WNT Mimetic-Induced Lacrimal Gland Regeneration Reverses Aqueous Tear Deficiency

Abstract

Purpose : Dry eye disease is a common chronic disease of the ocular surface characterized by abnormal tear film composition and inflammation. Tear fluid secreted from epithelial acinar cells in the exocrine lacrimal gland contributes to a protective layer on the surface of the eye. A disruption in the presence or secretory function of these cells can result in dry eye, leading to discomfort, damage, and vision loss. Patients with Sjögren's syndrome or graft-versus-host disease can experience similar symptoms. Although tear replacement and anti-inflammatory treatments have been thoroughly investigated, a method to induce epithelial restoration remains unknown at present. Here, we ask whether WNT signaling activation using a recombinant WNT mimetic platform can activate lacrimal gland acinar cells and restore tear secretion.

Methods : Primary murine lacrimal gland cells were used to establish three-dimensional acinar cell organoids. Dry eye disease was modeled in mice using a lacrimal gland IL-1a injection and lacrimal gland excretory duct ligation. Treatment groups for both in vitro and in vivo experiments consisted of antibody based WNT mimetic and controls.

Results : Frizzled and LRP5/6 receptors, essential for WNT signal transduction, are expressed in acinar cells in both mouse and human lacrimal glands. We show that murine acinar cells can be expanded as organoids using WNT signaling activation. Using two murine models of dry eye disease we demonstrate that intra-lacrimal gland treatment with a WNT mimetic reverses aqueous tear deficiency. In both IL-1a induced acute dry eye and excretory duct ligation damage, WNT mimetic treatment induces acinar cell proliferation and increases detectable tear volume production.

Conclusions : Our findings extend the potential of WNT pathway activation using a mimetics platform to lacrimal gland regeneration. Together, this study provides a novel approach to treat dry eye disease.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.