Decoding the proregenerative competence of regulatory T cells through complex tissue regeneration in zebrafish

Gupta, Samudra; Adhikary, Satadal; Hui, Subhra Prakash

doi:10.1111/cei.13661

Cited by 8 publications

(5 citation statements)

References 73 publications

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“…Notably, atm−/− fish have seemingly normal regenerative capacity, although cytokine induction upon injury is attenuated but not abolished. This is consistent with the fact that zebrafish is a highly regenerative organism [ 24 ] capable of regeneration even in the context of an attenuated inflammation response [ 25 , 26 , 27 , 28 ]. Finally, we show that atm mutation in zebrafish results in a different spectrum of tumors compared to mouse models, such as malignant peripheral nerve sheath tumors and myeloid leukemia.…”

Section: Introductionsupporting

confidence: 84%

Loss of atm in Zebrafish as a Model of Ataxia–Telangiectasia Syndrome

et al. 2022

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Ataxia–telangiectasia mutated (ATM) is a key DNA damage signaling kinase that is mutated in humans with ataxia–telangiectasia (A-T) syndrome. This syndrome is characterized by neurodegeneration, immune abnormality, cancer predisposition, and premature aging. To better understand the function of ATM in vivo, we engineered a viable zebrafish model with a mutated atm gene. Zebrafish atm loss-of-function mutants show characteristic features of A-T-like motor disturbance, including coordination disorders, immunodeficiency, and tumorigenesis. The immunological disorder of atm homozygote fish is linked to the developmental blockade of hematopoiesis, which occurs at the adulthood stage and results in a decrease in infection defense but, with little effect on wound healing. Malignant neoplasms found in atm mutant fish were mainly nerve sheath tumors and myeloid leukemia, which rarely occur in A-T patients or Atm−/− mice. These results underscore the importance of atm during immune cell development. This zebrafish A-T model opens up a pathway to an improved understanding of the molecular basis of tumorigenesis in A-T and the cellular role of atm.

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Section: Introductionsupporting

confidence: 84%

Loss of atm in Zebrafish as a Model of Ataxia–Telangiectasia Syndrome

et al. 2022

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“…To confirm whether the organ-specific secretary phenotype of Tregs also persists during zebrafish fin regeneration akin to our previous findings (37,44,45), we compared the igf2a and igf2b expression of fin blastema-derived Tregs with the injured spinal cord, retina, and heart derived Tregs. Strikingly, the gene expression of the pro-regenerative factors for the spinal cord (ntf3), the retina (igf1), and the heart (nrg1) was not detectable in the Tregs purified from fin blastema (Figure 3E).…”

Section: Resultsmentioning

confidence: 72%

Regulatory T cells regulate blastemal proliferation during zebrafish caudal fin regeneration

et al. 2022

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The role of T cells in appendage regeneration remains unclear. In this study, we revealed an important role for regulatory T cells (Tregs), a subset of T cells that regulate tolerance and tissue repair, in the epimorphic regeneration of zebrafish caudal fin tissue. Upon amputation, fin tissue-resident Tregs infiltrate into the blastema, a population of progenitor cells that produce new fin tissues. Conditional genetic ablation of Tregs attenuates blastemal cell proliferation during fin regeneration. Blastema-infiltrating Tregs upregulate the expression of igf2a and igf2b, and pharmacological activation of IGF signaling restores blastemal proliferation in Treg-ablated zebrafish. These findings further extend our understandings of Treg function in tissue regeneration and repair.

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“…Unlike in mammals, in zebrafish, spinal cord injury responses tend to be quite different, and they result in injury healing and functional recovery. Several cellular responses that are distinct from those in mammalian SCI are the following: (a) the development of a very brief inflammatory reaction mediated by numerous gene sets [ 113 , 114 ]; (b) the involvement of macrophages at the wound site, which is possibly involved in the clearance of myelin debris [ 115 , 116 , 117 ] and the upregulation of anti-inflammatory M2-type macrophage-related molecules, unlike in mammals, where pro-inflammatory macrophages are found at the lesion site and could be responsible for sustained dieback of damaged axons [ 64 , 118 ]; (c) rather limited cell loss due to necrosis and apoptosis following injury (although apoptotic cell death is normal in both mammalian and zebrafish SCI, the degree and magnitude of cell death vary in their spatiotemporal patterns and include upregulation of specific molecular sets relative to mammalian SCIs) [ 119 ]; (d) generation of permissive axonal regrowth conditions [ 119 ]; (e) proliferative response and pervasive neurogenesis [ 119 ]. Endogenous ventricular progenitor cells known as ependymo-radial glial cells (ERGs) accomplish restorative neurogenesis.…”

Section: Epigenetic Regulation Of Regeneration-competent Animals Afte...mentioning

confidence: 99%

Regenerative Potential of Injured Spinal Cord in the Light of Epigenetic Regulation and Modulation

Gupta

Dutta

Hui

2023

Cells

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A spinal cord injury is a form of physical harm imposed on the spinal cord that causes disability and, in many cases, leads to permanent mammalian paralysis, which causes a disastrous global issue. Because of its non-regenerative aspect, restoring the spinal cord’s role remains one of the most daunting tasks. By comparison, the remarkable regenerative ability of some regeneration-competent species, such as some Urodeles (Axolotl), Xenopus, and some teleost fishes, enables maximum functional recovery, even after complete spinal cord transection. During the last two decades of intensive research, significant progress has been made in understanding both regenerative cells’ origins and the molecular signaling mechanisms underlying the regeneration and reconstruction of damaged spinal cords in regenerating organisms and mammals, respectively. Epigenetic control has gradually moved into the center stage of this research field, which has been helped by comprehensive work demonstrating that DNA methylation, histone modifications, and microRNAs are important for the regeneration of the spinal cord. In this review, we concentrate primarily on providing a comparison of the epigenetic mechanisms in spinal cord injuries between non-regenerating and regenerating species. In addition, we further discuss the epigenetic mediators that underlie the development of a regeneration-permissive environment following injury in regeneration-competent animals and how such mediators may be implicated in optimizing treatment outcomes for spinal cord injurie in higher-order mammals. Finally, we briefly discuss the role of extracellular vesicles (EVs) in the context of spinal cord injury and their potential as targets for therapeutic intervention.

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Decoding the proregenerative competence of regulatory T cells through complex tissue regeneration in zebrafish

Cited by 8 publications

References 73 publications

Loss of atm in Zebrafish as a Model of Ataxia–Telangiectasia Syndrome

Loss of atm in Zebrafish as a Model of Ataxia–Telangiectasia Syndrome

Regulatory T cells regulate blastemal proliferation during zebrafish caudal fin regeneration

Regenerative Potential of Injured Spinal Cord in the Light of Epigenetic Regulation and Modulation

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