Nanoparticle-based targeting of microglia improves the neural regeneration enhancing effects of immunosuppression in the zebrafish retina.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
18 05 2023
18 05 2023
Historique:
received:
22
02
2021
accepted:
02
05
2023
medline:
22
5
2023
pubmed:
19
5
2023
entrez:
18
5
2023
Statut:
epublish
Résumé
Retinal Müller glia function as injury-induced stem-like cells in zebrafish but not mammals. However, insights gleaned from zebrafish have been applied to stimulate nascent regenerative responses in the mammalian retina. For instance, microglia/macrophages regulate Müller glia stem cell activity in the chick, zebrafish, and mouse. We previously showed that post-injury immunosuppression by the glucocorticoid dexamethasone accelerated retinal regeneration kinetics in zebrafish. Similarly, microglia ablation enhances regenerative outcomes in the mouse retina. Targeted immunomodulation of microglia reactivity may therefore enhance the regenerative potential of Müller glia for therapeutic purposes. Here, we investigated potential mechanisms by which post-injury dexamethasone accelerates retinal regeneration kinetics, and the effects of dendrimer-based targeting of dexamethasone to reactive microglia. Intravital time-lapse imaging revealed that post-injury dexamethasone inhibited microglia reactivity. The dendrimer-conjugated formulation: (1) decreased dexamethasone-associated systemic toxicity, (2) targeted dexamethasone to reactive microglia, and (3) improved the regeneration enhancing effects of immunosuppression by increasing stem/progenitor proliferation rates. Lastly, we show that the gene rnf2 is required for the enhanced regeneration effect of D-Dex. These data support the use of dendrimer-based targeting of reactive immune cells to reduce toxicity and enhance the regeneration promoting effects of immunosuppressants in the retina.
Identifiants
pubmed: 37202450
doi: 10.1038/s42003-023-04898-9
pii: 10.1038/s42003-023-04898-9
pmc: PMC10193316
doi:
Substances chimiques
Dendrimers
0
Dexamethasone
7S5I7G3JQL
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
534Subventions
Organisme : NIH HHS
ID : R01 OD020376
Pays : United States
Organisme : NEI NIH HHS
ID : F31 EY032790
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY025304
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY022810
Pays : United States
Organisme : NEI NIH HHS
ID : P30 EY001765
Pays : United States
Informations de copyright
© 2023. The Author(s).
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