Müller glia is believed to be pivotal during iERM formation and progression.
5,22 Cytokines, such as TGF-β, have been reported to impact Müller glia by inducing cell proliferation, migration, and GMT, which is in line with Müller glia behavior during iERM progression.
5,41 Like EMT, GMT is a transdifferentiation process represented by the upregulation of pro-fibrotic myofibroblast markers and downregulation of Müller glia markers.
5,23,41 To our knowledge, this research is the first to investigate the pro-fibrotic effect of IL-4 on Müller glia. Our results demonstrated that IL-4 stimulated Müller glia proliferation and migration and upregulated the fibrotic markers
COL1A1 and fibronectin, as well as the proliferation marker CCND1. This suggests that IL-4 has a functional role in activating pro-fibrotic behaviors of Müller glia. These findings echo previous reports showing that IL-4 could lead to cell proliferation and excessive ECM deposition in conjunctival cells.
17,18,38 Our results also support the speculation that glial cell proliferation occurs before ERM stage worsening is observed by OCT images and promotes ERM progression due to the stimulation of IL-4. However, in this study, expression of the myofibroblast marker α-SMA and Müller glia marker GFAP exhibited an insignificant but marginal increase and decrease, respectively. This could be explained by the concept of “partial GMT.”
5 GMT is a transitional process where cells shift their status from glial to mesenchymal, undergoing multiple yet uncharacterized metastable intermediary phases, which are known as partial GMT.
5 Therefore, partial GMT represents the intermediate hybrid glial and mesenchymal phenotypes, which may not exhibit complete marker changes as seen in fully mesenchymal status. Recently, a strong association between partial EMT and wound healing, fibrosis, and cancer progression has been identified, which suggests the importance of studying partial GMT in similar contexts.
42 Consequently, our findings suggest that IL-4 may contribute to iERM formation and early progression PCS by inducing Müller glia proliferation, migration, and GMT. This provides a theoretical basis for more targeted therapy research for iERM and improves the potential for clinical translation of these findings.