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

Laver, Christopher; Metcalfe, Alan; Szczygiel, Lukasz; Yanai, Anat; Sarunic, Marinko V.; Gregory-Evans, Kevin

doi:10.1038/eye.2015.24

Cited by 7 publications

(8 citation statements)

References 34 publications

(37 reference statements)

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“…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 .…”

Section: Discussionmentioning

confidence: 99%

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

Liu

Sodhi

Xue

et al. 2019

Preprint

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32Purpose: Short-term improvements in retinal anatomy are known to occur in preclinical models 33 of photoreceptor transplantation. However, correlative changes over the long term are poorly 34 understood. We aimed to develop a quantifiable imaging biomarker grading scheme, using non-35 invasive multimodal confocal scanning laser ophthalmoscopy (cSLO) imaging, to enable serial 36 evaluation of photoreceptor transplantation over the long term. 37Methods: Yellow-green fluorescent microspheres were transplanted into the vitreous cavity 38 and/or subretinal space of C57/BL6J mice. Photoreceptor cell suspensions or sheets from 39 rhodopsin-green fluorescent protein mice were transplanted subretinally, into either NOD.CB17-40 Prkdc scid /J or C3H/HeJ-Pde6b rd1 mice. Multimodal cSLO imaging was performed serially for up 41 to three months after transplantation. Imaging biomarkers were scored, and a grade was defined 42 for each eye by integrating the scores. Image grades were correlated with immunohistochemistry 43 (IHC) data. 44 Results: Multimodal imaging enabled the extraction of quantitative imaging biomarkers 45 including graft size, GFP intensity, graft length, on-target graft placement, intra-graft lamination, 46 hemorrhage, retinal atrophy, and peri-retinal proliferation. Migration of transplanted material 47 increasing the efficiency of preclinical retinal cell transplantation studies in rodents and other 53 animal models. 54 Key words: degenerative retinal diseases, age-related macular degeneration, stem cell therapy, 55 xenotransplantation, photoreceptor cell, retinal organoid, confocal scanning laser 56 ophthalmoscopy 57 Photoreceptor transplantation is being developed as a therapeutic modality to restore vision in 59 people affected by retinal degenerative diseases, including retinitis pigmentosa (RP) and age-60 related macular degeneration (AMD) 1-6 . Short term improvements in outer retinal anatomy after 61 photoreceptor cell transplantation have been observed, mainly by histological staining in 62 preclinical models of retinal degeneration 4,7 . However, histology is a relatively inefficient 63 method to track graft and recipient anatomy longitudinally over the long term. Histological 64 assays are labor-intensive, require large initial cohorts of recipients, and face the challenge of 65 recipient attrition over time. Non-invasive imaging could facilitate the longitudinal evaluation of 66 retinal anatomy in relatively smaller cohorts of recipient animals over time, without the need to 67 sacrifice animals at every assessment time point. 68 Recent advances in imaging techniques have enabled detailed imaging studies in mouse models 69 of retinal disease and regeneration 8-10 . Confocal scanning laser ophthalmoscopy (cSLO) can be 70 used to capture images in multiple imaging modes, including short-wavelength fluorescence 71 (SWF) excitation (488 nm) to detect photoreceptor cells labeled with green fluorescent protein 72 (GFP) in mouse recipients 1 . Multicolor reflectance (MR) imaging combines blue (488 nm)...

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Section: Discussionmentioning

confidence: 99%

“…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 .…”

Section: Introductionmentioning

confidence: 99%

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

Liu

Sodhi

Xue

et al. 2019

Preprint

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“…[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.…”

Section: Introductionmentioning

confidence: 99%

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

Liu

Sodhi

Xue

et al. 2020

Trans. Vis. Sci. Tech.

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Short-term improvements in retinal anatomy are known to occur in preclinical models of photoreceptor transplantation. However, correlative changes over the long term are poorly understood. We aimed to develop a quantifiable imaging biomarker grading scheme, using noninvasive multimodal confocal scanning laser ophthalmoscopy (cSLO) imaging, to enable serial evaluation of photoreceptor transplantation over the long term. Methods: Photoreceptor cell suspensions or sheets from rhodopsin-green fluorescent protein mice were transplanted subretinally, into either NOD.CB17-Prkdc scid /J or C3H/HeJ-Pde6b rd1 mice. Multimodal cSLO imaging was performed serially for up to three months after transplantation. Imaging biomarkers were scored, and a grade was defined for each eye by integrating the scores. Image grades were correlated with immunohistochemistry (IHC) data. Results: Multimodal imaging enabled the extraction of quantitative imaging biomarkers including graft size, GFP intensity, graft length, on-target graft placement, intra-graft lamination, hemorrhage, retinal atrophy, and periretinal proliferation. Migration of transplanted material was observed. Changes in biomarker scores and grades were detected in 14/16 and 7/16 eyes, respectively. A high correlation was found between image grades and IHC parameters. Conclusions: Serial evaluation of multiple imaging biomarkers, when integrated into a per-eye grading scheme, enabled comprehensive tracking of longitudinal changes in photoreceptor cell grafts over time. The application of systematic multimodal in vivo imaging could be useful in increasing the efficiency of preclinical retinal cell transplantation studies in rodents and other animal models. Translational Relevance: By allowing longitudinal evaluation of the same animal over time, and providing quantifiable biomarkers, non-invasive multimodal imaging improves the efficiency of retinal transplantation studies in animal models. Such assays will facilitate the development of cell therapy for retinal diseases.

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“…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] .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Magnetic resonance imaging (MRI) of superparamagnetic iron oxide-labeled cells can be used as a non-invasive technique to track stem cells after transplantation. The aim of this study was to (1) evaluate labeling efficiency of D-mannose-coated maghemite nanoparticles (D-mannose(γ-Fe2O3)) in neural stem cells (NSCs) in comparison to the uncoated nanoparticles, (2) assess nanoparticle utilization as MRI contrast agent to visualize NSCs transplanted into the mouse brain, and (3) test nanoparticle biocompatibility. D-mannose(γ-Fe2O3) labeled the NSCs better than the uncoated nanoparticles. The labeled cells were visualized by ex vivo MRI and their localization subsequently confirmed on histological sections. Although the progenitor properties and differentiation of the NSCs were not affected by labeling, subtle effects on stem cells could be detected depending on dose increase, including changes in cell proliferation, viability, and neurosphere diameter. D-mannose coating of maghemite nanoparticles improved NSC labeling and allowed for NSC tracking by ex vivo MRI in the mouse brain, but further analysis of the eventual side effects might be necessary before translation to the clinic.

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

Cited by 7 publications

References 34 publications

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

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

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

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

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