TY - JOUR
T1 - Long-Term Neuroprotective Effects of NT-4-Engineered Mesenchymal Stem Cells Injected Intravitreally in a Mouse Model of Acute Retinal Injury
AU - Machalinska, Anna
AU - Kawa, Milosz Piotr
AU - Pius-Sadowska, Ewa
AU - Stepniewski, Jacek
AU - Nowak, Witold
AU - Roginska, Dorota
AU - Kaczynska, Katarzyna
AU - Baumert, Bartlomiej
AU - Wiszniewska, Barbara
AU - Jozkowicz, Alicja
AU - Dulak, Jozef
AU - Machalinski, Boguslaw
PY - 2013/12
Y1 - 2013/12
N2 - 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.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.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 ?-? 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.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.
AB - 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.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.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 ?-? 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.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.
KW - electroretinography
KW - gene expression
KW - gene therapy
KW - MSCs
KW - neurotrophin-4
KW - retinal injury
KW - sodium iodate
U2 - 10.1167/iovs.13-12221
DO - 10.1167/iovs.13-12221
M3 - Article
C2 - 24265016
SN - 0146-0404
VL - 54
SP - 8292
EP - 8305
JO - Investigative Ophthalmology & Visual Science
JF - Investigative Ophthalmology & Visual Science
IS - 13
ER -