International Journal of Molecular Sciences Review Meibomian Gland Dysfunction: What Have Animal Models Taught Us? Mingxia Sun y , Isabel Y. Moreno y, Michelle Dang and Vivien J. Coulson-Thomas * College of Optometry, University of Houston, Houston, TX 77204, USA; [email protected] (M.S.); [email protected] (I.Y.M.); [email protected] (M.D.) * Correspondence: [email protected] or [email protected]; Tel.: +1-713-743-2042 Contributed equally. y Received: 31 October 2020; Accepted: 19 November 2020; Published: 21 November 2020 Abstract: Studies have estimated that currently 344 million people worldwide and 16.4 million adults in the US have some form of dry eye disease (DED). It is believed that approximately 70% of DED cases are due to some form of evaporative dry eye, for which Meibomian gland dysfunction (MGD) is the major cause. Unfortunately, currently there is no effective treatment for MGD, and solely palliative care is available. Given the importance of MGD in DED, there has been a growing interest in studying Meibomian gland development, homeostasis and pathology, and, also, in developing therapies for treating and/or preventing MGD. For such, animal models have shown to be a vital tool. Much of what is known today about the Meibomian gland and MGD was learnt from these important animal models. In particular, canine and rabbit models have been essential for studying the physiopathology and progression of DED, and the mouse model, which includes different knockout strains, has enabled the identification of specific pathways potentially involved in MGD. Herein, we provide a bibliographic review on the various animal models that have been used to study Meibomian gland development, Meibomian gland homeostasis and MGD, primarily focusing on publications between 2000 and 2020. Keywords: Meibomian gland; animal models; dry eye disease 1. Introduction In epidemiological studies performed globally, the prevalence of dry eye disease (DED) is estimated to range from 5% to 50%. DED affects 6.8% of the United States adult population (approximately 16.4 million people) and is the most commonly reported condition in eye care clinics [1]. There are primarily two types of DED that are categorized by their etiology: aqueous-deficient DED and evaporative DED (Figure1). Studies have shown that up to 87% of dry eye patients have evaporative DED, for which the major cause is Meibomian gland dysfunction (MGD). The Meibomian gland is a specialized sebaceous gland, which is embedded in the superior and inferior tarsal plates of the eyelids and produces a lipid secretion called meibum. The action of blinking causes Meibomian glands to secrete meibum, and, thereafter, evenly spreads this meibum across the ocular surface. This thin layer of meibum lies over the aqueous layer, protecting it from evaporation and thereby stabilizing the tear film. The tear film is vital in maintaining corneal homeostasis, nourishing and protecting corneal and conjunctival epithelial cells. Any functional changes to the Meibomian gland that alter its meibum production affect tear film stability, and, ultimately, disturb corneal homeostasis, leading to epithelial damage. Consequently, patients with MGD will report symptoms of eye irritation, such as ocular pain and discomfort, and will also show signs of inflammation [2,3]. The term MGD encompasses various functional abnormalities of the Meibomian gland. There are three types of MGD divided into two categories: low delivery and high delivery. Low delivery is associated with hyposecretory or obstructive MGD, while high delivery pertains to hypersecretory Int. J. Mol. Sci. 2020, 21, 8822; doi:10.3390/ijms21228822 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 25 Int. J. Mol. Sci. 2020, 21, 8822 2 of 25 MGD. Hyposecretory MGD involves decreased meibum secretion resulting from abnormal Meibomian gland function without orifice blockage, while obstructive MGD, the most common type MGD.of MGD, Hyposecretory results from MGD ductal involves obstruction. decreased High meibum delivery secretion MGD resultingis characterized from abnormal by hypersecretory Meibomian glandMeibomian function glands, without where orifice a large blockage, volume of while lipids obstructive is excreted MGD, onto the the surface most common of the lid typemargin of MGD,when resultspressure from is applied ductal obstruction.to the tarsal High plate. delivery Common MGD treatments is characterized for MGD by include hypersecretory maintaining Meibomian eyelid glands,hygiene, where warm a compresses, large volume and of anti-inflammatory lipids is excreted onto therapies the surface [4]. Studies of the have lid margin suggested when that pressure MGD isstarts applied with tothe the occlusion tarsal plate. of terminal Common ducts, treatments which leads for MGD to a cascade include of maintaining changes starting eyelid with hygiene, the warmaccumulation compresses, of meibum and anti-inflammatory within collecting therapies ducts, [causing4]. Studies a build- have suggestedup of pressure that MGD and startsultimately with theleading occlusion to the ofatrophy terminal and ducts, loss of which Meibomian leads to glands a cascade [5]. Hyperkeratinization of changes starting with has been the accumulation suggested to ofbe meibuma major cause within of obstructive collecting ducts, MGD. causingTo that effe a build-upct, hyperkeratinization of pressure and of ultimatelythe ductal epithelium leading to can the atrophylead to ductal and loss occlusion, of Meibomian which glands in turn [5 leads]. Hyperkeratinization to cystic dilation hasof the been duct suggested and, ultimately, to be a major results cause in ofgland obstructive drop out[6]. MGD. Recently, To that esomeffect, speculation hyperkeratinization has been ofraised the ductal that hyperkeratinization epithelium can lead is to a ductalmajor occlusion,contributor which of MGD in turn and leads research to cystic is dilation ongoing of theto ductsubstantiate and, ultimately, this [6–10]. results Recent in gland studies drop out have [6]. Recently,hypothesized some that speculation aging is has a potential been raised cause that hyperkeratinizationfor MGD, often referred is a major to as contributor age-related of MGD and(ARMGD). research Research is ongoing has to suggested substantiate that this ARMGD [6–10]. is Recent caused studies primarily have by hypothesized a decline in the that number aging is of a potentialdifferentiating cause meibocytes, for MGD, often which referred ultimately to as age-related leads to Meibomian MGD (ARMGD). gland drop Researchout and has abnormal suggested lipid that ARMGDexcretion is[6]. caused primarily by a decline in the number of differentiating meibocytes, which ultimately leads to Meibomian gland dropout and abnormal lipid excretion [6]. Figure 1. A flowchart representation of the categorization of dry eye disease (DED) according to etiology. Figure 1. A flowchart representation of the categorization of dry eye disease (DED) according to Ageetiology. and gender are considered to be the greatest risk factors for DED. Progressive Meibomian gland loss (drop-out) occurs with age, which is accompanied by reduced quality and quantity of meibumAge [and11–15 gender]. A cross-sectional are considered study to be involving the greatest 177 risk subjects factors aged for DED. 21–93 Progressive years found Meibomian that eyelid margingland loss and (drop-out) Meibomian occurs gland with abnormalities age, which are is significantly accompanied associated by reduced with age,quality while and no quantity significant of associationmeibum [11–15]. was found A cross-sectional between Meibomian study involving gland-related 177 subjects changes aged and 21–93 gender years [11 found]. 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