Lacrimal gland development: From signaling interactions to regenerative medicine

Abstract

The lacrimal gland plays a pivotal role in keeping the ocular surface lubricated, and protecting it from environmental exposure and insult. Dysfunction of the lacrimal gland results in deficiency of the aqueous component of the tear film, which can cause dryness of the ocular surface, also known as the aqueous-deficient dry eye disease. Left untreated, this disease can lead to significant morbidity, including frequent eye infections, corneal ulcerations, and vision loss. Current therapies do not treat the underlying deficiency of the lacrimal gland, but merely provide symptomatic relief. To develop more sustainable and physiological therapies, such as in vivo lacrimal gland regeneration or bioengineered lacrimal gland implants, a thorough understanding of lacrimal gland development at the molecular level is of paramount importance. Based on the structural and functional similarities between rodent and human eye development, extensive studies have been undertaken to investigate the signaling and transcriptional mechanisms of lacrimal gland development using mouse as a model system. In this review, we describe the current understanding of the extrinsic signaling interactions and the intrinsic transcriptional network governing lacrimal gland morphogenesis, as well as recent advances in the field of regenerative medicine aimed at treating dry eye disease. Developmental Dynamics 246:970-980, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: BMP; FGF; dry eye; lacrimal gland; regeneration; stem cell.

Figure 1. Schematic of Lacrimal gland functional unit

The lacrimal gland functional unit is comprised of a) the lacrimal gland, b) Sensory afferent nerves from the cornea and conjunctiva, c) motor efferent nerves originating from the central nervous system which innervate lacrimal gland, d) the excretory tear duct for drainage of the excess fluid. Impairment in any components of lacrimal gland function unit can destabilize the tear film and cause the dry eye disease.

Figure 2. Lacrimal gland development in mouse

Transverse sections of mouse embryos at different stages are shown. Lacrimal gland development begins with thickening of the CE at E13.5 induced by Fgf10 from the surrounding mesenchyme. These epithelial cells further grow and elongate into a bud from E14.5 through E15.5. Branching of LG initiates at E16.5 under the additional influence of BMP7 signaling, eventually forming a multi-lobular tubulo-acinar structure at E19.5. Lacrimal gland continues to develop even during post-natal stages to become a mature gland capable of regulated tear secretion in adults. L: lens, R: Retina, CE: conjunctival epithelium, LG: lacrimal gland.

Figure 3. Summary of signaling interactions during lacrimal gland morphogenesis

(Left) Fgf10 forms a heparan sulfates (HS)-dependent gradient in the periocular mesenchyme, inducing lacrimal gland budding by binding to both Fgfr2b and HS in the epithelium. This activates Shp2, which inhibits the Ras signaling repressor Spry2 and promotes Ras-Erk cascade to stimulate cell proliferation, survival and bud elongation. With transcription factors Sox9 and Barx2, FGF signaling also stimulates expressions of HS synthesizing enzymes (HSSE) and metalloproteinases to remodel the ECM, forming a positive feedback loop to enhance FGF signaling activity. (Right) Bmp7 signaling mediated by Foxc1 is important for mesenchymal condensation during branching morphogenesis. Both FGF and BMP signaling are counterbalanced by canonical Wnt signaling in the mesenchyme. In addition, Smad4-mediated BMP signaling and Sox9-Sox10 cascade also directly regulates the epithelial elongation.