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Controlling donor and newborn neuron migration and maturation in the eye through microenvironment engineering
Ongoing cell therapy trials have demonstrated the need for precision control of donor cell behavior within the recipient tissue. We present a methodology to guide stem cell–derived and endogenously regenerated neurons by engineering the microenvironment. Being an “approachable part of the brain,” th...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10655587/ https://www.ncbi.nlm.nih.gov/pubmed/37931105 http://dx.doi.org/10.1073/pnas.2302089120 |
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author | Soucy, Jonathan R. Todd, Levi Kriukov, Emil Phay, Monichan Malechka, Volha V. Rivera, John Dayron Reh, Thomas A. Baranov, Petr |
author_facet | Soucy, Jonathan R. Todd, Levi Kriukov, Emil Phay, Monichan Malechka, Volha V. Rivera, John Dayron Reh, Thomas A. Baranov, Petr |
author_sort | Soucy, Jonathan R. |
collection | PubMed |
description | Ongoing cell therapy trials have demonstrated the need for precision control of donor cell behavior within the recipient tissue. We present a methodology to guide stem cell–derived and endogenously regenerated neurons by engineering the microenvironment. Being an “approachable part of the brain,” the eye provides a unique opportunity to study neuron fate and function within the central nervous system. Here, we focused on retinal ganglion cells (RGCs)—the neurons in the retina are irreversibly lost in glaucoma and other optic neuropathies but can potentially be replaced through transplantation or reprogramming. One of the significant barriers to successful RGC integration into the existing mature retinal circuitry is cell migration toward their natural position in the retina. Our in silico analysis of the single-cell transcriptome of the developing human retina identified six receptor-ligand candidates, which were tested in functional in vitro assays for their ability to guide human stem cell–derived RGCs. We used our lead molecule, SDF1, to engineer an artificial gradient in the retina, which led to a 2.7-fold increase in donor RGC migration into the ganglion cell layer (GCL) and a 3.3-fold increase in the displacement of newborn RGCs out of the inner nuclear layer. Only donor RGCs that migrated into the GCL were found to express mature RGC markers, indicating the importance of proper structure integration. Together, these results describe an “in silico–in vitro–in vivo” framework for identifying, selecting, and applying soluble ligands to control donor cell function after transplantation. |
format | Online Article Text |
id | pubmed-10655587 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-106555872023-11-06 Controlling donor and newborn neuron migration and maturation in the eye through microenvironment engineering Soucy, Jonathan R. Todd, Levi Kriukov, Emil Phay, Monichan Malechka, Volha V. Rivera, John Dayron Reh, Thomas A. Baranov, Petr Proc Natl Acad Sci U S A Biological Sciences Ongoing cell therapy trials have demonstrated the need for precision control of donor cell behavior within the recipient tissue. We present a methodology to guide stem cell–derived and endogenously regenerated neurons by engineering the microenvironment. Being an “approachable part of the brain,” the eye provides a unique opportunity to study neuron fate and function within the central nervous system. Here, we focused on retinal ganglion cells (RGCs)—the neurons in the retina are irreversibly lost in glaucoma and other optic neuropathies but can potentially be replaced through transplantation or reprogramming. One of the significant barriers to successful RGC integration into the existing mature retinal circuitry is cell migration toward their natural position in the retina. Our in silico analysis of the single-cell transcriptome of the developing human retina identified six receptor-ligand candidates, which were tested in functional in vitro assays for their ability to guide human stem cell–derived RGCs. We used our lead molecule, SDF1, to engineer an artificial gradient in the retina, which led to a 2.7-fold increase in donor RGC migration into the ganglion cell layer (GCL) and a 3.3-fold increase in the displacement of newborn RGCs out of the inner nuclear layer. Only donor RGCs that migrated into the GCL were found to express mature RGC markers, indicating the importance of proper structure integration. Together, these results describe an “in silico–in vitro–in vivo” framework for identifying, selecting, and applying soluble ligands to control donor cell function after transplantation. National Academy of Sciences 2023-11-06 2023-11-14 /pmc/articles/PMC10655587/ /pubmed/37931105 http://dx.doi.org/10.1073/pnas.2302089120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Soucy, Jonathan R. Todd, Levi Kriukov, Emil Phay, Monichan Malechka, Volha V. Rivera, John Dayron Reh, Thomas A. Baranov, Petr Controlling donor and newborn neuron migration and maturation in the eye through microenvironment engineering |
title | Controlling donor and newborn neuron migration and maturation in the eye through microenvironment engineering |
title_full | Controlling donor and newborn neuron migration and maturation in the eye through microenvironment engineering |
title_fullStr | Controlling donor and newborn neuron migration and maturation in the eye through microenvironment engineering |
title_full_unstemmed | Controlling donor and newborn neuron migration and maturation in the eye through microenvironment engineering |
title_short | Controlling donor and newborn neuron migration and maturation in the eye through microenvironment engineering |
title_sort | controlling donor and newborn neuron migration and maturation in the eye through microenvironment engineering |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10655587/ https://www.ncbi.nlm.nih.gov/pubmed/37931105 http://dx.doi.org/10.1073/pnas.2302089120 |
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