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Submacular integration of hESC-RPE monolayer xenografts in a surgical non-human primate model
BACKGROUND: Human pluripotent stem cells (hPSCs) provide a promising cell source for retinal cell replacement therapy but often lack standardized cell production and live-cell shipment logistics as well as rigorous analyses of surgical procedures for cell transplantation in the delicate macula area....
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314642/ https://www.ncbi.nlm.nih.gov/pubmed/34315534 http://dx.doi.org/10.1186/s13287-021-02395-6 |
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author | Liu, Zengping Ilmarinen, Tanja Tan, Gavin S. W. Hongisto, Heidi Wong, Edmund Y. M. Tsai, Andrew S. H. Al-Nawaiseh, Sami Holder, Graham E. Su, Xinyi Barathi, Veluchamy Amutha Skottman, Heli Stanzel, Boris V. |
author_facet | Liu, Zengping Ilmarinen, Tanja Tan, Gavin S. W. Hongisto, Heidi Wong, Edmund Y. M. Tsai, Andrew S. H. Al-Nawaiseh, Sami Holder, Graham E. Su, Xinyi Barathi, Veluchamy Amutha Skottman, Heli Stanzel, Boris V. |
author_sort | Liu, Zengping |
collection | PubMed |
description | BACKGROUND: Human pluripotent stem cells (hPSCs) provide a promising cell source for retinal cell replacement therapy but often lack standardized cell production and live-cell shipment logistics as well as rigorous analyses of surgical procedures for cell transplantation in the delicate macula area. We have previously established a xeno- and feeder cell-free production system for hPSC differentiated retinal pigment epithelial (RPE) cells, and herein, a novel immunosuppressed non-human primate (NHP) model with a disrupted ocular immune privilege is presented for transplanting human embryonic stem cell (hESC)-derived RPE on a scaffold, and the safety and submacular graft integration are assessed. Furthermore, the feasibility of intercontinental shipment of live hESC-RPE is examined. METHODS: Cynomolgus monkeys were systemically immunosuppressed and implanted with a hESC-RPE monolayer on a permeable polyester-terephthalate (PET) scaffold. Microscope-integrated intraoperative optical coherence tomography (miOCT)-guided surgery, postoperative follow-up incorporated scanning laser ophthalmoscopy, spectral domain (SD-) OCT, and full-field electroretinography (ERG) were used as outcome measures. In addition, histology was performed after a 28-day follow-up. RESULTS: Intercontinental cell shipment, which took >30 h from the manufacturing to the transplantation site, did not alter the hESC-RPE quality. The submacular hESC-RPE xenotransplantation was performed in 11 macaques. The miOCT typically revealed foveal disruption. ERG showed amplitude and peak time preservation in cases with favorable surgical outcomes. Histology confirmed photoreceptor preservation above the grafts and in vivo phagocytosis by hESC-RPE, albeit evidence of cytoplasmic redistribution of opsin in photoreceptors and glia hypertrophy. The immunosuppression protocol efficiently suppressed retinal T cell infiltration and microglia activation. CONCLUSION: These results suggest both structural and functional submacular integrations of hESC-RPE xenografts. It is anticipated that surgical technique refinement will further improve the engraftment of macular cell therapeutics with significant translational relevance to improve future clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-021-02395-6. |
format | Online Article Text |
id | pubmed-8314642 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-83146422021-07-28 Submacular integration of hESC-RPE monolayer xenografts in a surgical non-human primate model Liu, Zengping Ilmarinen, Tanja Tan, Gavin S. W. Hongisto, Heidi Wong, Edmund Y. M. Tsai, Andrew S. H. Al-Nawaiseh, Sami Holder, Graham E. Su, Xinyi Barathi, Veluchamy Amutha Skottman, Heli Stanzel, Boris V. Stem Cell Res Ther Research BACKGROUND: Human pluripotent stem cells (hPSCs) provide a promising cell source for retinal cell replacement therapy but often lack standardized cell production and live-cell shipment logistics as well as rigorous analyses of surgical procedures for cell transplantation in the delicate macula area. We have previously established a xeno- and feeder cell-free production system for hPSC differentiated retinal pigment epithelial (RPE) cells, and herein, a novel immunosuppressed non-human primate (NHP) model with a disrupted ocular immune privilege is presented for transplanting human embryonic stem cell (hESC)-derived RPE on a scaffold, and the safety and submacular graft integration are assessed. Furthermore, the feasibility of intercontinental shipment of live hESC-RPE is examined. METHODS: Cynomolgus monkeys were systemically immunosuppressed and implanted with a hESC-RPE monolayer on a permeable polyester-terephthalate (PET) scaffold. Microscope-integrated intraoperative optical coherence tomography (miOCT)-guided surgery, postoperative follow-up incorporated scanning laser ophthalmoscopy, spectral domain (SD-) OCT, and full-field electroretinography (ERG) were used as outcome measures. In addition, histology was performed after a 28-day follow-up. RESULTS: Intercontinental cell shipment, which took >30 h from the manufacturing to the transplantation site, did not alter the hESC-RPE quality. The submacular hESC-RPE xenotransplantation was performed in 11 macaques. The miOCT typically revealed foveal disruption. ERG showed amplitude and peak time preservation in cases with favorable surgical outcomes. Histology confirmed photoreceptor preservation above the grafts and in vivo phagocytosis by hESC-RPE, albeit evidence of cytoplasmic redistribution of opsin in photoreceptors and glia hypertrophy. The immunosuppression protocol efficiently suppressed retinal T cell infiltration and microglia activation. CONCLUSION: These results suggest both structural and functional submacular integrations of hESC-RPE xenografts. It is anticipated that surgical technique refinement will further improve the engraftment of macular cell therapeutics with significant translational relevance to improve future clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-021-02395-6. BioMed Central 2021-07-27 /pmc/articles/PMC8314642/ /pubmed/34315534 http://dx.doi.org/10.1186/s13287-021-02395-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Liu, Zengping Ilmarinen, Tanja Tan, Gavin S. W. Hongisto, Heidi Wong, Edmund Y. M. Tsai, Andrew S. H. Al-Nawaiseh, Sami Holder, Graham E. Su, Xinyi Barathi, Veluchamy Amutha Skottman, Heli Stanzel, Boris V. Submacular integration of hESC-RPE monolayer xenografts in a surgical non-human primate model |
title | Submacular integration of hESC-RPE monolayer xenografts in a surgical non-human primate model |
title_full | Submacular integration of hESC-RPE monolayer xenografts in a surgical non-human primate model |
title_fullStr | Submacular integration of hESC-RPE monolayer xenografts in a surgical non-human primate model |
title_full_unstemmed | Submacular integration of hESC-RPE monolayer xenografts in a surgical non-human primate model |
title_short | Submacular integration of hESC-RPE monolayer xenografts in a surgical non-human primate model |
title_sort | submacular integration of hesc-rpe monolayer xenografts in a surgical non-human primate model |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314642/ https://www.ncbi.nlm.nih.gov/pubmed/34315534 http://dx.doi.org/10.1186/s13287-021-02395-6 |
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