RNAi-mediated suppression of vimentin or glial fibrillary acidic protein prevents the establishment of Müller glial cell hypertrophy in progressive retinal degeneration.

Autor: Hippert C; University College London Institute of Ophthalmology, London, UK., Graca AB; University College London Institute of Ophthalmology, London, UK., Basche M; University College London Institute of Ophthalmology, London, UK.; Centre for Cell and Gene Therapy, King's College London, Guy's Hospital, London, UK., Kalargyrou AA; University College London Institute of Ophthalmology, London, UK.; Centre for Cell and Gene Therapy, King's College London, Guy's Hospital, London, UK., Georgiadis A; University College London Institute of Ophthalmology, London, UK., Ribeiro J; University College London Institute of Ophthalmology, London, UK., Matsuyama A; University College London Institute of Ophthalmology, London, UK., Aghaizu N; University College London Institute of Ophthalmology, London, UK., Bainbridge JW; University College London Institute of Ophthalmology, London, UK., Smith AJ; University College London Institute of Ophthalmology, London, UK.; Centre for Cell and Gene Therapy, King's College London, Guy's Hospital, London, UK., Ali RR; University College London Institute of Ophthalmology, London, UK.; Centre for Cell and Gene Therapy, King's College London, Guy's Hospital, London, UK., Pearson RA; University College London Institute of Ophthalmology, London, UK.; Centre for Cell and Gene Therapy, King's College London, Guy's Hospital, London, UK.
Jazyk: angličtina
Zdroj: Glia [Glia] 2021 Sep; Vol. 69 (9), pp. 2272-2290. Date of Electronic Publication: 2021 May 24.
DOI: 10.1002/glia.24034
Abstrakt: Gliosis is a complex process comprising upregulation of intermediate filament (IF) proteins, particularly glial fibrillary acidic protein (GFAP) and vimentin, changes in glial cell morphology (hypertrophy) and increased deposition of inhibitory extracellular matrix molecules. Gliosis is common to numerous pathologies and can have deleterious effects on tissue function and regeneration. The role of IFs in gliosis is controversial, but a key hypothesized function is the stabilization of glial cell hypertrophy. Here, we developed RNAi approaches to examine the role of GFAP and vimentin in vivo in a murine model of inherited retinal degeneration, the Rhodopsin knockout (Rho -/- ) mouse. Specifically, we sought to examine the role of these IFs in the establishment of Müller glial hypertrophy during progressive degeneration, as opposed to (more commonly assessed) acute injury. Prevention of Gfap upregulation had a significant effect on the morphology of reactive Müller glia cells in vivo and, more strikingly, the reduction of Vimentin expression almost completely prevented these cells from undergoing degeneration-associated hypertrophy. Moreover, and in contrast to studies in knockout mice, simultaneous suppression of both GFAP and vimentin expression led to severe changes in the cytoarchitecture of the retina, in both diseased and wild-type eyes. These data demonstrate a crucial role for Vimentin, as well as GFAP, in the establishment of glial hypertrophy and support the further exploration of RNAi-mediated knockdown of vimentin as a potential therapeutic approach for modulating scar formation in the degenerating retina.
(© 2021 The Authors. GLIA published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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