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 Sjögren’s 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.

Lacrimal Gland Inflammation Deregulates Extracellular Matrix Remodeling and Alters Molecular Signature of Epithelial Stem/Progenitor Cells

“…[1][2][3] It has been shown recently that murine LG has a remarkable ability to repair itself upon acute injury; however, LG repair fails in the case of chronic inflammation. 4,5 The reason for lack of repair during chronic inflammation is not really clear; however, several reports suggest that permanent extracellular matrix (ECM) remodeling affects regeneration processes in diseased…”

“…[5][6][7] It also is possible that changes in the ECM during chronic inflammation may affect stem/progenitor cell function. 5 However, to our knowledge the last hypothesis has not been explored.…”

“…5,8 During EMT, epithelial cells lose cell-cell attachment and polarity, and epithelial-specific markers, undergo cytoskeletal remodeling and gain a mesenchymal phenotype. 9,10 During the repair phase, ECM is remodeled and replaced with new proteoglycans, collagen, and elastin fibers.…”

Isolation and Characterization of Progenitor Cells in Uninjured, Adult Rat Lacrimal Gland

“…7 The mechanisms of the destruction of the LG are not well understood. 8 Regardless of the cause, LG dysfunction results in aqueous deficient dry eye, which in severe cases can lead to eye infections, impaired wound healing, and scarring of the cornea. Thus, repair and/or regeneration of the lacrimal gland would be advantageous to ocular surface health and function.…”

Recovery of Radiation-Induced Dry Eye and Corneal Damage by Pretreatment with Adenoviral Vector-Mediated Transfer of Erythropoietin to the Salivary Glands in Mice

“…The complexity of this response has recently been reviewed and detailed and reported in mice after interleukin-1 injection in the LG (Zoukhri et al, 2007;Zoukhri, 2010).…”