TSPAN4-positive migrasome derived from retinal pigmented epithelium cells contributes to the development of proliferative vitreoretinopathy

Abstract

Background Proliferative vitreoretinopathy (PVR) is a blind-causing disease initiated by the activation of retinal pigmented epithelium (RPE) primarily induced by TGF-β families. Migrasome is a recently discovered type of extracellular vesicle related to cell migration. Results Here, we used ex vivo, in vitro, and in vivo models, to investigate the characteristics and functions of migrasomes in RPE activation and PVR development. Results indicated that the migrasome marker tetraspanin-4 (TSPAN4) was abundantly expressed in human PVR-associated clinical samples. The ex vivo model PVR microenvironment is simulated by incubating brown Norway rat RPE eyecups with TGF-β1. Electron microscope images showed the formation of migrasome-like vesicles during the activation of RPE. Further studies indicated TGF-β1 increased the expression of TSPAN4 which results in migrasome production. Migrasomes can be internalized by RPE and increase the migration and proliferation ability of RPE. Moreover, TSPAN4-inhibited RPE cells are with reduced ability of initiating experimental PVR. Mechanically, TSPAN4 expression and migrasome production are induced through TGF-β1/Smad2/3 signaling pathway. Conclusion In conclusion, migrasomes can be produced by RPE under PVR microenvironment. Migrasomes play a pivotal role in RPE activation and PVR progression. Thus, targeting TSPAN4 or blocking migrasome formation might be a new therapeutic method against PVR.

Seeing is believing: observation of migrasomes

“…Imaging and Biochemical data (Ding et al 2023 ; Huang et al 2019 ; Jiang et al 2019 ; Jiao et al 2021 ; Liang et al 2023 ; Ma et al 2015 ; Wu et al 2017 , 2022 ; Zhang et al 2022 ; Zhao et al 2019 )…”

“…Additionally, Migrasomes are excessively generated by macrophage lineage cells upon amyloid protein stimulation, thereby contributing to complement-dependent blood vessel damage (Hu et al 2023 ). Furthermore, it has been discovered that Migrasomes derived from Pigmented epithelium cells promote the progression of proliferative vitreoretinopathy (Wu et al 2022 ).…”

Migrasomes, a new mode of intercellular communication

“…Retinal pigmented epithelium (RPE) activated by cytokines can lead to proliferative vitreoretinopathy (PVR), causing retinal detachment and blindness [ 43 , 44 ]. Wu et al [ 45 ] found that human PVR samples express the migrasome marker, TSPAN4. RPE from Norway rat activated by TGF-β1 increases TSPAN4 expression and produces migrasomes.…”

A Review of the Roles of Specialized Extracellular Vesicles, Migrasomes, and Exosomes in Normal Cell Physiology and Disease

“…Migrasomes can be internalized by retinal pigmented epithelium (RPE), promoting RPE activation and proliferative vitreoretinopathy (PVR) progression by increasing the migration and proliferation ability of RPE [59]. TSPAN4 is abundant in the migrasome membrane and is one of the most effective tetraspanins for migrasome induction [46], stabilizing the migrasome structure and acting as a migrasome marker [6,60].…”

“…Moreover, neurons are found in close vicinity to migrasomes, and double immunofluorescent staining revealed co-localization of microglia migrasomes and neuron fragments, suggesting a potential interaction between the migrasomes and surrounding neurons [ 40 ]. Migrasomes can be internalized by retinal pigmented epithelium (RPE), promoting RPE activation and proliferative vitreoretinopathy (PVR) progression by increasing the migration and proliferation ability of RPE [ 59 ]. TSPAN4 is abundant in the migrasome membrane and is one of the most effective tetraspanins for migrasome induction [ 46 ], stabilizing the migrasome structure and acting as a migrasome marker [ 6 , 60 ].…”