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Dysregulated Polarized Secretion of Small Extracellular Vesicles in the Retinal Pigment Epithelium: Mechanisms and
Haoxin Guo1,2,3, Ruiyi Yan1,2,3, Xiaoxu Han1,2,3
1Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People's Republic of China.
Abstract:
The pathogenesis of age-related macular degeneration (AMD) is intrinsically driven by retinal pigment epithelium (RPE) dysfunction. Under physiological conditions, the strictly polarized secretion of small extracellular vesicles (sEVs) by the RPE dictates outer retinal homeostasis. In response to oxidative and hypoxic stress, this secretory architecture is profoundly disrupted, transforming sEVs into mediators of drusen formation, inflammation, and neovascularization. This review systematically delineates the molecular machinery governing RPE-sEV trafficking, unveiling the distinct protein and miRNA cargo profiles segregated between the apical and basolateral domains. We highlight the unique secretory features of RPE and elucidate how AMD stressors disrupt this polarity via cytoskeletal collapse, secretory autophagy, and Rab GTPase dysregulation. Consequently, this altered sEV secretion abolishes apical neurotrophic support while deteriorating the basolateral microenvironment. Crucially, this establishes a vicious pathological loop where microenvironmental deterioration and sEV dysregulation are mutually causative. Recognizing dysregulated sEV polarity as a contributing factor to AMD, we propose that repairing RPE intracellular trafficking offers a fundamental strategy to restore secretory homeostasis and impede disease progression.
Insights
Retinal pigment epithelium (RPE) dysfunction drives age-related macular degeneration (AMD). Dysfunctional small extracellular vesicles (sEVs) disrupt RPE polarity, worsening AMD; restoring RPE trafficking may impede disease progression.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Biology
Background:
- Age-related macular degeneration (AMD) pathogenesis involves retinal pigment epithelium (RPE) dysfunction.
- RPE's polarized secretion of small extracellular vesicles (sEVs) maintains retinal homeostasis.
- Stress disrupts RPE polarity, altering sEVs and promoting AMD pathology.
Purpose of the Study:
- To review the molecular mechanisms of RPE-sEV trafficking.
- To elucidate how AMD stressors disrupt RPE polarity and sEV secretion.
- To propose RPE intracellular trafficking repair as an AMD therapeutic strategy.
Main Methods:
- Systematic review of literature on RPE-sEV molecular machinery.
- Analysis of protein and miRNA cargo profiles in apical vs. basolateral sEVs.
- Examination of how oxidative and hypoxic stress impact RPE polarity.
Main Results:
- RPE-sEVs exhibit distinct apical and basolateral cargo.
- AMD stressors (oxidative/hypoxic) disrupt RPE polarity via cytoskeletal collapse, autophagy, and Rab GTPase dysregulation.
- Altered sEV secretion leads to loss of neurotrophic support and microenvironmental deterioration, creating a pathological loop.
Conclusions:
- Dysregulated sEV polarity is a key factor in AMD pathogenesis.
- RPE dysfunction and altered sEVs create a mutually causative pathological cycle.
- Restoring RPE intracellular trafficking offers a fundamental strategy to restore homeostasis and slow AMD progression.
