Dasatinib Plus Quercetin Alleviates Choroid Neovascularization by Reducing the Cellular Senescence Burden in the
Yinhao Wang1,2,3, Yulin Tseng2,3, Keyu Chen4
1Department of Ophthalmology, First Affiliated Hospital, Zhejiang University School of Medicine, China.
Purpose:
Wet AMD (wAMD) is associated with cellular senescence. However, senescent cell-targeted therapies for wAMD have rarely been comprehensively studied. This study aimed to explore the therapeutic effects of senolytic agents on choroidal neovascularization (CNV).
Methods:
RNA sequencing datasets were obtained from the Gene Expression Omnibus database and used to explore the association between senescence and wAMD. We explored the effects of senescent adult RPE cell line-19 cells on the proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells. A laser-induced CNV animal model was used to study wAMD. We studied a senescent cell elimination therapy for CNV progression using two types of senolytics and a transgenic method.
Results:
Cells in the retinal pigment epithelium-choroid of the CNV model were enriched in senescence, inflammation, and angiogenesis gene sets. AP20187 was used to specifically eliminate senescent cells and proven to alleviate CNV progression in INK-ATTAC transgenic mice. Senescent adult RPE cell line-1 cells produced elevated levels of senescence-associated secretory phenotypes, including VEGFs; they also demonstrated increased proliferation, migration, invasion, and tube formation in human umbilical vein endothelial cells. The number of senescent cells increased in the laser-induced CNV rat model, and intravitreal injections of dasatinib with quercetin reduced the expression of p16 in CNV and alleviated neovascularization.
Conclusions:
Senescent RPE cells can accelerate pathological neovascularization; thus, senescent cell-targeting therapy has great clinical potential for wAMD.
Insights
Targeting senescent cells shows promise for treating wet age-related macular degeneration (wAMD). This study found senolytic agents effectively reduced choroidal neovascularization (CNV) in animal models, suggesting a new therapeutic avenue for wAMD.
Area of Science:
- Ophthalmology
- Cell Biology
- Gerontology
Background:
- Wet age-related macular degeneration (wAMD) is linked to cellular senescence.
- Therapies targeting senescent cells for wAMD are underexplored.
- Cellular senescence plays a role in the pathogenesis of wAMD.
Purpose of the Study:
- To investigate the therapeutic potential of senolytic agents in treating choroidal neovascularization (CNV).
- To explore the association between senescence and wAMD using RNA sequencing data.
- To evaluate the impact of senescent retinal pigment epithelium (RPE) cells on endothelial cell function.
Main Methods:
- Analysis of Gene Expression Omnibus RNA sequencing datasets for senescence and wAMD association.
- In vitro studies using senescent RPE cells to assess effects on human umbilical vein endothelial cells (HUVECs).
- In vivo studies using a laser-induced CNV rat model and INK-ATTAC transgenic mice treated with senolytics (AP20187, dasatinib, quercetin).
Main Results:
- Retinal pigment epithelium-choroid cells in the CNV model showed enrichment in senescence, inflammation, and angiogenesis pathways.
- Elimination of senescent cells with AP20187 alleviated CNV progression in transgenic mice.
- Senescent RPE cells secreted factors (e.g., VEGFs) that enhanced HUVEC proliferation, migration, invasion, and tube formation.
- Senescent cell markers (p16) were reduced, and neovascularization was alleviated by dasatinib and quercetin treatment in a rat CNV model.
Conclusions:
- Senescent RPE cells contribute to the acceleration of pathological neovascularization in wAMD.
- Senescent cell-targeting therapy presents significant clinical potential for managing wAMD.
- Senolytic agents demonstrate efficacy in reducing CNV, supporting their therapeutic application in wAMD.
