A New Approach for Enhanced Graft-Host Cell Interaction to Improve Stem Cell and Gene Therapy for Retinal Degeneration.

The eye has become a leading organ for genetic and stem cell therapy. Graft-host cell communication is critical for tissue regeneration in both cell replacement and paracrine mechanism approaches. The grafted cells are currently delivered between the photoreceptors and the retinal pigment epithelium allowing proximity with the target tissue, but graft cells clumping and retinal layer detachment may compromise graft-host interaction. Cell injection into the vitreous is well established but does not target the graft to the retina, compromising graft-host cell communications. We developed an innovative system that allows targeting the graft to host retinal cells, allowing close interaction and better spreading in proximity to the retinal cells, reducing the minimal volume needed without graft cell clumping and host retinal interlayer separation and detachment. Human bone marrow mesenchymal stromal cells in (hBMSCs) were grafted using this approach in eyes of rabbits and an RCS rat model of retinal degeneration, resulting in a single layer of cells covering >80% of the area under the retina. Cell transplantation ameliorated retinal function in RCS rat model of retinal degeneration for 5 months. An extensive photoreceptor rescue was demonstrated in transplanted eyes, with 3-4 photoreceptor cell layers along the entire retina. No retinal detachment, choroidal hemorrhage, inflammation, or epiretinal membrane formation were detected in any of the injected eyes or contralateral control eyes in rats and rabbits. Our data demonstrate the importance of proximity and efficient spreading of the graft cells in the host retina for safe and efficient stem cells and genetic treatment.