Bimodal in vivo imaging provides early assessment of stem-cell-based photoreceptor engraftment

Subretinal transplantation of stem-cell-derived photoreceptor precursor cells (PPCs) is a promising and innovative approach to treating a range of blinding diseases. However, common barriers to efficient preclinical transplantation comes in the form of suboptimal graft architecture, limited graft survival, and immune-rejection, each of which cannot be assessed using conventional in vivo imaging (i.e., rodent ophthalmoscopy). With the majority of PPCs reported to die within the first few weeks after transplantation, understanding the mechanisms of graft failure, and ultimately devising preventative methods, currently relies on lengthy end point histology. To address these limitations, we hypothesized that combining two imaging modalities, optical coherence tomography (OCT) and fluorescence confocal scanning laser ophthalmoscopy (fcSLO), could provide a more rapid and comprehensive view of PPC engraftment.Human ESC-derived PPCs were transplanted into 15 retinal dystrophic rats that underwent bimodal imaging at 0, 8, and 15 days posttransplant.Bimodal imaging provided serial detection of graft: placement, architecture, and survival; each undetectable under ophthalmoscopy. Bimodal imaging determined graft placement to be either: subretinal (n=7), choroidal (n=4), or vitreal (n=4) indicating neural retinal perforation. Graft architecture was highly variable at the time of transplantation, with notable redistribution over time, while complete, or near complete, graft loss was observed in the majority of recipients after day 8. Of particular importance was detection of vitreal aggregates overlying the graft-possibly an indicator of host-site inflammation and rejection.Early real-time feedback of engraftment has the potential to greatly increase efficiency of preclinical trials in cell-based retinal therapeutics.