Identifying biomarkers of heterogeneity and transplantation efficacy in retinal pigment epithelial cells
Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of...
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Published in | The Journal of experimental medicine Vol. 220; no. 12 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
Rockefeller University Press
04.12.2023
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Abstract | Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here, we characterized an adult RPE stem cell-derived (RPESC-RPE) cell product using bulk and single-cell RNA sequencing (scRNA-seq), assessing functional cell integration in vitro into a mature RPE monolayer and in vivo efficacy by vision rescue in the Royal College of Surgeons rats. scRNA-seq revealed several distinct subpopulations in the RPESC-RPE product, some with progenitor markers. We identified RPE clusters expressing genes associated with in vivo efficacy and increased cell integration capability. Gene expression analysis revealed lncRNA (TREX) as a predictive marker of in vivo efficacy. TREX knockdown decreased cell integration while overexpression increased integration in vitro and improved vision rescue in the RCS rats. |
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AbstractList | Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here, we characterized an adult RPE stem cell-derived (RPESC-RPE) cell product using bulk and single-cell RNA sequencing (scRNA-seq), assessing functional cell integration in vitro into a mature RPE monolayer and in vivo efficacy by vision rescue in the Royal College of Surgeons rats. scRNA-seq revealed several distinct subpopulations in the RPESC-RPE product, some with progenitor markers. We identified RPE clusters expressing genes associated with in vivo efficacy and increased cell integration capability. Gene expression analysis revealed lncRNA (TREX) as a predictive marker of in vivo efficacy. TREX knockdown decreased cell integration while overexpression increased integration in vitro and improved vision rescue in the RCS rats. This study characterizes an adult retinal pigment epithelial stem cell–derived cell product through transplantation in RCS rats and bulk and single-cell RNA sequencing, identifying distinct subpopulations and a predictive lncRNA marker (TREX) affecting cell integration and vision rescue in rats. Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here, we characterized an adult RPE stem cell–derived (RPESC-RPE) cell product using bulk and single-cell RNA sequencing (scRNA-seq), assessing functional cell integration in vitro into a mature RPE monolayer and in vivo efficacy by vision rescue in the Royal College of Surgeons rats. scRNA-seq revealed several distinct subpopulations in the RPESC-RPE product, some with progenitor markers. We identified RPE clusters expressing genes associated with in vivo efficacy and increased cell integration capability. Gene expression analysis revealed lncRNA (TREX) as a predictive marker of in vivo efficacy. TREX knockdown decreased cell integration while overexpression increased integration in vitro and improved vision rescue in the RCS rats. |
Author | Zhao, Cuiping Wang, Yue Temple, Sally Manos, Justine D Prusky, Glen Alam, Nazia Boles, Nathan C Williams, Anne L Farjood, Farhad Stern, Jeffrey H Borden, Susan |
AuthorAffiliation | 1 https://ror.org/00x6sm138 Neural Stem Cell Institute , Rensselaer, NY, USA 3 Abbvie, Cambridge Research Center , Cambridge, MA, USA 2 https://ror.org/02r109517 Burke Neurological Institute at Weill Cornell Medicine , White Plains, NY, USA 4 Regeneron , Rensselaer, NY, USA |
AuthorAffiliation_xml | – name: 1 https://ror.org/00x6sm138 Neural Stem Cell Institute , Rensselaer, NY, USA – name: 2 https://ror.org/02r109517 Burke Neurological Institute at Weill Cornell Medicine , White Plains, NY, USA – name: 3 Abbvie, Cambridge Research Center , Cambridge, MA, USA – name: 4 Regeneron , Rensselaer, NY, USA |
