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Pharmacological Enhancement of Regeneration-Dependent Regulatory T Cell Recruitment in Zebrafish

Regenerative capacity varies greatly between species. Mammals are limited in their ability to regenerate damaged cells, tissues and organs compared to organisms with robust regenerative responses, such as zebrafish. The regeneration of zebrafish tissues including the heart, spinal cord and retina re...

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Autores principales: Zwi, Stephanie F., Choron, Clarisse, Zheng, Dawei, Nguyen, David, Zhang, Yuxi, Roshal, Camilla, Kikuchi, Kazu, Hesselson, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834363/
https://www.ncbi.nlm.nih.gov/pubmed/31635133
http://dx.doi.org/10.3390/ijms20205189
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author Zwi, Stephanie F.
Choron, Clarisse
Zheng, Dawei
Nguyen, David
Zhang, Yuxi
Roshal, Camilla
Kikuchi, Kazu
Hesselson, Daniel
author_facet Zwi, Stephanie F.
Choron, Clarisse
Zheng, Dawei
Nguyen, David
Zhang, Yuxi
Roshal, Camilla
Kikuchi, Kazu
Hesselson, Daniel
author_sort Zwi, Stephanie F.
collection PubMed
description Regenerative capacity varies greatly between species. Mammals are limited in their ability to regenerate damaged cells, tissues and organs compared to organisms with robust regenerative responses, such as zebrafish. The regeneration of zebrafish tissues including the heart, spinal cord and retina requires foxp3a+ zebrafish regulatory T cells (zTregs). However, it remains unclear whether the muted regenerative responses in mammals are due to impaired recruitment and/or function of homologous mammalian regulatory T cell (Treg) populations. Here, we explore the possibility of enhancing zTreg recruitment with pharmacological interventions using the well-characterized zebrafish tail amputation model to establish a high-throughput screening platform. Injury-infiltrating zTregs were transgenically labelled to enable rapid quantification in live animals. We screened the NIH Clinical Collection (727 small molecules) for modulators of zTreg recruitment to the regenerating tissue at three days post-injury. We discovered that the dopamine agonist pramipexole, a drug currently approved for treating Parkinson’s Disease, specifically enhanced zTreg recruitment after injury. The dopamine antagonist SCH-23390 blocked pramipexole activity, suggesting that peripheral dopaminergic signaling may regulate zTreg recruitment. Similar pharmacological approaches for enhancing mammalian Treg recruitment may be an important step in developing novel strategies for tissue regeneration in humans.
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spelling pubmed-68343632019-11-25 Pharmacological Enhancement of Regeneration-Dependent Regulatory T Cell Recruitment in Zebrafish Zwi, Stephanie F. Choron, Clarisse Zheng, Dawei Nguyen, David Zhang, Yuxi Roshal, Camilla Kikuchi, Kazu Hesselson, Daniel Int J Mol Sci Article Regenerative capacity varies greatly between species. Mammals are limited in their ability to regenerate damaged cells, tissues and organs compared to organisms with robust regenerative responses, such as zebrafish. The regeneration of zebrafish tissues including the heart, spinal cord and retina requires foxp3a+ zebrafish regulatory T cells (zTregs). However, it remains unclear whether the muted regenerative responses in mammals are due to impaired recruitment and/or function of homologous mammalian regulatory T cell (Treg) populations. Here, we explore the possibility of enhancing zTreg recruitment with pharmacological interventions using the well-characterized zebrafish tail amputation model to establish a high-throughput screening platform. Injury-infiltrating zTregs were transgenically labelled to enable rapid quantification in live animals. We screened the NIH Clinical Collection (727 small molecules) for modulators of zTreg recruitment to the regenerating tissue at three days post-injury. We discovered that the dopamine agonist pramipexole, a drug currently approved for treating Parkinson’s Disease, specifically enhanced zTreg recruitment after injury. The dopamine antagonist SCH-23390 blocked pramipexole activity, suggesting that peripheral dopaminergic signaling may regulate zTreg recruitment. Similar pharmacological approaches for enhancing mammalian Treg recruitment may be an important step in developing novel strategies for tissue regeneration in humans. MDPI 2019-10-19 /pmc/articles/PMC6834363/ /pubmed/31635133 http://dx.doi.org/10.3390/ijms20205189 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zwi, Stephanie F.
Choron, Clarisse
Zheng, Dawei
Nguyen, David
Zhang, Yuxi
Roshal, Camilla
Kikuchi, Kazu
Hesselson, Daniel
Pharmacological Enhancement of Regeneration-Dependent Regulatory T Cell Recruitment in Zebrafish
title Pharmacological Enhancement of Regeneration-Dependent Regulatory T Cell Recruitment in Zebrafish
title_full Pharmacological Enhancement of Regeneration-Dependent Regulatory T Cell Recruitment in Zebrafish
title_fullStr Pharmacological Enhancement of Regeneration-Dependent Regulatory T Cell Recruitment in Zebrafish
title_full_unstemmed Pharmacological Enhancement of Regeneration-Dependent Regulatory T Cell Recruitment in Zebrafish
title_short Pharmacological Enhancement of Regeneration-Dependent Regulatory T Cell Recruitment in Zebrafish
title_sort pharmacological enhancement of regeneration-dependent regulatory t cell recruitment in zebrafish
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834363/
https://www.ncbi.nlm.nih.gov/pubmed/31635133
http://dx.doi.org/10.3390/ijms20205189
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