An adult animal consists of cells of vastly different size and activity, but the regulation of cell size remains poorly understood. Recent studies uncovering some of the signaling pathways important ...for size/growth control, together with the identification of diseases resulting from aberrations in these pathways, have renewed interest in this field. This Review will discuss our current understanding of how a cell sets its size, how it can adapt its size to a changing environment, and how these processes are relevant to human disease.
How tissues are maintained over a lifetime and repaired following injury are fundamental questions in biology with a disruption to these processes underlying pathologies such as cancer and ...degenerative disorders. It is becoming increasingly clear that each tissue has a distinct mechanism to maintain homeostasis and respond to injury utilizing different types of stem/progenitor cell populations depending on the insult and/or with a contribution from more differentiated cells that are able to dedifferentiate to aid tissue regeneration. Peripheral nerves are highly quiescent yet show remarkable regenerative capabilities. Remarkably, there is no evidence for a classical stem cell population, rather all cell‐types within the nerve are able to proliferate to produce new nerve tissue. Co‐ordinating the regeneration of this tissue are Schwann cells (SCs), the main glial cells of the peripheral nervous system. SCs exist in architecturally stable structures that can persist for the lifetime of an animal, however, they are not postmitotic, in that following injury they are reprogrammed at high efficiency to a progenitor‐like state, with these cells acting to orchestrate the nerve regeneration process. During nerve regeneration, SCs show little plasticity, maintaining their identity in the repaired tissue. However, once free of the nerve environment they appear to exhibit increased plasticity with reported roles in the repair of other tissues. In this review, we will discuss the mechanisms underlying the homeostasis and regeneration of peripheral nerves and how reprogrammed progenitor‐like SCs have broader roles in the repair of other tissues with implications for pathologies such as cancer.
Main points
Adult peripheral nerves are highly quiescent but regenerative following injury.
SCs have multiple roles in orchestrating nerve regeneration.
SCs have limited plasticity but regulate tissue repair with implications for tumor growth and spread.
Following damage to peripheral nerves, a remarkable process of clearance and regeneration takes place. Axons downstream of the injury degenerate, while the nerve is remodeled to direct axonal ...regrowth. Schwann cells are important for this regenerative process. “Sensing” damaged axons, they dedifferentiate to a progenitor-like state, in which they aid nerve regeneration. Here, we demonstrate that activation of an inducible Raf-kinase transgene in myelinated Schwann cells is sufficient to control this plasticity by inducing severe demyelination in the absence of axonal damage, with the period of demyelination/ataxia determined by the duration of Raf activation. Remarkably, activation of Raf-kinase also induces much of the inflammatory response important for nerve repair, including breakdown of the blood-nerve barrier and the influx of inflammatory cells. This reversible in vivo model identifies a central role for ERK signaling in Schwann cells in orchestrating nerve repair and is a powerful system for studying peripheral neuropathies and cancer.
► We describe an inducible and reversible in vivo model of nerve demyelination ► Raf/ERK signaling drives Schwann cell dedifferentiation and demyelination in vivo ► The duration of Raf/MEK/ERK signaling determines the period of demyelination ► The Schwann cells induce an inflammatory response in the absence of injury
Napoli et al. find that activation of ERK signaling in myelinated Schwann cells, using an inducible Raf-kinase transgene, is sufficient to promote plasticity in an in vivo model of demyelinating nerve injury, including activation of an inflammatory response that may contribute to nerve repair.
Schwann cells develop from the neural crest in a well-defined sequence of events. This involves the formation of the Schwann cell precursor and immature Schwann cells, followed by the generation of ...the myelin and nonmyelin (Remak) cells of mature nerves. This review describes the signals that control the embryonic phase of this process and the organogenesis of peripheral nerves. We also discuss the phenotypic plasticity retained by mature Schwann cells, and explain why this unusual feature is central to the striking regenerative potential of the peripheral nervous system (PNS).
Highlights • Regeneration of the PNS is a complex, highly coordinated, multicellular process. • Macrophages have multiple roles to condition the environment for axonal regrowth. • Schwann cells guide ...and nurture regrowing axons back to their targets. • Polarised blood vessels direct Schwann cell migration across the region of injury.
