Age-Related Choroidal Involution Is Associated with the Senescence of Endothelial Progenitor Cells in the Choroid
Notice bibliographique
Résumé
Background: Choroidal involution is a common feature of age-related ischemic retinopathies such as age-related macular degeneration (AMD). It is now well recognized that endothelial progenitor cells (EPCs) are essential to endothelial repair processes and in maintaining vascular integrity. However, the contribution of EPCs and the role of senescence in age-related choroidal vascular degeneration remain to be investigated. In this study, we compared the senescent phenotype of EPCs in the choroid and performed whole-genome profiling of EPCs derived from young versus old rats. Methods and Results: We isolated and compared the retinas of young (6-weeks-old) and old (16–18-month-old) rats. The thickness of the choroid and outer nuclear layer (ONL), along with local quantification of CD34+ EPCs, was performed. Compared to young rats, older rats displayed a significant reduction in choroidal and ONL thickness associated with markedly fewer choroid-localized EPCs; this was attested by lower expression of several EPC markers (CXCR4, CD34, CD117, CD133, and KLF-2). Choroid and choroid-localized EPCs displayed abundant senescence as revealed by increased β-gal and P53 expression and decreased Lamin-B1 (immunostaining and RT-qPCR). Concordantly, choroidal cells and EPCs isolated from older rats were unable to form vascular networks ex vivo. To better understand the potential mechanisms associated with the dysfunctional EPCs linked to age-related choroidal involution, we performed whole-genome profiling (mRNA and miRNA) of EPCs derived from old and young rats using next-generation sequencing (NGS); 802 genes were significantly modulated in old vs. young EPCs, corresponding to ~2% of total genes expressed. Using a bioinformatic algorithm, the KEGG pathways suggested that these genes participate in the modulation of several key signaling processes including inflammation, G protein-coupled receptors, and hematopoietic cell lineages. Moreover, we identified 13 miRNAs involved in the regulation of immune system processes, cell cycle arrest and senescence, which are significantly modulated in EPCs from old rats compared to young ones. Conclusions: Our results suggest that age-related choroidal involution is associated with fewer EPCs, albeit displaying a senescence-like phenotype. One would be tempted to propose that biological modification of native EPCs (such as with senolytic agents) could potentially provide a new strategy to preserve the vascular integrity of the aged choroid, and evade progression to degenerative maculopathies.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».