Macrophages are required for adult salamander limb regeneration
Open accessAbstract
The failure to replace damaged body parts in adult mammals results from a muted growth response and fibrotic scarring. Although infiltrating immune cells play a major role in determining the variable outcome of mammalian wound repair, little is known about the modulation of immune cell signaling in efficiently regenerating species such as the salamander, which can regrow complete body structures as adults. Here we present a comprehensive analysis of immune signaling during limb regeneration in axolotl, an aquatic salamander, and reveal a temporally defined requirement for macrophage infiltration in the regenerative process. Although many features of mammalian cytokine/chemokine signaling are retained in the axolotl, they are more dynamically deployed, with simultaneous induction of inflammatory and anti-inflammatory markers within the first 24 h after limb amputation. Systemic macrophage depletion during this period resulted in wound closure but permanent failure of limb regeneration, associated with extensive fibrosis and disregulation of extracellular matrix component gene expression. Full limb regenerative capacity of failed stumps was restored by reamputation once endogenous macrophage populations had been replenished. Promotion of a regeneration-permissive environment by identification of macrophage-derived therapeutic molecules may therefore aid in the regeneration of damaged body parts in adult mammals.
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In adult salamander limb and zebrafish fin regeneration, innate immune cell influx, particularly macrophages, preceding blastema formation is essential for regeneration.
“yet, recent studies in both adult salamander limb and zebrafish fin regeneration indicate that an innate immune cell influx, particularly of macrophages, preceding blastema formation is an essential component of regeneration (134, 135).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [134]
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“In this regard, macrophages apparently are crucial for the regenerative capacity of organisms endowed with the capacity to fully regenerate lost limbs, like the aquatic salamander axolotl [73,74].”
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- Authors
- Godwin, J. W., Pinto, A. R., & Rosenthal, N. A.
- Affiliations
- Australian Regenerative Medicine Institute (AU)
- Corresponding author
- Godwin, James W.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-05-20
- Volume
- 110
- Issue
- 23
- Pages
- 9415-9420
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3677454
- OpenAlex
- W2155490506
- Cited by
- 829
- References
- 55
- Citations by year
- 2026: 39 · 2025: 40 · 2024: 47 · 2023: 51 · 2022: 79 · 2021: 104 · 2020: 79 · 2019: 70 · 2018: 67 · 2017: 74 · 2016: 60 · 2015: 48 · 2014: 60 · 2013: 10
- FWCI
- 26.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Australian Government
- Stem Cells Australia
- State Government of Victoria
- Medical Research Council
- Australian Research Council
- National Health and Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Planarian Biology and Electrostimulation
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- macrophages, limb regeneration, axolotl, salamander regeneration, macrophage depletion, wound healing, fibrosis, extracellular matrix, immune cell infiltration, amputation
- MeSH terms
- Ambystoma mexicanum, Analysis of Variance, Animals, Extracellular Matrix, Extremities, Flow Cytometry, Fluorescence, Gene Expression Regulation, Histological Techniques, Immunohistochemistry, Macrophages, Phagocytosis, Regeneration, Wound Healing, Signal Transduction, Cytokines, Myeloid Cells, Real-Time Polymerase Chain Reaction
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