Boundary Caps Give Rise to Neurogenic Stem Cells and Terminal Glia in the Skin

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe neural crest (NC) is an embryonic, multipotent cell population that migrates extensively through the periphery and gives rise to various cell lineages, including most of the glial and neuronal components of the peripheral nervous system (PNS). NC cell settlement is normally accompanied by restriction to particular cell fates (). However, recent studies have identified stem cell-like populations within adult NC targets, which show developmental potentials resembling those of NC cells (). Among these populations, adult multipotent skin stem cells have attracted particular attention because they are easy to access, which would facilitate their use in regenerative medicine.Fate-mapping studies have revealed the existence of different types of trunk skin stem cell populations that possess neurogenic and gliogenic potential, with both NC and non-NC origins. Stem cells confined to the dermal papillae of hair follicles originate from the mesoderm, whereas populations restricted to the glial and melanocyte lineages are derived from the NC (). These different cell populations can be cultured as floating spheres and generate neurons and Schwann cells under differentiation conditions (). However, a lack of specific markers has prevented their detailed localization and further characterization and purification.Another type of NC-derived stem cell-like population has been identified in the embryo at the interface between the CNS and PNS. These cells form the so-called boundary caps (BCs), which are transiently observed at the nerve root entry/exit points along the neural tube (). Fate analyses, taking advantage of BC-specific expression of the Krox20 (also known as Egr2) transcription factor gene and available knockins at this locus (), have established that BC cells give rise to the Schwann cell component of the nerve roots and, in the dorsal root ganglia (DRGs), to nociceptive neurons as well as glial satellite cells (). Furthermore, in culture, BC cells can generate Schwann cells, myofibroblasts, astrocytes, and neurons (), and, when grafted into the lesioned spinal cord, efficiently migrate toward the lesion and differentiate into functional myelinating Schwann cells (). Together, these studies indicate that BC cells have a broad differentiation potential and suggest that they constitute multipotent stem cells in the embryo.These fate analyses relied on the restriction of Krox20 expression to BC cells during early PNS development. However, from embryonic day 15.5 (E15.5), Krox20 also is expressed in Schwann cells (), thereby preventing later analysis of BC derivatives. To circumvent this problem, we have generated a Cre recombinase knockin in a novel BC-specific marker, Prss56, previously known as L20 (), and we used it to trace BC cell derivatives in the embryo and the adult. Prss56 encodes a trypsin-like serine protease and its mutation in the retina has been associated with microphtalmia in humans and mice (). In this study, we show that, during embryogenesis, some of the BC derivatives rapidly migrate along the peripheral nerves and settle in the skin, where they provide terminal glia as well as multipotent progenitors that have broad differentiation capacities in culture and after transplantation into adult mice. This work, therefore, reveals the embryonic origin, pathway of migration, and in vivo neurogenic potential of a multipotent stem cell-like population in the skin.