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.
Highlights
The capacity for regeneration varies greatly between species [1]
We established an in vivo screening platform for the quantification of Zebrafish Tregs (zTregs) that were recruited to regenerating fin tissue by three days post-injury (Figure 1a–c)
We used this model to perform an in vivo chemical screen to identify agents capable of modulating zTreg recruitment after injury
Summary
The capacity for regeneration varies greatly between species [1]. While humans are limited in their ability to replace lost cells, tissues and organs, regeneration occurs naturally in many fish and amphibian organs [2]. Tregs are centrally implicated in vertebrate tissue repair [18] In humans, they are necessary for a fully functional adaptive immune system and require the transcription factor Forkhead Box P3 (FOXP3) to functionally differentiate [19]. The current study seeks to identify modulators of zTreg infiltration to injury sites via a high throughput screen of the NIH Clinical Collection, a library of small molecules with a history of previous use in clinical trials. To this end, we optimized the zebrafish tail amputation assay to visualize transgenically labelled zTregs in actively regenerating tissue. Identification of molecules capable of enhancing zTreg recruitment may be useful in defining the steps for activating latent regenerative potential in humans
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