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Published on: December 22, 2014
XIAP therapy increases survival of transplanted rod precursors in a degenerating host retina
Jingyu Yao1, Kecia L Feathers, Hemant Khanna
1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA.
Purpose:
To assess the survival of rod precursor cells transplanted into the Rd9 mouse, a model of X-linked retinal degeneration, and the effect of antiapoptotic therapy with X-linked inhibitor of apoptosis (XIAP) on preventing cell loss.
Methods:
Dissociated retinal cells from P4 Nrlp-GFP mice were transplanted into the subretinal space of 2-, 5-, and 8-month-old Rd9 mice. Histology, immunohistochemistry, and quantification of integrated cells were performed every month for up to 3 months after transplantation. XIAP delivery to donor cells was accomplished by transfection with adenoassociated virus (AAV-XIAP). Intraretinal activation of immune modulators was assessed using a quantitative real-time polymerase chain reaction-based immune response array.
Results:
GFP-positive rod precursors were able to integrate into the outer nuclear layer (ONL) of the Rd9 retina. Transplanted cells underwent morphologic differentiation with the formation of inner and outer segments and synaptic projections to bipolar cells. Integration of donor cells into the ONL increased as a function of host age at the time of transplantation. The number of integrated cells was maximal at 1 month after transplantation and then decreased with time. Survival of integrated cells was significantly increased when donor cells were pretreated with AAV-XIAP. We did not detect any donor cell-specific activation of inflammation within the host retina.
Conclusions:
Survival of integrated cells decreases with time after transplantation but can be significantly increased with XIAP antiapoptotic therapy. Preventing programmed cell death through XIAP therapy may be an important component of future therapeutic retinal cell transplantation strategies.
Insights
Transplanted rod precursor cells survived in a mouse model of X-linked retinal degeneration. Anti-apoptotic therapy with X-linked inhibitor of apoptosis (XIAP) significantly improved cell survival, offering a promising strategy for retinal cell transplantation.
Area of Science:
- Ophthalmology
- Cell Biology
- Regenerative Medicine
Background:
- X-linked retinitis pigmentosa is a severe inherited retinal degeneration.
- Rod precursor cell transplantation is a potential therapy for retinal degeneration.
- Cell survival after transplantation remains a challenge.
Purpose of the Study:
- To evaluate rod precursor cell survival after transplantation into the Rd9 mouse model.
- To determine the efficacy of X-linked inhibitor of apoptosis (XIAP) in enhancing cell survival.
Main Methods:
- Rod precursor cells from Nrlp-GFP mice were transplanted into Rd9 mice of varying ages.
- Cell integration, differentiation, and survival were assessed via histology and immunohistochemistry.
- XIAP was delivered using adeno-associated virus (AAV-XIAP) for antiapoptotic therapy.
Main Results:
- Transplanted rod precursors integrated and differentiated in the Rd9 retina.
- Cell integration was higher in younger host mice and peaked at 1 month post-transplantation.
- AAV-XIAP treatment significantly increased the survival of transplanted cells.
- No significant donor cell-specific inflammation was observed.
Conclusions:
- Rod precursor cell survival decreases over time post-transplantation.
- XIAP therapy effectively enhances cell survival by preventing apoptosis.
- XIAP-mediated antiapoptotic therapy is a promising strategy for future retinal cell transplantation.
