title: Endogenous regeneration of damaged retinal pigment epithelium following low dose sodium iodate administration: an insight into the role of glial cells in retinal repair.
abstract: The retinal pigment epithelium (RPE) has been reported to demonstrate feasible self-regenerative potential under specific conditions. However, the precise underlying mechanisms involved in this process are still elusive. Here, we performed a sequential morphological, molecular, and functional analysis of retinal injury and subsequent tissue regeneration after intravenous administration of a low dose of sodium iodate (15 mg/kg) in mice over long-term observation, up to 3 months post-injury. To assess the kinetics of the injury/recovery process, the electroretinography (ERG) responses were correlated with ongoing alterations in retinal structure and the global gene expression profile of injured retinas using genome-wide RNA microarray technology, western blotting and immunohistochemical analyses. We observed considerable improvement in the rod cell-mediated ERG response, which was accompanied by the regeneration of RPE within the injury site by the 3rd month post-injury. Our results confirm that the repairing mechanisms within injured retinas involve a significant glial cell reaction marked by glial cell proliferation, migration from their original location toward the injury site, followed by a significant overproduction of NTs such as BDNF, GDNF and NT-3. The global gene expression analysis revealed that initially up-regulated genes associated with cell death, apoptosis, acute response to stress pathways underwent considerable down-regulation in the late post-injury period. Accordingly, the genes implicated in nervous tissue remodeling and neuron development, the regulation of synaptic transmission and the establishment of localization were substantially induced by the 3rd month. Collectively, our observations support the view that Müller glial cells might well play an active role not only in retinal cell reorganization following injury but potentially also in RPE regeneration, which appears to be the key event in retinal reparative process. Furthermore, we provided novel compelling evidence of the crucial role of neurotrophins in the pathophysiology of retinal repair and identified the signaling pathways that are activated during this process.
authors.affiliation: Department of General Pathology, Pomeranian Medical University, Al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland. annam@pum.edu.pl
authors.forename: Anna
authors.initials: A
authors.lastname: Machalińska
authors.forename: Miłosz Piotr
authors.initials: MP
authors.lastname: Kawa
authors.forename: Ewa
authors.initials: E
authors.lastname: Pius-Sadowska
authors.forename: Dorota
authors.initials: D
authors.lastname: Rogińska
authors.forename: Patrycja
authors.initials: P
authors.lastname: Kłos
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Baumert
authors.forename: Barbara
authors.initials: B
authors.lastname: Wiszniewska
authors.forename: Bogusław
authors.initials: B
authors.lastname: Machaliński
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004596:Electroretinography; D019084:Fluorescent Antibody Technique, Indirect; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D007452:Iodates / Q000633:toxicity*; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D040081:Protein Array Analysis; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D012162:Retinal Degeneration / Q000139:chemically induced / Q000503:physiopathology*; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007452:Iodates; D009414:Nerve Growth Factors; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; C518911:neurotropin 3, mouse; C032285:sodium iodate