期刊
CELL TRANSPLANTATION
卷 21, 期 5, 页码 871-887出版社
SAGE PUBLICATIONS INC
DOI: 10.3727/096368911X623871
关键词
Photoreceptor; Retina; Transplantation; Neurotrophic factors; Gene therapy; Stem cell
资金
- Wellcome Trust [082217]
- Medical Research Council UK [G03000341]
- Health Foundation
- Royal College of Surgeons
- Health Foundation Clinician Scientist Fellowship
- Great Ormond Street Hospital Children's Charity
- Department of Health's National Institute for Health Research Biomedical Research Centre at Mootfields Eye Hospital
- MRC [MR/J004553/1, G0700438, G0901550] Funding Source: UKRI
- Medical Research Council [G0700438, MR/J004553/1, G0901550] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10130] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1221, V1257] Funding Source: researchfish
Degeneration of the neural retina is the leading cause of untreatable blindness in the developed world. Stem cell replacement therapy offers a novel strategy for retinal repair. Postmitotic photoreceptor precursors derived from the early postnatal (P) retina are able to migrate and integrate into the adult mouse retina following transplantation into the subretinal space, but it is likely that a large number of these cells would be required to restore vision. The adult recipient retina presents a very different environment to that from which photoreceptor precursor donor cells isolated from the developing postnatal retina are derived. Here we considered the possibility that modulation of the recipient environment by ectopic expression of developmentally regulated growth factors, normally present during photoreceptor development, might enhance the migration and integration of transplanted cells into the adult neural retina. Adeno-associated viral (AAV) vectors were used to introduce three growth factors previously reported to play a role in photoreceptor development, IGF1, FGF2, and CNTF, into the adult retina, prior to transplantation of P4 cells derived from the Nrl.GFP(+ve) neural retina. At 3 weeks posttransplantation the number of integrated, differentiated photoreceptor cells present in AAV-mediated neurotrophic factor-treated eyes was assessed and compared to control treated contralateral eyes. We show, firstly, that it is possible to manipulate the recipient retinal microenvironment via rAAV-mediated gene transfer with respect to these developmentally relevant growth factors. Moreover, when combined with cell transplantation, AAV-mediated expression of IGF1 led to significantly increased levels of cell integration, while overexpression of FGF2 had no significant effect on integrated cell number. Conversely, expression of CNTF led to a significant decrease in cell integration and an exacerbated glial response that led to glial scarring. Together, these findings demonstrate the importance of the extrinsic environment of the recipient retina for photoreceptor cell transplantation and show for the first time that it is possible to manipulate this environment using viral vectors to influence photoreceptor transplantation efficiency.
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