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Int J Mol Sci. 2019 Oct 19;20(20). pii: E5189. doi: 10.3390/ijms20205189.

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

Author information

1
Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia. stephzwi@gmail.com.
2
Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia. clarisse.choron@estbb.ucly.fr.
3
Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia. d.zheng@victorchang.edu.au.
4
Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia. d.nguyen@garvan.org.au.
5
Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia. jialhs@hotmail.com.
6
Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia. camillaroshal@hotmail.com.
7
Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia. k.kikuchi@victorchang.edu.au.
8
St Vincent's Clinical School, University of New South Wales, Kensington, NSW 2052, Australia. k.kikuchi@victorchang.edu.au.

Abstract

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.

KEYWORDS:

dopamine signaling; pramipexole; regulatory T cell; small molecule screen; zebrafish

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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