The neural crest origins of skin-derived precursors: An accessible source of myelinating Schwann cells

Skin-derived precursors are multipotent stem cells capable of differentiation into neural and mesodermal progeny. Described here is evidence that SKPs are of a neural crest origin SKPs neural progeny are peripheral in subtype including peripheral catecholaminergic neurons and Schwann cells, SKPs express embryonic neural crest transcription factors, SKPs migrate via neural crest migratory pathways when transplanted into chick embryos and SKPs respond to factors know to influence neural crest stem cell differentiation in a similar manner. The expression of the neural crest transcription factors in situ identified the dermal papillae of hair follicles as a potential niche for SKPs in the skin. Cells isolated from microdissected vibrissae papillae generated spheres with SKPs properties when cultured under SKPs conditions and like SKPs, could be differentiated into neurons and smooth muscle. In agreement with the hypothesis that SKPs are of a neural crest origin, transgenic mice expressing beta-galactosidase in all neural crest progeny are characterized by beta-galactosidase expression in the dermal papillae, a potential SKPs niche and SKPs cultured from the whisker pads of these mice were also beta-galactosidase-positive. In order to demonstrate the functionality of SKP progeny as a proof of principle of their utility for potential therapeutic cell transplantation therapies, SKPs and SKP-derived Schwann cells were transplanted into various injury and disease models to assess their ability to myelinate. Cell culture protocols based on glial differentiation from the neural crest stem cell literature were adapted to selectively promote and expand Schwann cell differentiation from SKPs. SKP-derived Schwann cells transplanted into injured nerve were able to myelinate regenerating axons. SKPs and SKP-derived Schwann cells transplanted into congenitally dysmyelinated neonatal brains were able to form normal compact myelin. These data demonstrate the SKPs are a neural crest precursor that persists in adult skin that represents an accessible, autologous source of precursors capable of generating functional myelinating cells that could be used to treat disease and injury of the nervous system.