janus kinase; STAT, signal transducer and activator of transcription; pSTAT6, Phospho-STAT6; SPDEF, SAM-pointed domain ETS factor; IL-13, Interleukin-13; IL-13R, IL-13 receptor; β-Cat, β-catenin; KLF4, Krüppel-like factor-4; Lef/Tcf, Lymphoid enhancer factor/T-cell factor.

Figure 4.. Effect of ocular surface disorders on GCs.

Loss of GCs is associated with dry eye disease and certain autoimmune disorders that affect the eye. In contrast, GC hyperplasia and mucin hypersecretion are reported in allergic conjunctivitis, chronic injuries and conjunctival papilloma. Cyclical nature of these events and the known pathways that influence them are indicated in the lower panel. While the numerous inputs that lead to the ongoing damage are not shown, what is central is the role of GC mucins that lubricate and protect the ocular surface. The GCs can be damaged by cytokines and toxins (such as mitomycin-C during trabeculectomies), and the tear film can be further destabilized in a dry environment. We predict that a better understanding of the molecular mechanisms that regulate normal CGC differentiation in early postnatal stages, their functions in later stages, and how they are altered in diverse disease conditions will facilitate development of novel approaches for therapeutic modulation of GC numbers and functions in the near future.