Author_xml | – sequence: 1 givenname: Farhad orcidid: 0000-0002-8826-6721 surname: Farjood fullname: Farjood, Farhad organization: Neural Stem Cell Institute , Rensselaer, NY, USA – sequence: 2 givenname: Justine D orcidid: 0000-0002-4265-4016 surname: Manos fullname: Manos, Justine D organization: Abbvie, Cambridge Research Center, Cambridge, MA, USA – sequence: 3 givenname: Yue orcidid: 0009-0007-6647-3379 surname: Wang fullname: Wang, Yue organization: Neural Stem Cell Institute , Rensselaer, NY, USA – sequence: 4 givenname: Anne L orcidid: 0000-0002-2491-5294 surname: Williams fullname: Williams, Anne L organization: Neural Stem Cell Institute , Rensselaer, NY, USA – sequence: 5 givenname: Cuiping orcidid: 0009-0003-3885-7093 surname: Zhao fullname: Zhao, Cuiping organization: Regeneron, Rensselaer, NY, USA – sequence: 6 givenname: Susan orcidid: 0009-0001-2361-1686 surname: Borden fullname: Borden, Susan organization: Neural Stem Cell Institute , Rensselaer, NY, USA – sequence: 7 givenname: Nazia orcidid: 0000-0002-1941-2190 surname: Alam fullname: Alam, Nazia organization: Burke Neurological Institute at Weill Cornell Medicine , White Plains, NY, USA – sequence: 8 givenname: Glen orcidid: 0000-0001-9658-8598 surname: Prusky fullname: Prusky, Glen organization: Burke Neurological Institute at Weill Cornell Medicine , White Plains, NY, USA – sequence: 9 givenname: Sally orcidid: 0000-0001-7301-783X surname: Temple fullname: Temple, Sally organization: Neural Stem Cell Institute , Rensselaer, NY, USA – sequence: 10 givenname: Jeffrey H orcidid: 0000-0002-5272-5025 surname: Stern fullname: Stern, Jeffrey H organization: Neural Stem Cell Institute , Rensselaer, NY, USA – sequence: 11 givenname: Nathan C orcidid: 0000-0002-9253-9411 surname: Boles fullname: Boles, Nathan C organization: Neural Stem Cell Institute , Rensselaer, NY, USA |
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Cites_doi | 10.1038/nbt.4114 10.1126/science.1076997 10.1186/s13059-019-1874-1 10.1016/j.exer.2014.11.001 10.1016/j.ymthe.2017.06.002 10.1074/jbc.M800706200 10.1056/NEJMoa1608368 10.3389/fimmu.2016.00172 10.1167/iovs.10-6163 10.1371/journal.pone.0141597 10.1172/jci.insight.129299 10.1073/pnas.2117553119 10.17912/micropub.biology.000811 10.1182/blood-2005-09-3585 10.1073/pnas.1914143116 10.1073/pnas.0813144106 10.1093/bioinformatics/bts635 10.1101/2020.01.13.904730 10.1093/hmg/ddq129 10.1093/bioinformatics/btq046 10.1016/j.stemcr.2022.05.005 10.1038/s42003-022-03676-3 10.1152/physrev.00021.2004 10.1167/iovs.06-0868 10.1016/j.stem.2011.11.018 10.1038/s41467-020-14457-z 10.1016/j.biochi.2004.09.029 10.2174/156652410793937813 10.3791/55220 10.1167/iovs.04-0541 10.3389/fcell.2021.802457 10.1186/s12950-015-0109-9 10.1017/S0952523805225166 10.2217/bmm-2018-0272 10.1016/j.stemcr.2017.05.016 10.1371/journal.pone.0038673 10.1161/CIRCRESAHA.111.249433 10.1186/gb-2010-11-2-r14 10.1126/scitranslmed.aat5580 |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 C. Zhao’s current affiliation is Regeneron Pharmaceuticals, Rensselaer, NY, USA. J.H. Stern and N.C. Boles are co-senior authors. Disclosures: J.D. Manos is currently an employee at AbbVie. G. Prusky is the president of CerebralMechanics Inc. Equipment used in the study was manufactured by CerebralMechanics. She had no influence on how the data the study was generated. S. Temple reported a patent to US8481313B2 issued; and is a co-founder of LUXA Biotechnology, which is advancing RPE transplantation for patients with dry age-related macular degeneration (AMD). J.H. Stern is an officer of Luxa Biotechnology, which is advancing retinal pigment epithelial cell transplantation therapy for dry age-related macular degeneration. No other disclosures were reported. J.D. Manos’s current affiliation is Abbvie, Cambridge Research Center, Cambridge, MA, USA. |
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Snippet | Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular... This study characterizes an adult retinal pigment epithelial stem cell–derived cell product through transplantation in RCS rats and bulk and single-cell RNA... |
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SubjectTerms | Animals Biomarkers Epithelial Cells Gene Expression Profiling Neurons Neuroscience Rats Retinal Pigments Stem Cells & Regeneration |
Title | Identifying biomarkers of heterogeneity and transplantation efficacy in retinal pigment epithelial cells |
URI | https://www.ncbi.nlm.nih.gov/pubmed/37728563 https://search.proquest.com/docview/2866758047 https://pubmed.ncbi.nlm.nih.gov/PMC10510736 |
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