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Microglia-secreted TNF-α affects differentiation efficiency and viability of pluripotent stem cell-derived human dopaminergic precursors

Disease is a neurodegenerative disorder characterised by the progressive loss of dopaminergic cells of the substantia nigra pars compacta. Even though successful transplantation of dopamine-producing cells into the striatum exhibits favourable effects in animal models and clinical trials; transplant...

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Autores principales: Wenker, Shirley D., Farias, María Isabel, Gradaschi, Victoria, Garcia, Corina, Beauquis, Juan, Leal, María Celeste, Ferrari, Carina, Zeng, Xianmin, Pitossi, Fernando 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/PMC10521980/
https://www.ncbi.nlm.nih.gov/pubmed/37751438
http://dx.doi.org/10.1371/journal.pone.0263021
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author Wenker, Shirley D.
Farias, María Isabel
Gradaschi, Victoria
Garcia, Corina
Beauquis, Juan
Leal, María Celeste
Ferrari, Carina
Zeng, Xianmin
Pitossi, Fernando J.
author_facet Wenker, Shirley D.
Farias, María Isabel
Gradaschi, Victoria
Garcia, Corina
Beauquis, Juan
Leal, María Celeste
Ferrari, Carina
Zeng, Xianmin
Pitossi, Fernando J.
author_sort Wenker, Shirley D.
collection PubMed
description Disease is a neurodegenerative disorder characterised by the progressive loss of dopaminergic cells of the substantia nigra pars compacta. Even though successful transplantation of dopamine-producing cells into the striatum exhibits favourable effects in animal models and clinical trials; transplanted cell survival is low. Since every transplant elicits an inflammatory response which can affect cell survival and differentiation, we aimed to study in vivo and in vitro the impact of the pro-inflammatory environment on human dopaminergic precursors. We first observed that transplanted human dopaminergic precursors into the striatum of immunosuppressed rats elicited an early and sustained activation of astroglial and microglial cells after 15 days’ post-transplant. This long-lasting response was associated with Tumour necrosis factor alpha expression in microglial cells. In vitro, conditioned media from activated BV2 microglial cells increased cell death, decreased Tyrosine hydroxylase-positive cells and induced morphological alterations on human neural stem cells-derived dopaminergic precursors at two differentiation stages: 19 days and 28 days. Those effects were ameliorated by inhibition of Tumour necrosis factor alpha, a cytokine which was previously detected in vivo and in conditioned media from activated BV-2 cells. Our results suggest that a pro-inflammatory environment is sustained after transplantation under immunosuppression, providing a window of opportunity to modify this response to increase transplant survival and differentiation. In addition, our data show that the microglia-derived pro-inflammatory microenvironment has a negative impact on survival and differentiation of dopaminergic precursors. Finally, Tumour necrosis factor alpha plays a key role in these effects, suggesting that this cytokine could be an interesting target to increase the efficacy of human dopaminergic precursors transplantation in Parkinson’s Disease.
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spelling pubmed-105219802023-09-27 Microglia-secreted TNF-α affects differentiation efficiency and viability of pluripotent stem cell-derived human dopaminergic precursors Wenker, Shirley D. Farias, María Isabel Gradaschi, Victoria Garcia, Corina Beauquis, Juan Leal, María Celeste Ferrari, Carina Zeng, Xianmin Pitossi, Fernando J. PLoS One Research Article Disease is a neurodegenerative disorder characterised by the progressive loss of dopaminergic cells of the substantia nigra pars compacta. Even though successful transplantation of dopamine-producing cells into the striatum exhibits favourable effects in animal models and clinical trials; transplanted cell survival is low. Since every transplant elicits an inflammatory response which can affect cell survival and differentiation, we aimed to study in vivo and in vitro the impact of the pro-inflammatory environment on human dopaminergic precursors. We first observed that transplanted human dopaminergic precursors into the striatum of immunosuppressed rats elicited an early and sustained activation of astroglial and microglial cells after 15 days’ post-transplant. This long-lasting response was associated with Tumour necrosis factor alpha expression in microglial cells. In vitro, conditioned media from activated BV2 microglial cells increased cell death, decreased Tyrosine hydroxylase-positive cells and induced morphological alterations on human neural stem cells-derived dopaminergic precursors at two differentiation stages: 19 days and 28 days. Those effects were ameliorated by inhibition of Tumour necrosis factor alpha, a cytokine which was previously detected in vivo and in conditioned media from activated BV-2 cells. Our results suggest that a pro-inflammatory environment is sustained after transplantation under immunosuppression, providing a window of opportunity to modify this response to increase transplant survival and differentiation. In addition, our data show that the microglia-derived pro-inflammatory microenvironment has a negative impact on survival and differentiation of dopaminergic precursors. Finally, Tumour necrosis factor alpha plays a key role in these effects, suggesting that this cytokine could be an interesting target to increase the efficacy of human dopaminergic precursors transplantation in Parkinson’s Disease. Public Library of Science 2023-09-26 /pmc/articles/PMC10521980/ /pubmed/37751438 http://dx.doi.org/10.1371/journal.pone.0263021 Text en © 2023 Wenker 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
Wenker, Shirley D.
Farias, María Isabel
Gradaschi, Victoria
Garcia, Corina
Beauquis, Juan
Leal, María Celeste
Ferrari, Carina
Zeng, Xianmin
Pitossi, Fernando J.
Microglia-secreted TNF-α affects differentiation efficiency and viability of pluripotent stem cell-derived human dopaminergic precursors
title Microglia-secreted TNF-α affects differentiation efficiency and viability of pluripotent stem cell-derived human dopaminergic precursors
title_full Microglia-secreted TNF-α affects differentiation efficiency and viability of pluripotent stem cell-derived human dopaminergic precursors
title_fullStr Microglia-secreted TNF-α affects differentiation efficiency and viability of pluripotent stem cell-derived human dopaminergic precursors
title_full_unstemmed Microglia-secreted TNF-α affects differentiation efficiency and viability of pluripotent stem cell-derived human dopaminergic precursors
title_short Microglia-secreted TNF-α affects differentiation efficiency and viability of pluripotent stem cell-derived human dopaminergic precursors
title_sort microglia-secreted tnf-α affects differentiation efficiency and viability of pluripotent stem cell-derived human dopaminergic precursors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10521980/
https://www.ncbi.nlm.nih.gov/pubmed/37751438
http://dx.doi.org/10.1371/journal.pone.0263021
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