TY - JOUR
T1 - Quantifiable in vivo imaging biomarkers of retinal regeneration by photoreceptor cell transplantation
AU - Liu, Ying V.
AU - Sodhi, Simrat K.
AU - Xue, Gilbert
AU - Teng, Derek
AU - Agakishiev, Dzhalal
AU - McNally, Minda M.
AU - Harris-Bookman, Sarah
AU - McBride, Caitlin
AU - Konar, Gregory J.
AU - Singh, Mandeep S.
N1 - Funding Information:
We thank T. Wensel and Donald Zack for the kind gift of the Rho-GFP+ mice. We thank Diana Johnson and Karl A. Hudspith for their assistance. Supported by the Foundation Fighting Blindness (Career Development Award to MSS), the Shulsky Foundation, the Juliette RP Vision Foundation, Research to Prevent Blindness (unrestricted grant to the Wilmer Eye Institute), and the Core Grant EY001765.
Funding Information:
Supported by the Foundation Fighting Blindness (Career Development Award to MSS), the Shulsky Foundation, the Juliette RP Vision Foundation, Research to Prevent Blindness (unrestricted grant to the Wilmer Eye Institute), and the Core Grant EY001765.
Publisher Copyright:
© 2020 The Authors.
PY - 2020/6
Y1 - 2020/6
N2 - Purpose: 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 ophthal-moscopy (cSLO) imaging, to enable serial evaluation of photoreceptor transplantation over the long term. Methods: Photoreceptor cell suspensions or sheets from rhodopsin-green fluores-cent protein mice were transplanted subretinally, into either NOD.CB17-Prkdcscid /J or C3H/HeJ-Pde6brd1 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 immunohis-tochemistry (IHC) data. Results: Multimodal imaging enabled the extraction of quantitative imaging biomark-ers 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.
AB - Purpose: 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 ophthal-moscopy (cSLO) imaging, to enable serial evaluation of photoreceptor transplantation over the long term. Methods: Photoreceptor cell suspensions or sheets from rhodopsin-green fluores-cent protein mice were transplanted subretinally, into either NOD.CB17-Prkdcscid /J or C3H/HeJ-Pde6brd1 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 immunohis-tochemistry (IHC) data. Results: Multimodal imaging enabled the extraction of quantitative imaging biomark-ers 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.
KW - Age-related macular degeneration
KW - Confocal scanning laser ophthalmoscopy
KW - Degenerative retinal diseases
KW - Photoreceptor cell
KW - Retinal organoid
KW - Stem cell therapy
KW - Xenotransplantation
UR - http://www.scopus.com/inward/record.url?scp=85086033455&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85086033455&partnerID=8YFLogxK
U2 - 10.1167/tvst.9.7.5
DO - 10.1167/tvst.9.7.5
M3 - Article
C2 - 32832212
AN - SCOPUS:85086033455
SN - 2164-2591
VL - 9
JO - Translational Vision Science and Technology
JF - Translational Vision Science and Technology
IS - 7
M1 - 5
ER -