Zebrafish Regulatory T Cells Mediate Organ-Specific Regenerative Programs

Hui, Subhra Prakash; Sheng, Delicia Z.; Sugimoto, Kotaro; González-Rajal, Álvaro; Nakagawa, Shinichi; Hesselson, Daniel; Kikuchi, Kazu

doi:10.1016/j.devcel.2017.11.010

Cited by 221 publications

(210 citation statements)

References 83 publications

(118 reference statements)

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“…Our previous findings embodied these notions by linking the cardiac protective/reparative potential of allogeneic hCPC to their dual immunogenic immunemodulator character that promotes cell-contact-dependent tuning of immune/inflammatory T and NK cells but also monocytes/ macrophages toward immune/regulatory cells [14][15][16][17][18]. Furthermore support is provided by studies showing the crucial role of adaptive T cell immune response for tissue regeneration [62,63]. Our findings within an in vitro human model support EV/Exs secreted by allogeneic hCPC as sponsors of their cardiac bioactivity and corroborate previous studies in experimental-MI animal models [59,64].…”

Section: Discussionmentioning

confidence: 89%

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Hocine

Brunel

Chen

et al. 2019

Stem Cells Translational Medicine

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The positive effects of therapeutic human allogeneic cardiac stem/progenitor cells (hCPC) in terms of cardiac repair/regeneration are very likely mediated by paracrine effects. Our previous studies revealed the advantageous immune interactions of allogeneic hCPC and proposed them as part of the positive paracrine effects occurring upon their application postmyocardial infarction (MI). Currently, extracellular vesicles/exosomes (EV/Exs) released by stem/progenitor cells are also proposed as major mediators of paracrine effects of therapeutic cells. Along this line, we evaluated contribution of EV/Exs released by therapeutic hCPC to the benefit of their successful allogeneic clinical application. Through tailored allogeneic in vitro human assay models mimicking the clinical setting, we demonstrate that hCPC‐released EV/Exs were rapidly and efficiently up‐taken by chief cellular actors of cardiac repair/regeneration. This promoted MAPK/Erk1/2 activation, migration, and proliferation of human leukocyte antigens (HLA)‐mismatched hCPC, mimicking endogenous progenitor cells and cardiomyocytes, and enhanced endothelial cell migration, growth, and organization into tube‐like structures through activation of several signaling pathways. EV/Exs also acted as pro‐survival stimuli for HLA‐mismatched monocytes tuning their phenotype toward an intermediate anti‐inflammatory pro‐angiogenic phenotype. Thus, while positively impacting the intrinsic regenerative and angiogenic programs, EV/Exs released by therapeutic allogeneic hCPC can also actively contribute to shaping MI‐inflammatory environment, which could strengthen the benefits of hCPC allogeneic interactions. Collectively, our data might forecast the application of allogeneic hCPC followed by their cell‐free EV/Exs as a strategy that will not only elicit the cell‐contact mediated reparative/regenerative immune response but also have the desired long‐lasting effects through the EV/Exs. stem cells translational medicine 2019;8:911&924

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Section: Discussionmentioning

confidence: 89%

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Hocine

Brunel

Chen

et al. 2019

Stem Cells Translational Medicine

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“…Since the formal acceptance of this article, regulatory T cell-like cells have been described in zebrafish 194,195 . These cells express foxp3a , suppress tissue inflammation and can home to damaged organs to promote organ-specific regenerative responses.…”

Section: Note Added In Proofmentioning

confidence: 99%

A cold-blooded view of adaptive immunity

2018

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The adaptive immune system arose 500 million years ago in ectothermic (cold-blooded) vertebrates. Classically, the adaptive immune system has been defined by the presence of lymphocytes expressing recombination-activating gene (RAG)-dependent antigen receptors and the MHC. These features are found in all jawed vertebrates, including cartilaginous and bony fish, amphibians and reptiles and are most likely also found in the oldest class of jawed vertebrates, the extinct placoderms. However, with the discovery of an adaptive immune system in jawless fish based on an entirely different set of antigen receptors — the variable lymphocyte receptors — the divergence of T and B cells, and perhaps innate-like lymphocytes, goes back to the origin of all vertebrates. This Review explores how recent developments in comparative immunology have furthered our understanding of the origins and function of the adaptive immune system.

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“…Moreover, when Foxp3-deficient zebrafish T regs infiltrated the injured organs, they failed to express regenerative factors and thus could not contribute to wound healing. 31 Combined, these findings strongly suggest that T regs , in addition to an immune modulatory, 'damage-limiting' function, may also have a direct wound repair, 'damageresolving' function ( Fig. 1).…”

Section: Non-immune-mediated Roles Of Regulatory T-cells During Woundmentioning

confidence: 89%

“…In addition, in a study using established models of tissue regeneration in zebrafish, the conditional ablation of FoxP3-expressing zebrafish T regs hampered organ regeneration. 31 Dependent on the injured organ, infiltrating T regs stimulated the proliferation of tissue precursor cells through the secretion of organ-specific regenerative factors, such as Ntf3 for the spinal cord, Nrg1 for the heart, and Igf1 for the retina. Moreover, when Foxp3-deficient zebrafish T regs infiltrated the injured organs, they failed to express regenerative factors and thus could not contribute to wound healing.…”

Section: Non-immune-mediated Roles Of Regulatory T-cells During Woundmentioning

confidence: 99%

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

2019

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Summary The immune system has a well‐established contribution to tissue homeostasis and wound healing. However, in many cases immune responses themselves can cause severe tissue damage. Thus, the question arose to which extent cells of the immune system directly contribute to the process of wound healing and to which extent the resolution of excessive immune responses may indirectly contribute to wound healing. FoxP3‐expressing CD4 T‐cells, so‐called regulatory T‐cells (Tregs), have an important contribution in the regulation of immune responses; and, in recent years, it has been suggested that Tregs next to an immune‐regulatory, ‘damage‐limiting’ function may also have an immune‐independent ‘damage‐resolving’ direct role in wound healing. In particular, the release of the epidermal growth factor‐like growth factor Amphiregulin by tissue‐resident Tregs during wound repair suggested such a function. Our recent findings have now revealed that Amphiregulin induces the local release of bio‐active transforming growth factor (TGF)β, a cytokine involved both in immune regulation as well as in the process of wound repair. In light of these findings, we discuss whether, by locally activating TGFβ, Treg‐derived Amphiregulin may contribute to both wound repair and immune suppression. Furthermore, we propose that Treg‐derived Amphiregulin in an autocrine way may enable an IL‐33‐mediated survival and expansion of tissue‐resident Tregs upon injury. Furthermore, Treg‐derived Amphiregulin may contribute to a constitutive, low‐level release of bio‐active TGFβ within tissues, leading to continuous tissue regeneration and to an immune‐suppressive environment, which may keep inflammation‐prone tissues in an homeostatic state.

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Zebrafish Regulatory T Cells Mediate Organ-Specific Regenerative Programs

Cited by 221 publications

References 83 publications

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

A cold-blooded view of adaptive immunity

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

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