Schwann cells as drivers of tissue repair and regeneration
Introduction
While considerable progress has been made in the field of regenerative medicine over the last decade [1, 2], much still remains to be discovered regarding endogenous mechanisms of tissue repair. Despite our best efforts to capture the healing properties of somatic stem cells, the upstream cues and cell-to-cell interactions that ultimately instruct their activity are generally poorly defined. However, there is accumulating evidence that endogenous tissue-derived precursors are under nervous system control, with Schwann cells coming to the forefront as a ‘pro-regenerative’ cell type. In addition to their well-appreciated functions during peripheral nerve repair, which include remodelling of the damaged axonal environment and promoting guidance of regenerating axons, Schwann cells also possess impressive phenotypic plasticity [3] and likely play an understated role in the regeneration of additional tissues. Consequently, Schwann cells have a continually expanding list of non-canonical functions and represent a novel target of potential therapeutic application.
Section snippets
Schwann cells set the stage for limb regeneration in amphibians
The importance of Schwann cells in tissue regeneration is perhaps most evident in the case of appendage regrowth in amphibians. These classical studies revealed that salamanders are capable of performing spectacular feats of regeneration following the amputation of limbs [4]. However, it was not known until recently that these regenerative events are specifically contingent upon the presence of Schwann cells [5••]. Following amputation, reconstitution of the salamander limb begins with the
Trophic support for digit regeneration: role of dedifferentiated Schwann cells
In mammals, including both rodents and humans [8], the digit tip is one of the only known structures capable of completely regenerating multiple tissue types following injury, in a manner that largely recapitulates appendage regeneration in amphibians. In adult mice, amputation of the distal one-third of the terminal phalangeal element, while preserving the proximal nail components, results in nearly complete regeneration of the lost appendage over the course of 4 weeks [9]. This remarkable
Dedifferentiated Schwann cells coordinate skin repair
As a testament to the diversity of tissues in which DSCs function in a regenerative capacity, recent work has identified a role for their activity in skin wound healing (Figure 2). Much like the digit, skin is home to a multitude of stem and progenitor cell types; which within mammalian skin, reside in distinct dermal, epidermal and hypodermal layers. Thus, skin has a robust capacity for repair and regeneration through the directed actions of these progenitors following wounding [26, 27, 28].
Conclusion
Until recently, Schwann cells were historically accepted to act solely as support cells for nerve axons through their provision of both myelination as well as trophic factors to maintain homeostasis and promote axonal repair following injury. However, in an expanding number of contexts there is increasing evidence that peripheral glia possess much greater regenerative influence than once considered. While recent work has shed light on this novel role for DSCs, dissociating their actions from
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This research was supported by Canadian Institutes of Health Research (CIHR) grant MOP-64211.
References (47)
- et al.
Nerve-associated neural crest: peripheral glial cells generate multiple fates in the body
Curr Opin Genet Dev
(2017) The molecular and cellular choreography of appendage regeneration
Cell
(2016)- et al.
Regeneration and repair of human digits and limbs: fact and fiction
Regeneration
(2015) - et al.
Platelet-derived growth factor receptor alpha as a marker of mesenchymal stem cells in development and stem cell biology
Stem Cells Int
(2015) - et al.
SOX2 is a dose-dependent regulator of retinal neural progenitor competence
Genes Dev
(2006) - et al.
Temporal analysis of gene expression in the murine Schwann cell lineage and the acutely injured postnatal nerve
PLoS One
(2016) - et al.
Zeb2 recruits HDAC-NuRD to inhibit Notch and controls Schwann cell differentiation and remyelination
Nat Neurosci
(2016) - et al.
SKPs derive from hair follicle precursors and exhibit properties of adult dermal stem cells
Cell Stem Cell
(2009) - et al.
Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche
Cell
(2011) - et al.
The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem cell niche function
Elife
(2014)
Stem cells applications in regenerative medicine and disease therapeutics
Int J Cell Biol
Mesenchymal stem and progenitor cells in regeneration: tissue specificity and regenerative potential
Stem Cells Int
Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate
Science
Histological alterations in denervated non-regenerating limbs of urodele larvae
J Exp Zool
Nerve dependence in tissue, organ, and appendage regeneration
Trends Neurosci
The mouse digit tip: from wound healing to regeneration
Methods Mol Biol
Dedifferentiated Schwann cell precursors secreting paracrine factors are required for regeneration of the mammalian digit tip
Cell Stem Cell
Mouse digit tip regeneration is mediated by fate-restricted progenitor cells
Proc Natl Acad Sci
Wnt activation in nail epithelium couples nail growth to digit regeneration
Nature
Denervation retards but does not prevent toetip regeneration
Wound Repair Regen
Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration
Proc Natl Acad Sci U S A
Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice
Cell Stem Cell
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Nat Neurosci
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Permanent address: Department of Applied Human Sciences, Faculty of Science, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada.