The promise of perfect adult tissue repair and regeneration in mammals: Learning from regenerative amphibians and fish

Godwin, James

doi:10.1002/bies.201300144

Cited by 47 publications

(40 citation statements)

References 132 publications

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“…A popular hypothesis to explain why most mammals heal injuries with scar tissue is that they evolved a strong inflammatory and adaptive immune response that induces intense fibrosis in lieu of regeneration (Godwin, 2014; Mescher et al, 2017). Yet, the fact that some mammals exhibit epimorphic regeneration (e.g.…”

Section: Discussionmentioning

confidence: 99%

Macrophages are necessary for epimorphic regeneration in African spiny mice

Simkin

Gawriluk

Gensel

et al. 2017

eLife

157

162

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How the immune system affects tissue regeneration is not well understood. In this study, we used an emerging mammalian model of epimorphic regeneration, the African spiny mouse, to examine cell-based inflammation and tested the hypothesis that macrophages are necessary for regeneration. By directly comparing inflammatory cell activation in a 4 mm ear injury during regeneration (Acomys cahirinus) and scarring (Mus musculus), we found that both species exhibited an acute inflammatory response, with scarring characterized by stronger myeloperoxidase activity. In contrast, ROS production was stronger and more persistent during regeneration. By depleting macrophages during injury, we demonstrate a functional requirement for these cells to stimulate regeneration. Importantly, the spatial distribution of activated macrophage subtypes was unique during regeneration with pro-inflammatory macrophages failing to infiltrate the regeneration blastema. Together, our results demonstrate an essential role for inflammatory cells to regulate a regenerative response.DOI: http://dx.doi.org/10.7554/eLife.24623.001

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Section: Discussionmentioning

confidence: 99%

Macrophages are necessary for epimorphic regeneration in African spiny mice

Simkin

Gawriluk

Gensel

et al. 2017

eLife

157

162

View full text Add to dashboard Cite

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“…Only an overview of epimorphic regeneration will be given here, with the focus on how inflammation and immunity has been studied to date in these systems. Several recent reviews of this and other models of regeneration are also available (Godwin, 2014;Poss, 2010;Simon and Tanaka, 2013;Wehner and Weidinger, 2015) The inflammatory response provoked rapidly by injury appears to be essentially similar in all of these systems. Very rapid coagulation and vasoconstriction greatly reduce blood loss in amputated amphibian limbs.…”

Section: Different Modes Of Organ Regeneration In Vertebrates and Invmentioning

confidence: 99%

Inflammation and immunity in organ regeneration

Mescher¹,

Neff²,

King³

2017

Developmental & Comparative Immunology

121

101

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The ability of vertebrates to regenerate amputated appendages is increasingly well-understood at the cellular level. Cells mediating an innate immune response and inflammation in the injured tissues are a prominent feature of the limb prior to formation of a regeneration blastema, with macrophage activity necessary for blastema growth and successful development of the new limb. Studies involving either anti-inflammatory or pro-inflammatory agents suggest that the local inflammation produced by injury and its timely resolution are both important for regeneration, with blastema patterning inhibited in the presence of unresolved inflammation. Various experiments with Xenopus larvae at stages where regenerative competence is declining show improved digit formation after treatment with certain immunosuppressive, anti-inflammatory, or antioxidant agents. Similar work with the larval Xenopus tail has implicated adaptive immunity with regenerative competence and suggests a requirement for regulatory T cells in regeneration, which also occurs in many systems of tissue regeneration. Recent analyses of the human nail organ indicate a capacity for local immune tolerance, suggesting roles for adaptive immunity in the capacity for mammalian appendage regeneration. New information and better understanding regarding the neuroendocrine-immune axis in the response to stressors, including amputation, suggest additional approaches useful for investigating effects of the immune system during repair and regeneration.

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“…Xenopus ) can achieve functional recovery after spinal cord transection (Filoni et al, 1984; Becker et al, 1997; Tanaka and Ferretti, 2009; Díaz-Quiroz and Echeverri, 2013; Lee-Liu et al, 2013). In mammals, regeneration and tissue repair are restricted to the early stages of life and are progressively lost during development (reviewed in Ferretti et al, 2003; Godwin, 2014). Anuran amphibians such as Xenopus laevis represent an interesting case of stage-dependent spinal cord regeneration.…”

Section: Introductionmentioning

confidence: 99%

Regeneration of Xenopus laevis spinal cord requires Sox2/3 expressing cells

Muñoz¹,

Edwards-Faret²,

Moreno³

et al. 2015

Developmental Biology

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Spinal cord regeneration is very inefficient in humans, causing paraplegia and quadriplegia. Studying model organisms that can regenerate the spinal cord in response to injury could be useful for understanding the cellular and molecular mechanisms that explain why this process fails in humans. Here, we use Xenopus laevis as a model organism to study spinal cord repair. Histological and functional analyses showed that larvae at pre-metamorphic stages restore anatomical continuity of the spinal cord and recover swimming after complete spinal cord transection. These regenerative capabilities decrease with onset of metamorphosis. The ability to study regenerative and non-regenerative stages in Xenopus laevis makes it a unique model system to study regeneration. We studied the response of Sox2/3 expressing cells to spinal cord injury and their function in the regenerative process. We found that cells expressing Sox2 and/or Sox3 are present in the ventricular zone of regenerative animals and decrease in non-regenerative froglets. Bromodeoxyuridine (BrdU) experiments and in vivo time-lapse imaging studies using green fluorescent protein (GFP) expression driven by the Sox3 promoter showed a rapid, transient and massive proliferation of Sox2/3+ cells in response to injury in the regenerative stages. The in vivo imaging also demonstrated that Sox2/3+ neural progenitor cells generate neurons in response to injury. In contrast, these cells showed a delayed and very limited response in non-regenerative froglets. Sox2 knockdown and overexpression of a dominant negative form of Sox2 disrupts locomotor and anatomical-histological recovery. We also found that neurogenesis markers increase in response to injury in regenerative but not in non-regenerative animals. We conclude that Sox2 is necessary for spinal cord regeneration and suggest a model whereby spinal cord injury activates proliferation of Sox2/3 expressing cells and their differentiation into neurons, a mechanism that is lost in non-regenerative froglets.

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The promise of perfect adult tissue repair and regeneration in mammals: Learning from regenerative amphibians and fish

Cited by 47 publications

References 132 publications

Macrophages are necessary for epimorphic regeneration in African spiny mice

Macrophages are necessary for epimorphic regeneration in African spiny mice

Inflammation and immunity in organ regeneration

Regeneration of Xenopus laevis spinal cord requires Sox2/3 expressing cells

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