Neural crest stem cells undergo multilineage differentiation in developing peripheral nerves to generate endoneurial fibroblasts in addition to Schwann cells

Abstract

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 Crerecombinase 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.

Embryonic origin and Hox status determine progenitor cell fate during adult bone regeneration

“…1D). In the limbs, neural crest-derived Schwann cells (D'Amico-Martel and Noden, 1983) were GFPpositive, whereas the surrounding mesoderm-derived perineurium (Joseph et al, 2004) was not ( Fig. 1E).…”

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

“…They generate immature Schwann cells, endoneurial fibroblasts of fetal nerves as well as melanocytes, parasympathetic neurons and odontoblasts (Joseph et al, 2004;Adameyko et al, 2009;Dyachuk et al, 2014;Espinosa-Medina et al, 2014;Kaukua et al, 2014). Schwann cell progenitors give rise to immature Schwann cells around E16 (Jessen et al, 2015).…”

Development of the Schwann cell lineage: From the neural crest to the myelinated nerve

“…Recently, using Cre recombinase-mediated fate mapping, it was shown that the small population of endoneurial fibroblasts present in P11 mice sciatic nerves were derived from cells present in E12 embryonic nerves (Joseph et al, 2004). The large majority of the cells in the E12 nerves are SCPs, i.e.…”