Joseph, N.M. et al. Neural crest stem cells undergo multilineage differentiation in developing peripheral nerves to generate endoneurial fibroblasts in addition to Schwann cells. Development 131, 5599-5612

Department of Cell Biology, Erasmus Universiteit Rotterdam, Rotterdam, South Holland, Netherlands
Development (Impact Factor: 6.46). 12/2004; 131(22):5599-612. DOI: 10.1242/dev.01429
Source: PubMed


Neural crest stem cells (NCSCs) persist in peripheral nerves throughout late gestation but their function is unknown. Current models of nerve development only consider the generation of Schwann cells from neural crest, but the presence of NCSCs raises the possibility of multilineage differentiation. We performed Cre-recombinase fate mapping to determine which nerve cells are neural crest derived. Endoneurial fibroblasts, in addition to myelinating and non-myelinating Schwann cells, were neural crest derived, whereas perineurial cells, pericytes and endothelial cells were not. This identified endoneurial fibroblasts as a novel neural crest derivative, and demonstrated that trunk neural crest does give rise to fibroblasts in vivo, consistent with previous studies of trunk NCSCs in culture. The multilineage differentiation of NCSCs into glial and non-glial derivatives in the developing nerve appears to be regulated by neuregulin, notch ligands, and bone morphogenic proteins, as these factors are expressed in the developing nerve, and cause nerve NCSCs to generate Schwann cells and fibroblasts, but not neurons, in culture. Nerve development is thus more complex than was previously thought, involving NCSC self-renewal, lineage commitment and multilineage differentiation.

    • "). However, the investigators never found lacZ þ perineurial cells, and, thus, concluded that the perineurium did not share the same origin as these other two nerve elements (Joseph et al. 2004). "
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    ABSTRACT: Although the ultrastructure of peripheral nerves has been known for nearly 200 years, the developmental origins and functional roles of all five main components of these specialized nervous system conduits are still poorly understood. One of these understudied nerve elements, the perineurium, is a component of the blood-nerve barrier and is essential for protecting axons and their associated Schwann cells from ionic flux, toxins, and infection. However, until recently, it was thought that this vital nerve tissue was derived from the mesoderm and simply served a structural/barrier function with no other influence on the development, maintenance, or regeneration of peripheral nerves. Recent work in zebrafish using in vivo time-lapse imaging, genetic manipulation, and laser axotomy is shedding light on the origin and roles of this previously ignored glial nerve component and is changing how we view development of the nervous system. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    No preview · Article · Mar 2015 · Cold Spring Harbor perspectives in biology
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    • "The perineurium is a critical peripheral nerve component responsible for ensheathing and protecting axons from environmental insult. Although the importance of the mature perineurium is not debated, its origin has been for many years, and the paucity of perineurial cell specific markers has made tracing its origin very difficult (Bunge et al., 1989; Joseph et al., 2004; Kucenas et al., 2008). Here, our results describe the characterization of Nkx2.2 expression in the PNS of mice using three distinct lines in combination with immunohistochemistry and in situ hybridization. "
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    ABSTRACT: Background: All vertebrate peripheral nerves connect the central nervous system (CNS) with targets in the periphery and are composed of axons, layers of ensheathing glia and connective tissue. Although the structure of these conduits is well established, very little is known about the origin and developmental roles of some of their elements. One understudied component, the perineurium, ensheaths nerve fascicles and is a component of the blood-nerve-barrier. In zebrafish, the motor nerve perineurium is composed of CNS-derived nkx2.2a(+) perineurial glia, which establish the motor exit point (MEP) during development. To determine if mouse perineurial cells also originate within the CNS and perform a similar function, we created a Nkx2.2:EGFP transgenic reporter line. Results: In conjunction with RNA expression analysis and antibody labeling, we observed Nkx2.2(+) cells along peripheral motor nerves at all stages of development and in adult tissue. Additionally, in mice lacking Nkx2.2, we demonstrate that Nkx2.2(+) perineurial glia are essential for motor nerve development and Schwann cell differentiation. Conclusions: Our studies reveal that a subset of mouse perineurial cells are CNS-derived, express Nkx2.2, and are essential for motor nerve development. This work highlights an under-appreciated but essential contribution of CNS-derived cells to the development of the mammalian peripheral nervous system (PNS).
    Full-text · Article · Sep 2014 · Developmental Dynamics
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    • "NG2 expression is not common to all fibroblasts, as it was previously shown that cultured peripheral nerve fibroblasts express large amounts of NG2, whereas skin fibroblasts do not (Morgenstern et al. 2003). This distinction might be related to the fact that most EFLCs are of a neural crest origin (Joseph et al. 2004), whereas common fibroblasts have a mesenchymal origin. The role of NG2 expression in EFLCs remains unclear, although it has been suggested that NG2 could have facilitatory roles with respect to axonal regeneration, by promoting enhanced mobility of non-neuronal cells after injury or confining regenerating axons within the endoneurial compartment (Rezajooi et al. 2004). "
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    ABSTRACT: Endoneurial fibroblast-like cells (EFLCs) are one of the cell populations present in the peripheral nervous system. The role and immunophenotypic characteristics of EFLCs are not well known and led us to perform a histological and cytological study of EFLCs in normal human and rat peripheral nerves. We found that all EFLCs express CD34, neural/glial antigen 2 (NG2), and prolyl-4-hydrolase-beta. In addition, half of the EFLCs in normal peripheral nerves express platelet-derived growth factor receptor- (PDGFR-) and some also express the intermediate filament nestin in vivo (at a lower level than Schwann cells, which express high levels of nestin). Using cell cultures of purified EFLCs, we characterized subpopulations of EFLCs expressing PDGFR- alone or PDGFR- and nestin. Experimental nerve lesions in rat resulted in an increase in nestin-positive EFLCs, which returned to normal levels after 8 days. This suggests that some EFLCs could have a different proliferative and/or regenerative potential than others, and these EFLCs may play a role in the initial phase of nerve repair. These activated EFLCs share some immunophenotypic similarities with pericytes and Interstitial cells of Cajal, which have progenitor cell potentials. This raises the questions as to whether a proportion of EFLCs have a possible role as endoneurial progenitor cells.
    Full-text · Article · Mar 2014 · Journal of Histochemistry and Cytochemistry
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