The immune response of stem cells in subretinal transplantation

Stem cell transplantation is a potential curative treatment for degenerative diseases of the retina. Among cell injection sites, the subretinal space (SRS) is particularly advantageous as it is maintained as an immune privileged site by the retinal pigment epithelium (RPE) layer. Thus, the success of subretinal transplantation depends on maintenance of RPE integrity. Moreover, both embryonic stem cells (ESCs) and mesenchymal stem cells (MSCs) have negligible immunogenicity and in fact are immunosuppressive. Indeed, many studies have demonstrated that immunosuppressive drugs are not necessary for subretinal transplantation of stem cells if the blood-retinal barrier is not breached during surgery. The immunogenicity of induced pluripotent stem cells (iPSCs) appears more complex, and requires careful study before clinical application. Despite low rates of graft rejection in animal models, survival rates for ESCs, MSCs, and iPSCs in retina are generally poor, possibly due to resident microglia activated by cell transplantation. To improve graft survival in SRS transplantation, damage to the blood-retinal barrier must be minimized using appropriate surgical techniques. In addition, agents that inhibit microglial activation may be required. Finally, immunosuppressants may be required, at least temporarily, until the blood-retinal barrier heals. We review surgical methods and drug regimens to enhance the likelihood of graft survival after SRS transplantation.