The adult hair follicle: Cradle for pluripotent neural crest stem cells

Abstract

This review focuses on the recent identification of two novel neural crest-derived cells in the adult mammalian hair follicle, pluripotent stem cells, and Merkel cells. Wnt1-cre/R26R compound transgenic mice, which in the periphery express beta-galactosidase in a neural crest-specific manner, were used to trace neural crest cells. Neural crest cells invade the facial epidermis as early as embryonic day 9.5. Neural crest-derived cells are present along the entire extent of the whisker follicle. This includes the bulge area, an epidermal niche for keratinocyte stem cells, as well as the matrix at the base of the hair follicle. We have determined by in vitro clonal analysis that the bulge area of the adult whisker follicle contains pluripotent neural crest stem cells. In culture, beta-galactosidase-positive cells emigrate from bulge explants, identifying them as neural crest-derived cells. When these cells are resuspended and grown in clonal culture, they give rise to colonies that contain multiple differentiated cell types, including neurons, Schwann cells, smooth muscle cells, pigment cells, chondrocytes, and possibly other types of cells. This result provides evidence for the pluripotentiality of the clone-forming cell. Serial cloning showed that bulge-derived neural crest cells undergo self-renewal, which identifies them as stem cells. Pluripotent neural crest cells are also localized in the back skin hair of adult mice. The bulge area of the whisker follicle is surrounded by numerous Merkel cells, which together with innervating nerve endings form slowly adapting mechanoreceptors that transduce steady skin indentation. Merkel cells express beta-galactosidase in double transgenic mice, which confirms their neural crest origin. Taken together, our data indicate that the epidermis of the adult hair follicle contains pluripotent neural crest stem cells, termed epidermal neural crest stem cells (eNCSCs), and one newly identified neural crest derivative, the Merkel cell. The intrinsic high degree of plasticity of eNCSCs and the fact that they are easily accessible in the skin make them attractive candidates for diverse autologous cell therapy strategies.

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

“…Shih et al 43 isolated dermal stem cells from human adult scalp, Toma et al 44 isolated dermal stem cells from foreskin, and Belicchi et al 45 isolated dermal stem cells from fetal skin. 45 Neural-crest-like stem cells have been isolated from mouse whisker hair using a medium containing chick embryo extract and fetal calf serum 17,18 ; these mouse hair stem cells grew as adherent monolayer cells. However, human hair follicle-derived stem cells were not able to proliferate using their medium condition (data not shown), suggesting different biological behavior of mouse and human stem cells.…”

“…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.…”

Neural Potential of a Stem Cell Population in the Hair Follicle

“…22,23,40,41 Furthermore, a multipotent cell population with properties of neural crest cells has been discovered in the adult dermis. 8,27 Clearly, the described populations, which were identified and isolated using different approaches, can overlap with each other to different degree or even represent the same population of cells.…”

“…19 Furthermore, the bulge region of the whisker follicle also contains cells of neural crest origin which can self-renew and, upon explantation, produce neurons, Schwann cells, smooth muscle cells and melanocytes. 22,23 The bulge region also contains a population of cells expressing nestin, an intermediate filament and a marker of neural stem and early progenitor cells; [24][25][26] these cells can reconstitute much of the outer root sheath of the hair follicle with each hair cycle and behave as stem cells for the follicle. 25 Importantly, these different populations in the bulge region have been identified using different approaches and it is plausible that there is an overlap or even identity between these groups of cells.…”

Emergence of form from function—Mechanical engineering approaches to probe the role of stem cell mechanoadaptation in sealing cell fate

“…[42][43][44][45][46][47] These tissue borders are defined by the presence of basement membranes (BM) which separate cells from the surrounding ECM. Furthermore, the BM has been reported to create niches of stem cells between the basal lamina and various tissues, including skeletal muscle, 48 epithelium, 42,[49][50][51][52] hair follicles, 50,53,54 peripheral nerves, 55 blood vessels, 56 bone 57-61 and teeth. 62 A recent discovery that stem cells are generated during mesenchymal to epithelial transitions provides further support for this hypothesis.…”