title: Long-term neuroprotective effects of NT-4-engineered mesenchymal stem cells injected intravitreally in a mouse model of acute retinal injury.
abstract: OBJECTIVE
  Retinal degenerative diseases targeting the RPE and adjacent photoreceptors affect millions of people worldwide. The field of stem cell- and gene-based therapy holds great potential for the treatment of such diseases. The present study sought to graft genetically engineered mesenchymal stem cells (MSCs) that continuously produce neurotrophin-4 (NT-4) into the murine eye after the onset of acute retinal injury.
  
  
  METHODS
  C57BL/6 mice were subjected to acute retinal damage using a low dose of sodium iodate (20 mg/kg of body weight), followed by intravitreal injection of lentivirally modified MSC-NT-4 into the right eye. At 3 months after the MSC transplantation grafted cell survival, retinal function and gene expression were analyzed.
  
  
  RESULTS
  Immunofluorescence analysis confirmed that transplanted MSCs survived for at least 3 months after intravitreal injection and preferentially migrated toward sites of injury within the retina. MSC-NT-4 actively produced NT-4 in the injured retina and significantly protected damaged retinal cells, as evaluated by ERG and optical coherence tomography (OCT). Of importance, the long-term therapy with MSC-NT-4 was also associated with induction of prosurvival signaling, considerable overexpression of some subsets of transcripts, including several members of the crystallin β-γ superfamily (Cryba4, Crybb3, Cryba2, Crybb1, Crybb2, Cryba1, and Crygc) and significant upregulation of biological processes associated with visual perception, sensory perception of light stimulus, eye development, sensory organ development, and system development.
  
  
  CONCLUSIONS
  Transplantation of genetically modified MSCs that produce neurotrophic growth factors may represent a useful strategy for treatment of different forms of retinopathies in the future.
authors.affiliation: Department of Histology and Embryology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Machalińska
authors.forename: Miłosz
authors.initials: M
authors.lastname: Kawa
authors.forename: Ewa
authors.initials: E
authors.lastname: Pius-Sadowska
authors.forename: Jacek
authors.initials: J
authors.lastname: Stępniewski
authors.forename: Witold
authors.initials: W
authors.lastname: Nowak
authors.forename: Dorota
authors.initials: D
authors.lastname: Rogińska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kaczyńska
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Baumert
authors.forename: Barbara
authors.initials: B
authors.lastname: Wiszniewska
authors.forename: Alicja
authors.initials: A
authors.lastname: Józkowicz
authors.forename: Józef
authors.initials: J
authors.lastname: Dulak
authors.forename: Bogusław
authors.initials: B
authors.lastname: Machaliński
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002465:Cell Movement; D002470:Cell Survival; D004195:Disease Models, Animal; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000502:physiology; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D015316:Genetic Therapy; D005822:Genetic Vectors; D058449:Intravitreal Injections; D007452:Iodates / Q000633:toxicity; D016086:Lentivirus / Q000235:genetics; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000235:genetics*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000187:drug effects; D012162:Retinal Degeneration / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*
chemical_list: D015415:Biomarkers; D007452:Iodates; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; C073922:neurotrophin 4; C032285:sodium iodate
keywords: MSCs; electroretinography; gene expression; gene therapy; neurotrophin-4; retinal injury; sodium iodate