MSC Transplantation Improves Lacrimal Gland Regeneration after Surgically Induced Dry Eye Disease in Mice

Jana Dietrich,Stefan Schrader,Mathias Roth,Gerd Geerling,Sonja Mertsch,Joana Witt,Lolita Ott

doi:10.1038/s41598-019-54840-5

Abstract

Dry eye disease (DED) is a multifactorial disease characterized by a disrupted tear film homeostasis and inflammation leading to visual impairments and pain in patients. Aqueous-deficient dry eye (ADDE) causes the most severe progressions and depends mainly on the loss of functional lacrimal gland (LG) tissue. Despite a high prevalence, therapies remain palliative. Therefore, it is of great interest to develop new approaches to curatively treat ADDE. Mesenchymal stem/stromal cells (MSC) have been shown to induce tissue regeneration and cease inflammation. Moreover, an increasing amount of MSC was found in the regenerating LG of mice. Therefore, this study investigated the therapeutic effect of MSC transplantation on damaged LGs using duct ligation induced ADDE in mice. Due to the transplantation of sex-mismatched and eGFP-expressing MSC, MSC could be identified and detected until day 21. MSC transplantation significantly improved LG regeneration, as the amount of vital acinar structures was significantly increased above the intrinsic regeneration capacity of control. Additionally, MSC transplantation modulated the immune reaction as macrophage infiltration was delayed and TNFα expression decreased, accompanied by an increased IL-6 expression. Thus, the application of MSC appears to be a promising therapeutic approach to induce LG regeneration in patients suffering from severe DED/ADDE.

Highlights

Dry eye disease (DED) is a multifactorial disease affecting the entire lacrimal functional unit (LFU) including the ocular surface, the lacrimal glands (LG), the meibomian glands, the nervous innervation and the lids
One promising source for stem cell therapy to induce LG regeneration might be the use of mesenchymal stem/ stromal cells (MSC), as these cells can be isolated from many different adult tissues and have already shown to exert therapeutic effects on the regeneration of glandular tissues, like pancreas, salivary gland (SG) and LG with chronic DED5–7
To verify the phenotype of MSC isolated from genetically modified eGFP-mice, the cells were characterized according to the defined minimal criteria[24]

Summary

Introduction

Dry eye disease (DED) is a multifactorial disease affecting the entire lacrimal functional unit (LFU) including the ocular surface, the lacrimal glands (LG), the meibomian glands, the nervous innervation and the lids. Any impairment or loss of functional LG tissue lead to an imbalance of tear film homeostasis and can result in the development of aqueous deficient dry eye (ADDE). This DED subtype causes the most severe courses of the disease. The LG, like other glandular tissues, retains the ability of self-regeneration after acute damage throughout its life-time, it can be impaired due to chronic pathological conditions[20] For this reason, the re-opening of the duct in the DL mouse model initiated a phase of new tissue formation/regeneration in juvenile mice, shown by the partial regeneration of vital acinar structures after 21 days by our working group[11]. This regeneration process was accompanied by an increase of intrinsic MSC

Methods

Results

Conclusion