Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state

Transplantation of stem cell–derived retinal pigment epithelial (RPE) cells is considered a viable therapeutic option for age-related macular degeneration (AMD). Several landmark Phase I/II clinical trials have demonstrated safety and tolerability of RPE transplants in AMD patients, albeit with limi...

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Main Authors: Parikh, Bhav Harshad, Blakeley, Paul, Regha, Kakkad, Liu, Zengping, Yang, Binxia, Bhargava, Mayuri, Wong, Daniel Soo Lin, Tan, Queenie Shu Woon, Wong, Claudine See Wei, Wang, Hao Fei, Al-Mubaarak, Abdurrahmaan, Chou, Chai, Cheung, Gemmy Chui Ming, Lim Kah-Leong, Barathi, Veluchamy Amutha, Hunziker, Walter, Lingam, Gopal, Hu, Tim Xiaoming, Su, Xinyi
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
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Language:English
Published: 2024
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Online Access:https://hdl.handle.net/10356/174340
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spelling sg-ntu-dr.10356-1743402024-03-31T15:39:56Z Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state Parikh, Bhav Harshad Blakeley, Paul Regha, Kakkad Liu, Zengping Yang, Binxia Bhargava, Mayuri Wong, Daniel Soo Lin Tan, Queenie Shu Woon Wong, Claudine See Wei Wang, Hao Fei Al-Mubaarak, Abdurrahmaan Chou, Chai Cheung, Gemmy Chui Ming Lim Kah-Leong Barathi, Veluchamy Amutha Hunziker, Walter Lingam, Gopal Hu, Tim Xiaoming Su, Xinyi Lee Kong Chian School of Medicine (LKCMedicine) Medicine, Health and Life Sciences Pluripotent stem cell Retinal pigment epithelium Transplantation of stem cell–derived retinal pigment epithelial (RPE) cells is considered a viable therapeutic option for age-related macular degeneration (AMD). Several landmark Phase I/II clinical trials have demonstrated safety and tolerability of RPE transplants in AMD patients, albeit with limited efficacy. Currently, there is limited understanding of how the recipient retina regulates the survival, maturation, and fate specification of transplanted RPE cells. To address this, we transplanted stem cell–derived RPE into the subretinal space of immunocompetent rabbits for 1 mo and conducted single-cell RNA sequencing analyses on the explanted RPE monolayers, compared to their age-matched in vitro counterparts. We observed an unequivocal retention of RPE identity, and a trajectory-inferred survival of all in vitro RPE populations after transplantation. Furthermore, there was a unidirectional maturation toward the native adult human RPE state in all transplanted RPE, regardless of stem cell resource. Gene regulatory network analysis suggests that tripartite transcription factors (FOS, JUND, and MAFF) may be specifically activated in posttransplanted RPE cells, to regulate canonical RPE signature gene expression crucial for supporting host photoreceptor function, and to regulate prosurvival genes required for transplanted RPE’s adaptation to the host subretinal microenvironment. These findings shed insights into the transcriptional landscape of RPE cells after subretinal transplantation, with important implications for cell-based therapy for AMD. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Ministry of Health (MOH) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This work was supported by Competitive Research Program (CRP) by National Research Foundation (NRF) [NRF-CRP21-2018-0008], Central Research Fund, Use-Inspired Basic Research by Agency for Science, Technology and Research Biomedical Research Council (A*STAR, BMRC) [SC15/22-118400-0SXY-OOE], Ministry of Education (MOE) for its MOE Academic Research Fund Tier 3 (science, technology, engineering, and mathematics) [MOE-T3-2020-0001], The Industry Alignment Fund – Industry Collaboration Project (IAF-ICP) by A*STAR (BMRC) [I2101E0004], and Clinician Scientist Award by National Medical Research Council [MOH-001076]. 2024-03-27T04:41:11Z 2024-03-27T04:41:11Z 2023 Journal Article Parikh, B. H., Blakeley, P., Regha, K., Liu, Z., Yang, B., Bhargava, M., Wong, D. S. L., Tan, Q. S. W., Wong, C. S. W., Wang, H. F., Al-Mubaarak, A., Chou, C., Cheung, G. C. M., Lim Kah-Leong, Barathi, V. A., Hunziker, W., Lingam, G., Hu, T. X. & Su, X. (2023). Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state. Proceedings of the National Academy of Sciences, 120(26), e2214842120-. https://dx.doi.org/10.1073/PNAS.2214842120 0027-8424 https://hdl.handle.net/10356/174340 10.1073/PNAS.2214842120 120 2-s2.0-85163922719 26 120 e2214842120 en NRF-CRP21-2018-0008 SC15/22-118400-0SXY-OOE MOE-T3-2020-0001 I2101E0004 MOH-001076 Proceedings of the National Academy of Sciences © 2023 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY). application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Medicine, Health and Life Sciences
Pluripotent stem cell
Retinal pigment epithelium
spellingShingle Medicine, Health and Life Sciences
Pluripotent stem cell
Retinal pigment epithelium
Parikh, Bhav Harshad
Blakeley, Paul
Regha, Kakkad
Liu, Zengping
Yang, Binxia
Bhargava, Mayuri
Wong, Daniel Soo Lin
Tan, Queenie Shu Woon
Wong, Claudine See Wei
Wang, Hao Fei
Al-Mubaarak, Abdurrahmaan
Chou, Chai
Cheung, Gemmy Chui Ming
Lim Kah-Leong
Barathi, Veluchamy Amutha
Hunziker, Walter
Lingam, Gopal
Hu, Tim Xiaoming
Su, Xinyi
Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state
description Transplantation of stem cell–derived retinal pigment epithelial (RPE) cells is considered a viable therapeutic option for age-related macular degeneration (AMD). Several landmark Phase I/II clinical trials have demonstrated safety and tolerability of RPE transplants in AMD patients, albeit with limited efficacy. Currently, there is limited understanding of how the recipient retina regulates the survival, maturation, and fate specification of transplanted RPE cells. To address this, we transplanted stem cell–derived RPE into the subretinal space of immunocompetent rabbits for 1 mo and conducted single-cell RNA sequencing analyses on the explanted RPE monolayers, compared to their age-matched in vitro counterparts. We observed an unequivocal retention of RPE identity, and a trajectory-inferred survival of all in vitro RPE populations after transplantation. Furthermore, there was a unidirectional maturation toward the native adult human RPE state in all transplanted RPE, regardless of stem cell resource. Gene regulatory network analysis suggests that tripartite transcription factors (FOS, JUND, and MAFF) may be specifically activated in posttransplanted RPE cells, to regulate canonical RPE signature gene expression crucial for supporting host photoreceptor function, and to regulate prosurvival genes required for transplanted RPE’s adaptation to the host subretinal microenvironment. These findings shed insights into the transcriptional landscape of RPE cells after subretinal transplantation, with important implications for cell-based therapy for AMD.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Parikh, Bhav Harshad
Blakeley, Paul
Regha, Kakkad
Liu, Zengping
Yang, Binxia
Bhargava, Mayuri
Wong, Daniel Soo Lin
Tan, Queenie Shu Woon
Wong, Claudine See Wei
Wang, Hao Fei
Al-Mubaarak, Abdurrahmaan
Chou, Chai
Cheung, Gemmy Chui Ming
Lim Kah-Leong
Barathi, Veluchamy Amutha
Hunziker, Walter
Lingam, Gopal
Hu, Tim Xiaoming
Su, Xinyi
format Article
author Parikh, Bhav Harshad
Blakeley, Paul
Regha, Kakkad
Liu, Zengping
Yang, Binxia
Bhargava, Mayuri
Wong, Daniel Soo Lin
Tan, Queenie Shu Woon
Wong, Claudine See Wei
Wang, Hao Fei
Al-Mubaarak, Abdurrahmaan
Chou, Chai
Cheung, Gemmy Chui Ming
Lim Kah-Leong
Barathi, Veluchamy Amutha
Hunziker, Walter
Lingam, Gopal
Hu, Tim Xiaoming
Su, Xinyi
author_sort Parikh, Bhav Harshad
title Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state
title_short Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state
title_full Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state
title_fullStr Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state
title_full_unstemmed Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state
title_sort single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state
publishDate 2024
url https://hdl.handle.net/10356/174340
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