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Effects of acute low-moderate dose ionizing radiation to human brain organoids

Human exposure to low-to-moderate dose ionizing radiation (LMD-IR) is increasing via environmental, medical, occupational sources. Acute exposure to LMD-IR can cause subclinical damage to cells, resulting in altered gene expression and cellular function within the human brain. It has been difficult...

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Autores principales: Oyefeso, Foluwasomi A., Goldberg, Gabriela, Opoku, Nana Yaa P. S., Vazquez, Marcelo, Bertucci, Antonella, Chen, Zhong, Wang, Charles, Muotri, Alysson R., Pecaut, Michael J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10231836/
https://www.ncbi.nlm.nih.gov/pubmed/37256873
http://dx.doi.org/10.1371/journal.pone.0282958
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author Oyefeso, Foluwasomi A.
Goldberg, Gabriela
Opoku, Nana Yaa P. S.
Vazquez, Marcelo
Bertucci, Antonella
Chen, Zhong
Wang, Charles
Muotri, Alysson R.
Pecaut, Michael J.
author_facet Oyefeso, Foluwasomi A.
Goldberg, Gabriela
Opoku, Nana Yaa P. S.
Vazquez, Marcelo
Bertucci, Antonella
Chen, Zhong
Wang, Charles
Muotri, Alysson R.
Pecaut, Michael J.
author_sort Oyefeso, Foluwasomi A.
collection PubMed
description Human exposure to low-to-moderate dose ionizing radiation (LMD-IR) is increasing via environmental, medical, occupational sources. Acute exposure to LMD-IR can cause subclinical damage to cells, resulting in altered gene expression and cellular function within the human brain. It has been difficult to identify diagnostic and predictive biomarkers of exposure using traditional research models due to factors including lack of 3D structure in monolayer cell cultures, limited ability of animal models to accurately predict human responses, and technical limitations of studying functional human brain tissue. To address this gap, we generated brain/cerebral organoids from human induced pluripotent stem cells to study the radiosensitivity of human brain cells, including neurons, astrocytes, and oligodendrocytes. While organoids have become popular models for studying brain physiology and pathology, there is little evidence to confirm that exposing brain organoids to LMD-IR will recapitulate previous in vitro and in vivo observations. We hypothesized that exposing brain organoids to proton radiation would (1) cause a time- and dose-dependent increase in DNA damage, (2) induce cell type-specific differences in radiosensitivity, and (3) increase expression of oxidative stress and DNA damage response genes. Organoids were exposed to 0.5 or 2 Gy of 250 MeV protons and samples were collected at 30 minute, 24 hour, and 48 hour timepoints. Using immunofluorescence and RNA sequencing, we found time- and dose-dependent increases in DNA damage in irradiated organoids; no changes in cell populations for neurons, oligodendrocytes, and astrocytes by 24 hours; decreased expression of genes related to oligodendrocyte lineage, astrocyte lineage, mitochondrial function, and cell cycle progression by 48 hours; increased expression of genes related to neuron lineage, oxidative stress, and DNA damage checkpoint regulation by 48 hours. Our findings demonstrate the possibility of using organoids to characterize cell-specific radiosensitivity and early radiation-induced gene expression changes within the human brain, providing new avenues for further study of the mechanisms underlying acute neural cell responses to IR exposure at low-to-moderate doses.
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spelling pubmed-102318362023-06-01 Effects of acute low-moderate dose ionizing radiation to human brain organoids Oyefeso, Foluwasomi A. Goldberg, Gabriela Opoku, Nana Yaa P. S. Vazquez, Marcelo Bertucci, Antonella Chen, Zhong Wang, Charles Muotri, Alysson R. Pecaut, Michael J. PLoS One Research Article Human exposure to low-to-moderate dose ionizing radiation (LMD-IR) is increasing via environmental, medical, occupational sources. Acute exposure to LMD-IR can cause subclinical damage to cells, resulting in altered gene expression and cellular function within the human brain. It has been difficult to identify diagnostic and predictive biomarkers of exposure using traditional research models due to factors including lack of 3D structure in monolayer cell cultures, limited ability of animal models to accurately predict human responses, and technical limitations of studying functional human brain tissue. To address this gap, we generated brain/cerebral organoids from human induced pluripotent stem cells to study the radiosensitivity of human brain cells, including neurons, astrocytes, and oligodendrocytes. While organoids have become popular models for studying brain physiology and pathology, there is little evidence to confirm that exposing brain organoids to LMD-IR will recapitulate previous in vitro and in vivo observations. We hypothesized that exposing brain organoids to proton radiation would (1) cause a time- and dose-dependent increase in DNA damage, (2) induce cell type-specific differences in radiosensitivity, and (3) increase expression of oxidative stress and DNA damage response genes. Organoids were exposed to 0.5 or 2 Gy of 250 MeV protons and samples were collected at 30 minute, 24 hour, and 48 hour timepoints. Using immunofluorescence and RNA sequencing, we found time- and dose-dependent increases in DNA damage in irradiated organoids; no changes in cell populations for neurons, oligodendrocytes, and astrocytes by 24 hours; decreased expression of genes related to oligodendrocyte lineage, astrocyte lineage, mitochondrial function, and cell cycle progression by 48 hours; increased expression of genes related to neuron lineage, oxidative stress, and DNA damage checkpoint regulation by 48 hours. Our findings demonstrate the possibility of using organoids to characterize cell-specific radiosensitivity and early radiation-induced gene expression changes within the human brain, providing new avenues for further study of the mechanisms underlying acute neural cell responses to IR exposure at low-to-moderate doses. Public Library of Science 2023-05-31 /pmc/articles/PMC10231836/ /pubmed/37256873 http://dx.doi.org/10.1371/journal.pone.0282958 Text en © 2023 Oyefeso et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Oyefeso, Foluwasomi A.
Goldberg, Gabriela
Opoku, Nana Yaa P. S.
Vazquez, Marcelo
Bertucci, Antonella
Chen, Zhong
Wang, Charles
Muotri, Alysson R.
Pecaut, Michael J.
Effects of acute low-moderate dose ionizing radiation to human brain organoids
title Effects of acute low-moderate dose ionizing radiation to human brain organoids
title_full Effects of acute low-moderate dose ionizing radiation to human brain organoids
title_fullStr Effects of acute low-moderate dose ionizing radiation to human brain organoids
title_full_unstemmed Effects of acute low-moderate dose ionizing radiation to human brain organoids
title_short Effects of acute low-moderate dose ionizing radiation to human brain organoids
title_sort effects of acute low-moderate dose ionizing radiation to human brain organoids
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10231836/
https://www.ncbi.nlm.nih.gov/pubmed/37256873
http://dx.doi.org/10.1371/journal.pone.0282958
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