TY - JOUR
T1 - Transplantation of retinal pigment epithelium and photoreceptors generated concomitantly via small molecule-mediated differentiation rescues visual function in rodent models of retinal degeneration
AU - Surendran, Harshini
AU - Nandakumar, Swapna
AU - Reddy K, Vijay Bhaskar
AU - Stoddard, Jonathan
AU - Mohan K, Varsha
AU - Upadhyay, Pramod K.
AU - McGill, Trevor J.
AU - Pal, Rajarshi
N1 - Funding Information:
Cellular and Molecular Platforms (C-CAMP), NCBS-TIFR Campus, Bengaluru, is acknowledged for the support in the form of incubation and core facilities. The authors acknowledge Dr. Abinaya Sundari, Eyestem; Dr. Indumathi Mariappan, LV Prasad Eye Institute; and Dr. Renjitha Gopurappilly, National Centre for Biological Sciences (TIFR), for the technical help. We are thankful to Dr. Dhruv Sareen, Dr. Jogin Desai, and Dr. Rajani Battu for the crucial suggestions during the course of this study.
Funding Information:
This work was jointly funded by two grants from the Biotechnology Industry Research Assistance Council (BIRAC), Department of Biotechnology (DBT), Ministry of Science and Technology, a Government of India Enterprise (# BIRAC/CCAMP0450/BIG-10/17 and # BT/BIPP1128/44/18).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Background: Age-related macular degeneration (AMD) is a result of degeneration/damage of the retinal pigment epithelium (RPE) while retinitis pigmentosa (RP), an inherited early-onset disease, results from premature loss of photoreceptors. A promising therapeutic approach for both is the replacement of lost/damaged cells with human induced pluripotent stem cell (hiPSC)-derived retinal cells. Methods: The aim of this study was to investigate the in vivo functionality of RPE and photoreceptor progenitor (PRP) cells derived from a clinical-grade hiPSC line through a unified protocol. De novo-generated RPE and PRP were characterized extensively to validate their identity, purity, and potency. Results: RPE expressed tight junction proteins, showed pigmentation and ciliation, and secreted polarization-related factors vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). PRP expressed neural retina proteins and cone and rod markers, and responded to KCl-induced polarization. Transcriptomic analysis demonstrated an increase in the expression of mature retinal tissue-specific genes coupled with concomitant downregulation of genes from undesired lineages. RPE transplantation rescued visual function in RCS rats shown via optokinetic tracking and photoreceptor rescue. PRP transplantation improved light perception in NOD.SCID-rd1 mice, and positive electroretinography signals indicated functional photoreceptor activity in the host’s outer nuclear layer. Graft survival and integration were confirmed using immunohistochemistry, and no animals showed teratoma formation or any kind of ectopic growth in the eye. Conclusions: To our knowledge, this is the first demonstration of a unified, scalable, and GMP-adaptable protocol indicating strong animal efficacy and safety data with hiPSC-derived RPE and PRP cells. These findings provide robust proof-of-principle results for IND-enabling studies to test these potential regenerative cell therapies in patients.
AB - Background: Age-related macular degeneration (AMD) is a result of degeneration/damage of the retinal pigment epithelium (RPE) while retinitis pigmentosa (RP), an inherited early-onset disease, results from premature loss of photoreceptors. A promising therapeutic approach for both is the replacement of lost/damaged cells with human induced pluripotent stem cell (hiPSC)-derived retinal cells. Methods: The aim of this study was to investigate the in vivo functionality of RPE and photoreceptor progenitor (PRP) cells derived from a clinical-grade hiPSC line through a unified protocol. De novo-generated RPE and PRP were characterized extensively to validate their identity, purity, and potency. Results: RPE expressed tight junction proteins, showed pigmentation and ciliation, and secreted polarization-related factors vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). PRP expressed neural retina proteins and cone and rod markers, and responded to KCl-induced polarization. Transcriptomic analysis demonstrated an increase in the expression of mature retinal tissue-specific genes coupled with concomitant downregulation of genes from undesired lineages. RPE transplantation rescued visual function in RCS rats shown via optokinetic tracking and photoreceptor rescue. PRP transplantation improved light perception in NOD.SCID-rd1 mice, and positive electroretinography signals indicated functional photoreceptor activity in the host’s outer nuclear layer. Graft survival and integration were confirmed using immunohistochemistry, and no animals showed teratoma formation or any kind of ectopic growth in the eye. Conclusions: To our knowledge, this is the first demonstration of a unified, scalable, and GMP-adaptable protocol indicating strong animal efficacy and safety data with hiPSC-derived RPE and PRP cells. These findings provide robust proof-of-principle results for IND-enabling studies to test these potential regenerative cell therapies in patients.
KW - Age-related macular degeneration
KW - Induced pluripotent stem cells
KW - Photoreceptor
KW - Retinal pigment epithelium
KW - Retinitis pigmentosa
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U2 - 10.1186/s13287-021-02134-x
DO - 10.1186/s13287-021-02134-x
M3 - Article
C2 - 33468244
AN - SCOPUS:85100154929
SN - 1757-6512
VL - 12
JO - Stem Cell Research and Therapy
JF - Stem Cell Research and Therapy
IS - 1
M1 - 70
ER -