title: BDNF-treated retinal progenitor sheets transplanted to degenerate rats: improved restoration of visual function.
abstract: The aim of this study was to evaluate the functional efficacy of retinal progenitor cell (RPC) containing sheets with BDNF microspheres following subretinal transplantation in a rat model of retinal degeneration. Sheets of E19 RPCs derived from human placental alkaline phosphatase (hPAP) expressing transgenic rats were coated with poly-lactide-co-glycolide (PLGA) microspheres containing brain-derived neurotrophic factor (BDNF) and transplanted into the subretinal space of S334ter line 3 rhodopsin retinal degenerate rats. Controls received transplants without BDNF or BDNF microspheres alone. Visual function was monitored using optokinetic head-tracking behavior. Visually evoked responses to varying light intensities were recorded from the superior colliculus (SC) by electrophysiology at 60days after surgery. Frozen sections were studied by immunohistochemistry for photoreceptor and synaptic markers. Visual head tracking was significantly improved in rats that received BDNF-coated RPC sheets. Relatively more BDNF-treated transplanted rats (80%) compared to non-BDNF transplants (57%) responded to a "low light" intensity of 1cd/m2 in a confined SC area. With bright light, the onset latency of SC responses was restored to a nearly normal level in BDNF-treated transplants. No significant improvement was observed in the BDNF-only and no surgery transgenic control rats. The bipolar synaptic markers mGluR6 and PSD-95 showed normal distribution in transplants and abnormal distribution of the host retina, both with or without BDNF treatment. Red-green cones were significantly reduced in the host retina overlying the transplant in the BDNF-treated group. In summary, BDNF coating improved the functional efficacy of RPC grafts. The mechanism of the BDNF effects--either promoting functional integration between the transplant and the host retina and/or synergistic action with other putative humoral factors released by the RPCs--still needs to be elucidated.
authors.affiliation: Ophthalmology-USC, Doheny, Los Angeles, CA, USA.
authors.forename: Magdalene J
authors.initials: MJ
authors.lastname: Seiler
authors.forename: Biju B
authors.initials: BB
authors.lastname: Thomas
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Chen
authors.forename: Shinichi
authors.initials: S
authors.lastname: Arai
authors.forename: Sridhar
authors.initials: S
authors.lastname: Chadalavada
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Mahoney
authors.forename: Srinivas R
authors.initials: SR
authors.lastname: Sadda
authors.forename: Robert B
authors.initials: RB
authors.lastname: Aramant
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D004195:Disease Models, Animal; D004594:Electrophysiology; D005074:Evoked Potentials, Visual; D019416:Head Movements; D008863:Microspheres; D009039:Motion Perception; D010775:Photic Stimulation / Q000379:methods; D051381:Rats; D011922:Rats, Mutant Strains; D012160:Retina / Q000166:cytology / Q000187:drug effects* / Q000473:pathology / Q000637:transplantation*; D012162:Retinal Degeneration / Q000473:pathology / Q000503:physiopathology / Q000523:psychology / Q000628:therapy*; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000187:drug effects; D013477:Superior Colliculi / Q000187:drug effects / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D019208:Brain-Derived Neurotrophic Factor