title: Activation of neural progenitor cells in human eyes with proliferative vitreoretinopathy.
abstract: In addition to the ability for self-renewal and functional differentiation, neural stem/progenitor cells (NSCs) can respond to CNS injuries by targeted migration. In lower vertebrates, retinal injury is known to activate NSCs in the ciliary marginal zone (CMZ). Cells expressing markers of NSCs are also present in the ciliary body epithelium (CE) and in Müller glia in the peripheral retina (PR) of the adult human eye. However, these cells seem to be quiescent in the adult human eye and recent reports have shown that CE cells have limited properties of NSCs. In order to further clarify whether NSCs exist in the adult human eye, we tested whether NSC-like cells could be activated in eyes with proliferative vitreoretinopathy (PVR). The PR and CE were studied for NSC-associated markers in human enucleated control eyes and eyes with confirmed PVR, as well as in a mouse model of PVR. Furthermore, cells isolated from vitreous samples obtained during vitrectomies for retinal detachment were directly fixed or cultured in a stem cell-promoting medium and compared to cells cultured from the post-mortem retina and CE. In situ characterization of the normal eyes revealed robust expression of markers present in NSCs (Nestin, Sox2, Pax6) only around peripheral cysts of the proximal pars plana region and the PR, the latter population also staining for the glial marker GFAP. Although there were higher numbers of dividing cells in the CE of PVR eyes than in controls, we did not detect NSC-associated markers in the CE except around the proximal pars plana cysts. In the mice PVR eyes, Nestin activation was also found in the CE. In human PVR eyes, proliferation of both non-glial and glial cells co-staining NSC-associated markers was evident around the ora serrata region. Spheres formed in 7/10 vitreous samples from patients with PVR compared to 2/15 samples from patients with no known PVR, and expressed glial - and NSC-associated markers both after direct fixation and repetitive passages. In conclusion, the adult human eye may harbor two different populations of neuroepithelial stem/progenitor cells; a non-glial population located in the proximal pars plana around peripheral cysts in addition to a population with Müller glia characteristics. Yet, we only found that the glial population was able to respond to retinal injury by targeted migration into the vitreous.
authors.affiliation: Center for Eye Research, Department of Ophthalmology, Oslo University Hospital and University of Oslo, Norway.
authors.forename: Erik O
authors.initials: EO
authors.lastname: Johnsen
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Frøen
authors.forename: Réka
authors.initials: R
authors.lastname: Albert
authors.forename: Bente K
authors.initials: BK
authors.lastname: Omdal
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Sarang
authors.forename: András
authors.initials: A
authors.lastname: Berta
authors.forename: Bjørn
authors.initials: B
authors.lastname: Nicolaissen
authors.forename: Goran
authors.initials: G
authors.lastname: Petrovski
authors.forename: Morten C
authors.initials: MC
authors.lastname: Moe
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002924:Ciliary Body / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000378:metabolism; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000378:metabolism / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism; D012163:Retinal Detachment / Q000473:pathology / Q000601:surgery; D055351:Retinal Neurons / Q000378:metabolism / Q000473:pathology*; D012243:Rhodopsin / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D018630:Vitreoretinopathy, Proliferative / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D014822:Vitreous Body / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015820:Cadherins; D005136:Eye Proteins; D005904:Glial Fibrillary Acidic Protein; D018398:Homeodomain Proteins; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D012243:Rhodopsin