Sustained production of ROS triggers compensatory proliferation and is required for regeneration to proceed

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Abstract

A major issue in regenerative medicine is the role of injury in promoting cell plasticity. Here we explore the function of reactive oxygen species (ROS) induced through lesions in adult zebrafish. We show that ROS production, following adult fin amputation, is tightly regulated in time and space for at least 24 hours, whereas ROS production remains transient (2 hours) in mere wound healing. In regenerative tissue, ROS signaling triggers two distinct parallel pathways: one pathway is responsible for apoptosis, and the other pathway is responsible for JNK activation. Both events are involved in the compensatory proliferation of stump epidermal cells and are necessary for the progression of regeneration. Both events impact the Wnt, SDF1 and IGF pathways, while apoptosis only impacts progenitor marker expression. These results implicate oxidative stress in regeneration and provide new insights into the differences between healing and regeneration.

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A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish

Philipp Niethammer, Clemens Grabher, A. Thomas Look … (2009)

Barrier structures (e.g. epithelia around tissues, plasma membranes around cells) are required for internal homeostasis and protection from pathogens. Wound detection and healing represent a dormant morphogenetic program that can be rapidly executed to restore barrier integrity and tissue homeostasis. In animals, initial steps include recruitment of leukocytes to the site of injury across distances of hundreds of micrometers within minutes of wounding. The spatial signals that direct this immediate tissue response are unknown. Due to their fast diffusion and versatile biological activities, reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are interesting candidates for wound-to-leukocyte signalling. We probed the role of H2O2 during the early events of wound responses in zebrafish larvae expressing a genetically encoded H2O2 sensor1. This reporter revealed a sustained rise in H2O2 concentration at the wound margin, starting ∼3 min after wounding and peaking at ∼20 min, which extended ∼100−200 μm into the tail fin epithelium as a decreasing concentration gradient. Using pharmacological and genetic inhibition, we show that this gradient is created by Dual oxidase (Duox), and that it is required for rapid recruitment of leukocytes to the wound. This is the first observation of a tissue-scale H2O2 pattern, and the first evidence that H2O2 signals to leukocytes in tissues, in addition to its known antiseptic role.

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Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.

Hideaki Kamata, Shi-Ichi Honda, Shin Maeda … (2005)

TNFalpha is a pleiotropic cytokine that induces either cell proliferation or cell death. Inhibition of NF-kappaB activation increases susceptibility to TNFalpha-induced death, concurrent with sustained JNK activation, an important contributor to the death response. Sustained JNK activation in NF-kappaB-deficient cells was suggested to depend on reactive oxygen species (ROS), but how ROS affect JNK activation was unclear. We now show that TNFalpha-induced ROS, whose accumulation is suppressed by mitochondrial superoxide dismutase, cause oxidation and inhibition of JNK-inactivating phosphatases by converting their catalytic cysteine to sulfenic acid. This results in sustained JNK activation, which is required for cytochrome c release and caspase 3 cleavage, as well as necrotic cell death. Treatment of cells or experimental animals with an antioxidant prevents H(2)O(2) accumulation, JNK phosphatase oxidation, sustained JNK activity, and both forms of cell death. Antioxidant treatment also prevents TNFalpha-mediated fulminant liver failure without affecting liver regeneration.

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Cells keep a memory of their tissue origin during axolotl limb regeneration.

Martin Kragl, Dunja Knapp, Eugen Nacu … (2009)

During limb regeneration adult tissue is converted into a zone of undifferentiated progenitors called the blastema that reforms the diverse tissues of the limb. Previous experiments have led to wide acceptance that limb tissues dedifferentiate to form pluripotent cells. Here we have reexamined this question using an integrated GFP transgene to track the major limb tissues during limb regeneration in the salamander Ambystoma mexicanum (the axolotl). Surprisingly, we find that each tissue produces progenitor cells with restricted potential. Therefore, the blastema is a heterogeneous collection of restricted progenitor cells. On the basis of these findings, we further demonstrate that positional identity is a cell-type-specific property of blastema cells, in which cartilage-derived blastema cells harbour positional identity but Schwann-derived cells do not. Our results show that the complex phenomenon of limb regeneration can be achieved without complete dedifferentiation to a pluripotent state, a conclusion with important implications for regenerative medicine.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 27 June 2013

Publication date Collection: 2013

Volume: 3

Electronic Location Identifier: 2084

Affiliations

[1 ]Université Paris Diderot , Sorbonne Paris Cité. Paris - France

[2 ]Centre Interdisciplinaire de Recherche en biologie (CIRB) CNRS UMR 7241/INSERM U1050/Collège de France. Paris - France

[3 ]Department of Biology - Ecole Normale Supérieure. Paris – France

[4 ]These authors contributed equally to this work.

[5 ]Current address: Department of Molecular, Cellular, and Developmental Biology Yale University- New Haven, CT, USA.

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[a ] vriz@ 123456univ-paris-diderot.fr

Article

Publisher Item ID: srep02084

DOI: 10.1038/srep02084

PMC ID: 3694286

PubMed ID: 23803955

SO-VID: b593890a-205c-4047-b9b5-4c7d757ede68

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

Sustained production of ROS triggers compensatory proliferation and is required for regeneration to proceed

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Most cited references 45

A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish

Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.

Cells keep a memory of their tissue origin during axolotl limb regeneration.

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