ABSTRACT
Woundhealing disorders characterized by impaired or delayed re-epithelialization are a serious medical problem that is painful and difficult to treat. Gelsolin (GSN), a known actin modulator, supports epithelial cell regeneration and apoptosis. The aim of this study was to estimate the potential of recombinant gelsolin (rhu-pGSN) for ocular surface regeneration to establish a novel therapy for delayed or complicated wound healing. We analyzed the influence of gelsolin on cell proliferation and wound healing in vitro, in vivo/ex vivo and by gene knockdown. Gelsolin is expressed in all tested tissues of the ocular system as shown by molecular analysis. The concentration of GSN is significantly increased in tear fluid samples of patients with dry eye disease. rhu-pGSN induces cell proliferation and faster wound healing in vitro as well as in vivo/ex vivo. TGF-ß dependent transcription of SMA is significantly decreased after GSN gene knockdown. Gelsolin is an inherent protein of the ocular system and is secreted into the tear fluid. Our results show a positive effect on corneal cell proliferation and wound healing. Furthermore, GSN regulates the synthesis of SMA in myofibroblasts, which establishes GSN as a key protein of TGF-ß dependent cell differentiation.
Subject(s)
Conjunctiva/metabolism , Cornea/metabolism , Dry Eye Syndromes/genetics , Gelsolin/genetics , Re-Epithelialization/genetics , Actins/genetics , Actins/metabolism , Animals , Cell Differentiation , Cell Proliferation , Conjunctiva/pathology , Cornea/pathology , Dry Eye Syndromes/blood , Dry Eye Syndromes/pathology , Epithelial Cells/cytology , Epithelial Cells/metabolism , Eyelids/cytology , Eyelids/metabolism , Female , Gelsolin/blood , Gene Expression Regulation , Humans , Lacrimal Apparatus/metabolism , Lacrimal Apparatus/pathology , Male , Mice , Myofibroblasts/cytology , Nasolacrimal Duct/cytology , Nasolacrimal Duct/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Signal Transduction , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Wound Healing/geneticsSubject(s)
Diplopia/diagnosis , Exophthalmos/diagnosis , Eye Pain/etiology , Graves Ophthalmopathy/diagnostic imaging , Immunoglobulin G/immunology , Nephritis, Interstitial/diagnosis , Aged , Diagnosis, Differential , Diplopia/immunology , Exophthalmos/complications , Exophthalmos/immunology , Eye Pain/diagnosis , Eye Pain/immunology , Graves Ophthalmopathy/immunology , Humans , Magnetic Resonance Imaging/methods , Male , Nephritis, Interstitial/immunologyABSTRACT
Meibomian gland dysfunction is a leading cause of ocular surface disease. However, little is known about the regulatory processes that control the development and maintenance of this sebaceous gland. Here, we identify a novel function for CD147, a transmembrane protein that promotes tissue remodeling through induction of matrix metalloproteinases, in regulating meibocyte differentiation and activity. We found that CD147 localized along basal cells and within discrete membrane domains of differentiated meibocytes in glandular acini containing gelatinolytic activity. Induction of meibocyte differentiation in vitro promoted CD147 clustering and MMP9 secretion, whereas RNAi-mediated abrogation of CD147 impaired MMP9 secretion, concomitant with a reduction in the number of proliferative cells and cytoplasmic lipids. Meibomian glands of CD147 knockout mice had a lower number of acini in both the superior and inferior tarsal plates of the eyelids, and were characterized by loss of lipid-filled meibocytes compared with control mice. Together, our data provide evidence showing that gelatinolytic activity in meibocytes is dependent on CD147, and supports a role for CD147 in maintaining the normal development and function of the meibomian gland.
