Mechanisms involved in injury and repair of the murine lacrimal gland: role of programmed cell death and mesenchymal stem cells

Abstract

The non-keratinized epithelia of the ocular surface are constantly challenged by environmental insults, such as smoke, dust, and airborne pathogens. Tears are the sole physical protective barrier for the ocular surface. Production of tears in inadequate quantity or of inadequate quality results in constant irritation of the ocular surface, leading to dry eye disease, also referred to as keratoconjunctivitis sicca (KCS). Inflammation of the lacrimal gland, such as occurs in Sjogren syndrome, sarcoidosis, chronic graft-versus-host disease, and other pathological conditions, results in inadequate secretion of the aqueous layer of the tear film and is a leading cause of dry eye disease. The hallmarks of lacrimal gland inflammation are the presence of immune cell infiltrates, loss of acinar epithelial cells (the secreting cells), and increased production of proinflammatory cytokines. To date, the mechanisms leading to acinar cell loss and the associated decline in lacrimal gland secretion are still poorly understood. It is also not understood why the remaining lacrimal gland cells are unable to proliferate in order to regenerate a functioning lacrimal gland. This article reviews recent advances in exocrine tissue injury and repair, with emphasis on the roles of programmed cell death and stem/progenitor cells.

Figure 1

Major cellular components of the lacrimal gland. The acinar cells, which account for 80% of the cell types present in the lacrimal gland, and ductal cells were stained with hematoxylin and eosin. The myoepithelial cells were identified immunohistochemicaly (brown stain) using an antibody against [ALPHA]α-smooth muscle actin.

Figure 2

Effects of inflammation on the lacrimal gland and the ocular surface. Schematic diagram summarizing how inflammation of the lacrimal gland can lead to damage of the ocular surface.

Figure 3

Schematic diagram of the FGFR and listing of ligand specificity for FGFR isoforms. FGF7 and 10 are considered to be mesenchymally expressed, and FGF 2, 4, 6, 8, 9 and 17 are considered to be expressed in epithelia.

Figure 4

Schematic diagram of signaling through BMP receptors. Upon binding of BMP7, type II receptor phosphorylate type I receptors that, in turn, phosphorylate Smads1, 5, and 8. Phosphorylated Smads1/5/8 associate with Smad4 and translocate to the nucleus where, along with cofactors, initiate the transcription of BMP response genes.

Figure 5

Similarities and differences between apoptosis and autophagy. The electron micrographs depict the cellular changes that occur during apoptosis and autophagy, including membrane blebbing and accumulation of autophagic vacuoles.

Figure 6

Autophagic cell death in injured lacrimal glands. Lacrimal glands from saline (control) and IL-1 injected animals were processed for transmission electron microscopy. In control lacrimal glands, the acinar cells are highly polarized with basally located nuclei (N); they have a very dense, rough endoplasmic reticulum (ER) network, and the cytoplasm is filled with secretory granules (SG). In contrast, in IL-1-injected lacrimal glands, the acinar cells have lost their polarity, the ER network is disorganized, and the cytoplasm is filled with vacuoles (V), some of which are double-membrane-delimited (inset). Arrows point to potential autophagosomes or lysosomes.