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

Abstract

Purpose 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 (ie, 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. Methods Human ESC-derived PPCs were transplanted into 15 retinal dystrophic rats that underwent bimodal imaging at 0, 8, and 15 days posttransplant. Results 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. Conclusion Early real-time feedback of engraftment has the potential to greatly increase efficiency of preclinical trials in cell-based retinal therapeutics.

QuantifiableIn VivoImaging Biomarkers of Retinal Regeneration by Photoreceptor Cell Transplantation

“…cSLO fluorescence imaging has been used to detect red dye-labeled photoreceptor cells in the rat eye in short-term transplantation studies 19,35 . However, fluorescence dye is not a reliable indicator of graft survival because it is non-specific to living cells and could also leak into recipient cells 36 .…”

“…Conventional time-domain optical coherence tomography (OCT) has been applied to study transplantation outcomes in the short term 15–18 . Spectral domain OCT (SD-OCT) produces high-resolution images, enabling the identification of distinct retinal layers in the recipient 19–22 .…”

Quantifiable In Vivo Imaging Biomarkers of Retinal Regeneration by Photoreceptor Cell Transplantation

“…[15][16][17][18] Spectral domain OCT (SD-OCT) produces high-resolution images, enabling the identification of distinct retinal layers in the recipient. [19][20][21][22] The utility of multimodal in vivo photoreceptor graft imaging for long-term observation has not yet been fully explored. We hypothesized that a noninvasive multimodal in vivo imaging system would provide comprehensive longitudinal information regarding graft survival and recipient retinal status.…”

D-mannose-Coating of Maghemite Nanoparticles Improved Labeling of Neural Stem Cells and Allowed Their Visualization by ex vivo MRI after Transplantation in the Mouse Brain

“…Recent studies show that neural stem cells (NSCs) can enhance functional recovery after stroke via secretion of neurotrophic factors, immunomodulation, and stimulation of endogenous neurogenesis and neovascularization [1][2][3][4] . Similar therapeutic strategies could be applied in the treatment of spinal cord injury, retinal degenerative disease, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis or other neurodegenerative diseases [5][6][7][8] .…”