Pluripotent neural crest stem cells in the adult hair follicle

Abstract

We report the presence of pluripotent neural crest stem cells in the adult mammalian hair follicle. Numerous neural crest cells reside in the outer root sheath from the bulge to the matrix at the base of the follicle. Bulge explants from adult mouse whisker follicles yield migratory neural crest cells, which in clonal culture form colonies consisting of over a thousand cells. Clones contain neurons, smooth muscle cells, rare Schwann cells and melanocytes, demonstrating pluripotency of the clone-forming cell. Targeted differentiation into Schwann cells and chondrocytes was achieved with neuregulin-1 and bone morphogenetic protein-2, respectively. Serial cloning in vitro demonstrated self-renewal capability. Together, the data show that the adult mouse whisker follicle contains pluripotent neural crest stem cells, termed epidermal neural crest cells (eNCSC). eNCSC are promising candidates for diverse cell therapy paradigms because of their high degree of inherent plasticity and due to their easy accessibility in the skin.

Isolation of a Novel Population of Multipotent Adult Stem Cells from Human Hair Follicles

“…16 Neural-crest-like stem cells have been identified in mouse whisker hair follicles, and bulge cells from mouse whisker hairs grow as adherent monolayer cells and appear to be multipotent. 17,18 The hair bulge has also been found to serve as a local reservoir for mast cell precursors. 19 These data suggest that the hair bulge is a unique differentiation-restricted area for adult stem cells.…”

The proliferating field of neural crest stem cells

“…This explanation is a fascinating idea, supported by analogy with development of embryonic NCSCs, in which sympathetic neuron specification (activation of MASH-1 and Phox2b expression) is initiated, but differentiation is transiently inhibited, by Sox10 (Kim et al, 2003). However, the recent demonstration of other neural crest-derived stem cells with much broader potential, including melanocytes, in the skin and hair follicles (see below; Sieber-Blum et al, 2004), suggests the possibility that MSCs might in fact be generated by differentiation of other neural crest stem cells in the hair follicle. In this context, it would be of great interest to know whether other NC-derived stem cells in the hair follicle (see below) express Pax3 and how these relate, if at all, to the MSCs.…”

“…However, in recent years, several other types of stem cells, of unexpectedly broad potential, have also been identified in the skin. These cells have been labeled epidermal neural crest stem cells (EPI-NCSCs, formerly epidermal NCSCs or even eNCSCs) and SKin-derived Precursors (SKPs; Toma et al, 2001;Sieber-Blum et al, 2004;Wong et al, 2006). EPI-NCSCs were identified by noting large numbers of neural crest-derived cells in the facial and back skin of adult mouse and were isolated by microdissection from the bulge area of whisker follicles (Sieber-Blum et al, 2004).…”

“…The authors distinguish SKPs from mesenchymal stem cells on the basis of marker expression, behavior in floating culture and morphology, and from eNCSCs by lack of p75 (very low level in human SKPs; Toma et al, 2001Toma et al, , 2005Fernandes et al, 2004) and NCAM expression. They can be distinguished from EPI-NCSCs by their expression of SHOX2 and Dermo-1 (Fernandes et al, 2004;Sieber-Blum et al, 2004). However, their relationship to other stem cells, including mesenchymal stem cells, is unknown (Fernandes et al, 2007).…”

“…For the NC-derived stem cells discussed here, the precise location of their niche is poorly defined, let alone the details of the signals provided by the niche that promote stem cell self-renewal and prevent differentiation. The hair follicle bulge is apparently the niche for MSCs (Nishimura et al, 2002) along with EPI-NCSCs (Sieber-Blum et al, 2004), SKPs (Wong et al, 2006), as well as the keratinocyte stem cells (Cotsarelis et al, 1990). There is, thus, an excellent opportunity to dissect the specialized cellular microenvironment and its influences on these diverse stem cell types (Nishikawa and Osawa, 2007).…”