Notch Inhibition Promotes Regeneration and Immunosuppression Supports Cone Survival in a Zebrafish Model of Inherited Retinal Dystrophy.

Autor:	Fogerty J; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195., Song P; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195., Boyd P; Department of Biological Sciences, Center for Zebrafish Research, and Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Notre Dame, Indiana 46556., Grabinski SE; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195., Hoang T; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205., Reich A; Florida Research and Innovation Center, Lerner Research Institute, Cleveland Clinic, Port St. Lucie, Florida 34987., Cianciolo LT; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195., Blackshaw S; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205., Mumm JS; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205., Hyde DR; Department of Biological Sciences, Center for Zebrafish Research, and Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Notre Dame, Indiana 46556., Perkins BD; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195 perkinb2@ccf.org.; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio 44195.; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio 44195.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2022 Jun 29; Vol. 42 (26), pp. 5144-5158. Date of Electronic Publication: 2022 Jun 07.
DOI:	10.1523/JNEUROSCI.0244-22.2022
Abstrakt:	Photoreceptor degeneration leads to irreversible vision loss in humans with retinal dystrophies such as retinitis pigmentosa. Whereas photoreceptor loss is permanent in mammals, zebrafish possesses the ability to regenerate retinal neurons and restore visual function. Following acute damage, Müller glia (MG) re-enter the cell cycle and produce multipotent progenitors whose progeny differentiate into mature neurons. Both MG reprogramming and proliferation of retinal progenitor cells require reactive microglia and associated inflammatory signaling. Paradoxically, in zebrafish models of retinal degeneration, photoreceptor death does not induce the MG to reprogram and regenerate lost cells. Here, we used male and female zebrafish cep290 mutants to demonstrate that progressive cone degeneration generates an immune response but does not stimulate MG proliferation. Acute light damage triggered photoreceptor regeneration in cep290 mutants but cones were only restored to prelesion densities. Using irf8 mutant zebrafish, we found that the chronic absence of microglia reduced inflammation and rescued cone degeneration in cep290 mutants. Finally, single-cell RNA-sequencing revealed sustained expression of notch3 in MG of cep290 mutants and inhibition of Notch signaling induced MG to re-enter the cell cycle. Our findings provide new insights on the requirements for MG to proliferate and the potential for immunosuppression to prolong photoreceptor survival. SIGNIFICANCE STATEMENT Inherited retinal degenerations (IRDs) are genetic diseases that lead to the progressive loss of photoreceptors and the permanent loss of vision. Zebrafish can regenerate photoreceptors after acute injury by reprogramming Müller glia (MG) into stem-like cells that produce retinal progenitors, but this regenerative process fails to occur in zebrafish models of IRDs. Here, we show that Notch pathway inhibition can promote photoreceptor regeneration in models of progressive degeneration and that immunosuppression can prevent photoreceptor loss. These results offer insight into the pathways that promote MG-dependent regeneration and the role of inflammation in photoreceptor degeneration. (Copyright © 2022 the authors.)
Databáze:	MEDLINE
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