Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation
Open accessAbstract
We review the mounting evidence that regeneration is induced in wounds in skin and peripheral nerves by a simple modification of the wound healing process. Here, the process of induced regeneration is compared to the other two well‐known processes by which wounds close, i.e., contraction and scar formation. Direct evidence supports the hypothesis that the mechanical force of contraction (planar in skin wounds, circumferential in nerve wounds) is the driver guiding the orientation of assemblies of myofibroblasts (MFB) and collagen fibers during scar formation in untreated wounds. We conclude that scar formation depends critically on wound contraction and is, therefore, a healing process secondary to contraction. Wound contraction and regeneration did not coincide during healing in a number of experimental models of spontaneous (untreated) regeneration described in the literature. Furthermore, in other studies in which an efficient contraction‐blocker, a collagen scaffold named dermis regeneration template (DRT), and variants of it, were grafted on skin wounds or peripheral nerve wounds, regeneration was systematically observed in the absence of contraction. We conclude that contraction and regeneration are mutually antagonistic processes. A dramatic change in the phenotype of MFB was observed when the contraction‐blocking scaffold DRT was used to treat wounds in skin and peripheral nerves. The phenotype change was directly observed as drastic reduction in MFB density, dispersion of MFB assemblies and loss of alignment of the long MFB axes. These observations were explained by the evidence of a surface‐biological interaction of MFB with the scaffold, specifically involving binding of MFB integrins α 1 β 1 and α 2 β 1 to ligands GFOGER and GLOGER naturally present on the surface of the collagen scaffold. In summary, we show that regeneration of wounded skin and peripheral nerves in the adult mammal can be induced simply by appropriate control of wound contraction, rather than of scar formation.
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Myofibroblasts are responsible for contraction of the wound.
“This remodeling phase is largely driven by myofibroblasts, which develop from fibroblasts in response to both mechanical tension and TGF-β signaling and are responsible for contraction of the wound [94].”
From Immunology of Wound Healing (2018) · cites this paper as [94]
SMA is responsible for generating the contractile force attributed to myofibroblasts.
“Myofibroblasts express smooth muscle actin (SMA), which is responsible for generating the contractile force attributed to this cell type [94, 95].”
From Immunology of Wound Healing (2018) · cites this paper as [94]
The remodeling phase is largely driven by myofibroblasts.
“This remodeling phase is largely driven by myofibroblasts, which develop from fibroblasts in response to both mechanical tension and TGF-β signaling and are responsible for contraction of the wound [94].”
From Immunology of Wound Healing (2018) · cites this paper as [94]
Myofibroblasts develop from fibroblasts in response to mechanical tension and TGF-β signaling.
“This remodeling phase is largely driven by myofibroblasts, which develop from fibroblasts in response to both mechanical tension and TGF-β signaling and are responsible for contraction of the wound [94].”
From Immunology of Wound Healing (2018) · cites this paper as [94]
Myofibroblasts express smooth muscle actin (SMA).
“Myofibroblasts express smooth muscle actin (SMA), which is responsible for generating the contractile force attributed to this cell type [94, 95].”
From Immunology of Wound Healing (2018) · cites this paper as [94]
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- Authors
- Yannas, I. V., Tzeranis, D. S., & So, P. T. C.
- Affiliations
- Massachusetts Institute of Technology (US)
- Corresponding author
- Yannas, Ioannis V.
- Venue
- Wound Repair and Regeneration
- Publisher
- Wiley
- Published
- 2017-04
- Volume
- 25
- Issue
- 2
- Pages
- 177-191
- ISSN
- 1067-1927 (ISSN-L)
- 1524-475X
- PMC
- PMC5520812
- OpenAlex
- W2605241618
- Cited by
- 119
- References
- 71
- Citations by year
- 2026: 16 · 2025: 10 · 2024: 14 · 2023: 12 · 2022: 11 · 2021: 16 · 2020: 17 · 2019: 11 · 2018: 6 · 2017: 6
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Wound Repair and Regeneration (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- PMC
- Funders
- National Institutes of Health (RO1 NS051320, 5‐P41‐EB015871‐28)
- Horizon 2020 (DLV‐658850)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Planarian Biology and Electrostimulation
- Keywords
- wound contraction, scar formation, peripheral nerve regeneration, skin wound healing, myofibroblasts, collagen scaffolds, integrin binding, collagen fiber alignment, natural regeneration
- MeSH terms
- Animals, Cicatrix, Collagen, Disease Models, Animal, Humans, Nerve Regeneration, Peripheral Nerves, Skin, Surface Properties, Wound Healing, Wounds and Injuries, Guided Tissue Regeneration, Tissue Scaffolds
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