Review article
Cell transdifferentiation in ocular disease: Potential role for connexin channels

https://doi.org/10.1016/j.yexcr.2021.112823Get rights and content

Highlights

  • Cell transdifferentiation including EMT and EndMT is a pathological process in a number of ocular diseases.

  • Gap junction channels and connexin hemichannels play a role in cell transdifferentiation in ocular diseases.

  • Connexin-blocking therapies demonstrate efficacy in ocular disease models.

  • Future studies could explore connexin-based therapies for prevention and treatment of pathological transdifferentiation.

Abstract

Cell transdifferentiation is the conversion of a cell type to another without requiring passage through a pluripotent cell state, and encompasses epithelial- and endothelial-mesenchymal transition (EMT and EndMT). EMT and EndMT are well defined processes characterized by a loss of epithelial/endothelial phenotype and gain in mesenchymal spindle shaped morphology, which results in increased cell migration and decreased apoptosis and cellular senescence. Such cells often develop invasive properties. Physiologically, these processes may occur during embryonic development and can resurface, for example, to promote wound healing in later life. However, they can also be a pathological process. In the eye, EMT, EndMT and cell transdifferentiation have all been implicated in development, homeostasis, and multiple diseases affecting different parts of the eye. Connexins, constituents of connexin hemichannels and intercellular gap junctions, have been implicated in many of these processes. In this review, we firstly provide an overview of the molecular mechanisms induced by transdifferentiation (including EMT and EndMT) and its involvement in eye diseases. We then review the literature for the role of connexins in transdifferentiation in the eye and eye diseases. The evidence presented in this review supports the need for more studies into the therapeutic potential for connexin modulators in prevention and treatment of transdifferentiation related eye diseases, but does indicate that connexin channel modulation may be an upstream and unifying approach for regulating these otherwise complex processes.

Introduction

Epithelial-mesenchymal transition (EMT) and Endothelial-mesenchymal transition (EndMT) are processes in which epithelial or endothelial cells respectively undergo a change in cell morphology to a spindle shape and show increased migratory and proliferative capacity [1,2]. Through EMT and EndMT, cells develop an invasive phenotype and become resistant to apoptosis and senescence. In many cases, they develop an ability to degrade the extracellular matrix, further aiding invasion and cell dispersion [1,2]. EMT and EndMT are normal processes in embryonic development, and can be reactivated in postnatal wound healing, fibrosis, cancer and metastasis [1]. Understanding the pathways involved in EMT and EndMT has important ramifications in the development of therapies for fibrotic diseases, cancer and metastasis. Whilst ‘EMT’ and ‘EndMT’ have been carefully defined recently [3], much of previous literature on EMT and EndMT would no longer fit these strict definitions. Therefore in this review we used the broad umbrella term ‘cell transdifferentiation’ to encompass EMT and EndMT-like processes in cells in the eye that are not strictly epithelial or endothelial. While many studies illustrate the importance of connexins in the eye and eye diseases, the involvement of gap junctions and connexin hemichannels in cell transdifferentiation is a poorly researched area. This review summarises and analyses the literature describing the role of connexins in cell transdifferentiation in the eye, including EMT and EndMT, and their role in ocular diseases.

Section snippets

Overview of EMT and EndMT

A typical epithelial (and endothelial) cell has an apical and a basal side, and adheres to and communicates with other epithelial cells via four kinds of junctions (tight junctions, adherens junctions, desmosomes, and gap junctions) (Fig. 1) [4]. Epithelial cell layers usually function as a permeability barrier in tissues and organs, and interact with a basement membrane [4]. Epithelial cells such as retinal pigment epithelium or endothelial cells such as corneal endothelium can be stimulated

Cell transdifferentiation in the eye and eye diseases

Cell transdifferentiation is implicated in diseases of the eye in which cells turn into a mesenchymal and fibrotic phenotype (Fig. 2) [33]. Pterygium, for example, is an invasion of the cornea and breakdown of Bowman's membrane by transformed conjunctival epithelial cells, and is characterized by increased proliferation, reduced apoptosis, and expression of all 3 TGF-β isoforms and their receptors [33]. Corneal fibrotic disease is characterized by trans-differentiation of keratocytes into

Connexins and transdifferentiation

Connexins (Cx) are the protein building blocks of gap junctions (GJs) [39]. Gap junction intercellular communication (GJIC) allows passage of molecules less than 1000 Da between cells, and are required for many cell processes including control of cell proliferation, embryogenesis, differentiation, and coordinated contraction of heart [39]. There are 21 connexin types in the human body, named according to their molecular weight. Cx43 is the most widely expressed connexin in the body [39]. The

Conjunctiva

Failed blebs in glaucoma filtration surgery show dense collagenous connective tissue with visible fibroblasts, suggesting cell transdifferentiation of subconjunctival fibroblasts [34]. This occurs concomitant to Cx43 upregulation. The translation of Cx43 mRNA into protein could be transiently blocked using antisense oligodeoxynucleotides (AsODN), first developed in 1999 to unveil the role of Cx43 in morphogenesis in chick embryos [48]. Cx43 AsODN accelerated wound healing and reduced scar size

Conclusion

This review presents evidence suggesting that cell transdifferentiation (including EMT and EndMT) has a role in wound healing and differentiation, but it can also become a pathological process in a number of ocular diseases. Furthermore, connexin channels have been shown to play a role in the development and progression of the EMT processes in corneal epithelial, stromal, and endothelial wound healing, lens wound healing, failure of glaucoma filtration surgery, age-related macular degeneration,

Patents

CRG is the co-founder of OcuNexus Therapeutics and InflammX Therapeutics which hold intellectual property related to the use of connexin channel modulators in the treatment of ocular disease. CRG and OOM are both inventors on patents related to connexin-based therapeutics for chronic inflammatory diseases.

Credit author statement

Conceptualization, J.Z, C.R.G. and O.O.M; Writing—original draft preparation, J.Z. and O.O.M; Writing—review and editing, C.R.G. All authors have read and agreed to the published version of the manuscript.

Funding

O.O.M is supported by a Neurological Foundation of New Zealand First Fellowship [2001 FFE]. J.Z. is supported by the New Zealand Health Research Council and the New Zealand Royal Society. CRG holds the B&W Hadden Chair in Ophthalmology and is grateful to Bruce and Wendy Hadden for their support.

Declaration of competing interest

CRG is the co-founder of OcuNexus Therapeutics and InflammX Therapeutics which hold intellectual property related to the use of connexin channel modulators in the treatment of ocular disease. CRG and OOM are both inventors on patents related to connexin-based therapeutics for chronic inflammatory diseases.

O.O.M is supported by a Neurological Foundation of New Zealand First Fellowship [2001 FFE]. J.Z. is supported by the New Zealand Health Research Council and the New Zealand Royal Society. CRG

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