Schwann cell dedifferentiation from a myelinating to a progenitor-like cell underlies the remarkable ability of peripheral nerves to regenerate following injury. However, the molecular identity of ...the differentiated and dedifferentiated states in vivo has been elusive. Here, we profiled Schwann cells acutely purified from intact nerves and from the wound and distal regions of severed nerves. Our analysis reveals novel facets of the dedifferentiation response, including acquisition of mesenchymal traits and a Myc module. Furthermore, wound and distal dedifferentiated Schwann cells constitute different populations, with wound cells displaying increased mesenchymal character induced by localized TGFβ signaling. TGFβ promotes invasion and crosstalks with Eph signaling via N-cadherin to drive collective migration of the Schwann cells across the wound. Consistently, Tgfbr2 deletion in Schwann cells resulted in misdirected and delayed reinnervation. Thus, the wound microenvironment is a key determinant of Schwann cell identity, and it promotes nerve repair through integration of multiple concerted signals.
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•Wound Schwann cells have a distinct dedifferentiation program•TGFβ signaling reprograms wound Schwann cells to invasive mesenchymal-like cells•TGFβ crosstalks with Eph signaling to drive collective Schwann cell migration•Loss of TGFβ signaling in Schwann cells delays nerve regeneration
Clements et al. show that the nerve-injury-induced Schwann cell dedifferentiation program is modulated by the wound microenvironment through TGFβ. TGFβ promotes regeneration by reprogramming Schwann cells to invasive, mesenchymal-like cells and crosstalking with Eph signaling to drive collective migration.
The peripheral nervous system has remarkable regenerative capacities in that it can repair a fully cut nerve. This requires Schwann cells to migrate collectively to guide regrowing axons across a ...‘bridge’ of new tissue, which forms to reconnect a severed nerve. Here we show that blood vessels direct the migrating cords of Schwann cells. This multicellular process is initiated by hypoxia, selectively sensed by macrophages within the bridge, which via VEGF-A secretion induce a polarized vasculature that relieves the hypoxia. Schwann cells then use the blood vessels as “tracks” to cross the bridge taking regrowing axons with them. Importantly, disrupting the organization of the newly formed blood vessels in vivo, either by inhibiting the angiogenic signal or by re-orienting them, compromises Schwann cell directionality resulting in defective nerve repair. This study provides important insights into how the choreography of multiple cell-types is required for the regeneration of an adult tissue.
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•Hypoxia within the nerve bridge is selectively sensed by macrophages•Macrophage-derived VEGF-A induces a polarized vasculature within the bridge•Blood vessels are used as tracks to direct Schwann cell migration across the wound•Macrophage-induced blood vessels are essential for nerve regeneration
Repairing a cut nerve requires collective migration of Schwann cells guided by a polarized vasculature that is induced by macrophages within the hypoxic bridge.
Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary ...seeks to describe the burgeoning field of “cancer neuroscience” and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions.
Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of “cancer neuroscience” and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions.
The peripheral nervous system has astonishing regenerative capabilities in that cut nerves are able to reconnect and re-establish their function. Schwann cells are important players in this process, ...during which they dedifferentiate to a progenitor/stem cell and promote axonal regrowth. Here, we report that fibroblasts also play a key role. Upon nerve cut, ephrin-B/EphB2 signaling between fibroblasts and Schwann cells results in cell sorting, followed by directional collective cell migration of Schwann cells out of the nerve stumps to guide regrowing axons across the wound. Mechanistically, we find that cell-sorting downstream of EphB2 is mediated by the stemness factor Sox2 through N-cadherin relocalization to Schwann cell-cell contacts. In vivo, loss of EphB2 signaling impaired organized migration of Schwann cells, resulting in misdirected axonal regrowth. Our results identify a link between Ephs and Sox proteins, providing a mechanism by which progenitor cells can translate environmental cues to orchestrate the formation of new tissue.
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► Fibroblasts sort Schwann cells into cords at nerve wounds via ephrin-B signaling ► The Schwann cell cords then guide axonal regrowth across the wound site ► Sox2 promotes relocalization of N-cadherin to Schwann cell junctions ► EphB2 loss in vivo disrupts directed Schwann cell migration and axon regrowth
Human adult stem cells are being evaluated widely for various therapeutic approaches. Several recent clinical trials have reported their safety, showing them to be highly resistant to transformation. ...The clear similarities between stem cell and cancer stem cell genetic programs are nonetheless the basis of a recent proposal that some cancer stem cells could derive from human adult stem cells. Here we show that although they can be managed safely during the standard ex vivo expansion period (6-8 weeks), human mesenchymal stem cells can undergo spontaneous transformation following long-term in vitro culture (4-5 months). This is the first report of spontaneous transformation of human adult stem cells, supporting the hypothesis of cancer stem cell origin. Our findings indicate the importance of biosafety studies of mesenchymal stem cell biology to efficiently exploit their full clinical therapeutic potential.
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