Genetic Mosaic Analysis Indicates That the Bulb Region of Coat Hair Follicles Contains a Resident Population of Several Active Multipotent Epithelial Lineage Progenitors

Abstract

The hair follicle represents an excellent model system for exploring the properties of lineage-forming units in a dynamic epithelium containing multiple cell types. During its growth (anagen) phase, the proximal-distal axis of the mouse coat hair (pelage) follicle provides a historical record of all epithelial lineages generated from its resident stem cell population. An unresolved question in the field is whether the bulb region of anagen pelage follicles contains multipotential progenitors and whether their individual contribution to cellular census fluctuates over time. To address this issue, chimeric follicles were harvested in midanagen from three types of genetic mosaic mouse models. Analysis of the distribution of genotypic markers, including digital three-dimensional reconstruction of serially sectioned chimeric follicles, revealed that on average the bulb contains four or fewer active progenitors, each capable of giving rise to all six follicular epithelial fates. Moreover, analysis of mosaic pelage, as well as cultured whisker follicles provided evidence that bulb-associated progenitors can give rise to expanding descendant clones during midanagen, leading to the conclusion that the bulb contains dormant or symmetrically dividing stem cells. This latter feature resembles the behavior of hematopoietic stem cells after bone marrow transplantation, and raises the question of whether this property may be shared by stem cells in other self-renewing epithelia.

Hair follicle renewal: organization of stem cells in the matrix and the role of stereotyped lineages and behaviors

“…However, they show that the matrix is not composed of equivalent cells, a finding that complements the results of Kopan and collaborators (Kopan et al, 2002). We also show that each HF inner structure is produced by two categories of precursors: permanent precursors with attributes of stem cells [selfrenewal, asymmetric division and their location in the germinative layer, whose proximity with the DP provides a specific micro-environment that may constitute a niche ] and transient progenitors that divide symmetrically and produce postmitotic cells (Fig.…”

“…Proximodistal organization of cell fates Several analyses have suggested the existence of different precursors in the matrix (Ghazizadeh and Taichman, 2001;Kamimura et al, 1998;Kopan et al, 2002;Kulessa et al, 2000). Our analysis demonstrates the existence of three distinct sectors in the matrix corresponding to IRS precursors, precursors for the cuticle and the cortex and precursors for the medulla.…”

“…However, the expression patterns of developmental genes have not yet identified distinct cell populations within the matrix involved in producing the different layers. The prevalent hypothesis is that the matrix is primarily a structure in which multipotent (Kopan et al, 2002) cells proliferate, perhaps owing to the control of BMP levels (Kulessa et al, 2000). When cells leave this structure they acquire their final identity (Niemann and Hair follicles (HFs) are renewed via multipotent stem cells located in a reservoir (the bulge); however, little is known about how they generate multi-tissue HFs from a proliferative zone (the matrix).…”

Redefining the structure of the hair follicle by 3D clonal analysis

“…At each new cycle, the HF undergoes neomorphogenesis, which is achieved by a group of HF stem cells that survive catagen and give rise to ORS progenitors and the germinative layer. The germinative layer cells are clonally related to each other (Kopan et al, 2002;Legué et al, 2010). This widely accepted scheme is based on clonal analysis and morphological approaches (Blanpain and Fuchs, 2006;Legué et al, 2012).…”

Notch signaling in bulge stem cells is not required for selection of hair follicle fate

“…In the anagen hair follicle bulb, three Notch receptors are expressed in partially overlapping domains (Pan et al, 2004). Each follicle is derived from two to four multi-potent bulge stem cells (Jaks et al, 2008;Kopan et al, 2002), which give rise to oligo-lineage hair follicular progenitors (Legue and Nicolas, 2005) located adjacent to the dermal papilla in the matrix. Notch proteins are not expressed in these oligo-lineage progenitors (Kopan and Weintraub, 1993;Pan et al, 2004;Powell et al, 1998).…”