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Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation.

ABSTRACT: 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 ?1 ?1 and ?2 ?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.

SUBMITTER: Yannas IV

PROVIDER: S-EPMC5520812 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation.

Yannas Ioannis V IV Tzeranis Dimitrios S DS So Peter T C PTC

Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 20170427 2

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 o ...[more]

PMID: 28370669

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Project description:IntroductionExtensive scar tissue formation after peripheral nerve injury or surgery is a common problem. To avoid perineural scarring, implanting a mechanical barrier protecting the nerve from inflammation processes in the perineural environment has shown promising results for functional recovery. This study investigates the potential of an acellular collagen-elastin matrix wrapped around a peripheral nerve after induction of scar tissue formation.Materials and methodsIn the present study, 30 Lewis rats were separated into three groups and sciatic nerve scarring was induced with 2.5% glutaraldehyde (GA-CM) or 2.5% glutaraldehyde with a supplemental FDA-approved acellular collagen-elastin matrix application (GA+CM). Additionally, a sham group was included for control. Nerve regeneration was assessed by functional analysis using the Visual Statisc Sciatic Index (SSI) and MR neurography during the 12-week regeneration period. Histological and histomorphometry analysis were performed to evaluate the degree of postoperative scar tissue formation.ResultsHistological analysis showed an extensive scar tissue formation for GA-CM. Connective tissue ratio was significantly (p < 0.009) reduced for GA+CM (1.347 ± 0.017) compared to GA-CM (1.518 ± 0.057). Similarly, compared to GA+CM, MR-Neurography revealed extensive scar tissue formation for GA-CM with a direct connection between nerve and paraneural environment. Distal to the injury site, quantitative analysis presented significantly higher axon density (p = 0.0145), thicker axon diameter (p = 0.0002) and thicker myelinated fiber thickness (p = 0.0008) for GA+CM compared to GA-CM. Evaluation of functional recovery revealed a significantly faster regeneration for GA+CM.ConclusionThe supplemental application of an acellular collagen-elastin matrix showed beneficial effects in histological, radiological, and functional analysis. Therefore, applying a collagen-elastin matrix around the nerve after peripheral nerve injury or surgery may have beneficial effects on preventing scar tissue formation in the long run. This represents a feasible approach to avoid scar tissue formation in peripheral nerve surgery.

Project description:X-linked Charcot-Marie-Tooth disease (CMT1X) is an inherited peripheral neuropathy caused by mutations in GJB1, the human gene for Connexin32 (Cx32). This present study uses Ilumina Ref8-v2 BeadArray to examine the expression profiles of injured and uninjured sciatic nerves at 5, 7, and 14 days post-crush injury (dpi) from Wild Type (WT) and Cx32-knockout (Cx32KO) mice to identify the genes and signaling pathways that are dysregulated in the absence of Schwann cell Cx32. Given the assumption that loss of Schwann cell Cx32 disrupts the regeneration and maintenance of myelinated nerve leading to a demyelinating neuropathy in CMT1X, we initially hypothesized that nerve crush injury would result in significant increases in differential gene expression in Cx32KO mice relative to WT nerves. However, microarray analysis revealed a striking collapse in the number of differentially expressed genes at 5 and 7 dpi in Cx32KO nerves relative to WT, while uninjured and 14 dpi time points showed large numbers of differentially regulated genes. Further comparisons within each genotype showed limited changes in Cx32KO gene expression following crush injury when compared to uninjured Cx32KO nerves. By contrast, WT nerves exhibited robust changes in gene expression at 5 and 7 dpi with no significant differences in gene expression by 14dpi relative to uninjured WT nerve samples. Taken together, these data suggest that the gene expression profile in uninjured Cx32KO sciatic nerve strongly resembles that of a WT nerve following injury and that loss of Schwann cell Cx32 leads to a basal state of gene expression similar to that of an injured WT nerve. These findings support a role for Cx32 in non-myelinating and regenerating populations of Schwann cells in normal axonal maintenance in re-myelination, and regeneration of peripheral nerve following injury. Disruption of Schwann cell-axonal communication in CMT1X may cause dysregulation of signaling pathways that are essential for the maintenance of intact myelinated peripheral nerves and to establish the necessary conditions for successful regeneration and remyelination following nerve injury.

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Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation.

Publications

Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation.

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