EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

Abstract

Epithelial–mesenchymal transition (EMT) and endothelial–mesenchymal transition (EndMT) are physiological processes required for normal embryogenesis. However, these processes can be hijacked in pathological conditions to facilitate tissue fibrosis and cancer metastasis. In the eye, EMT and EndMT play key roles in the pathogenesis of subretinal fibrosis, the end-stage of age-related macular degeneration (AMD) that leads to profound and permanent vision loss. Predominant in subretinal fibrotic lesions are matrix-producing mesenchymal cells believed to originate from the retinal pigment epithelium (RPE) and/or choroidal endothelial cells (CECs) through EMT and EndMT, respectively. Recent evidence suggests that EMT of RPE may also be implicated during the early stages of AMD. Transforming growth factor-beta (TGFβ) is a key cytokine orchestrating both EMT and EndMT. Investigations in the molecular mechanisms underpinning EMT and EndMT in AMD have implicated a myriad of contributing factors including signaling pathways, extracellular matrix remodelling, oxidative stress, inflammation, autophagy, metabolism and mitochondrial dysfunction. Questions arise as to differences in the mesenchymal cells derived from these two processes and their distinct mechanistic contributions to the pathogenesis of AMD. Detailed discussion on the AMD microenvironment highlights the synergistic interactions between RPE and CECs that may augment the EMT and EndMT processes in vivo. Understanding the differential regulatory networks of EMT and EndMT and their contributions to both the dry and wet forms of AMD can aid the development of therapeutic strategies targeting both RPE and CECs to potentially reverse the aberrant cellular transdifferentiation processes, regenerate the retina and thus restore vision.

The Role of Inflammation in Age-Related Macular Degeneration

“…Subretinal fibrosis is a clinical manifestation of later period of nAMD [91], which is a wound healing response after CNV, together with the damage of photoreceptors, RPE and choroidal blood vessels, causing irreparable visual impairment [19]. Cellular and ECM constituents, and the growth factor mediated EMT act as important roles in the RPE and the complex signaling networks of fibrosis in AMD [28].…”

“…Cellular and ECM constituents, and the growth factor mediated EMT act as important roles in the RPE and the complex signaling networks of fibrosis in AMD [28]. There are two important processes, including EMT and endothelial-mesenchymal transition (EndMT), and TGF-β is the main regulator and the Snail superfamily are key transcription factors [91]. Snail superfamily can bind to the DNA promoter region and stimulate the mesenchymal changes, cell migration and proliferation of different epithelial cells, thereby inhibiting the effects of epithelial molecules [92].…”

Polarity and epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy

“…Therapeutic interventions against RPE EMT have largely been explored in mechanistic experiments using in vitro cell culture and in vivo animal models. To date, some promising drug candidates have been trialed in preclinical studies of PVR, including TGF-β receptor inhibitors, peroxisome proliferator-activated receptor (PPAR)-γ agonists, retinoic acid receptor-γ (RAR-γ) agonists and methotrexate ( Shu, Butcher & Saint-Geniez, 2020 ; Zhou et al, 2020 ). Nassar et al (2014) found that TGF-β receptor 1 inhibitor LY-364947 (LY) attenuates RPE cell transdifferentiation in vitro, and that intravitreal injection of LY completely prevents PVR and TRD in vivo.…”

Peer Review #1 of "Polarity and epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy (v0.1)"

“…Therapeutic interventions against RPE EMT have largely been explored in mechanistic experiments using in vitro cell culture and in vivo animal models. To date, some promising drug candidates have been trialed in preclinical studies of PVR, including TGF-β receptor inhibitors, peroxisome proliferator-activated receptor (PPAR)-γ agonists, retinoic acid receptor-γ (RAR-γ) agonists and methotrexate (Shu et al 2020;Zhou et al 2020). Nassar et al (2014) found that TGF-β receptor 1 inhibitor LY-364947 (LY) attenuates RPE cell transdifferentiation in vitro, and that intravitreal injection of LY completely prevents PVR and TRD in vivo.…”