Skin Stem Cell Heterogeneity
The structure and function of the skin are dependent on various populations of epidermal cells and dermal fibroblasts. Communication between the epidermis and dermis is essential for skin formation, maintenance, and repair. While numerous stem cell populations with diverse sites and roles have been identified in the epidermis, it is now understood that the mesenchymal cells of the dermis also exhibit a degree of heterogeneity.
The skin epithelium consists of hair follicles, sebaceous glands, and sweat glands. A single layer of ectodermal cells gives rise to the complete interfollicular epidermis (IFE) and its appendages throughout early development. Following morphogenesis, the hair follicle undergoes cyclical phases of regression, rest, and growth. During the resting phase of the hair cycle, the permanent portion of the hair follicle is separated into many anatomically and biochemically distinct compartments. These include the infundibulum, which is adjacent to the IFE in the uppermost portion of the hair follicle; the isthmus, which is situated directly below the infundibulum and above the hair follicle bulge; and the hair germ, which is located directly below the bulge and on top of the dermal papilla, a cluster of specialized mesenchymal cells required for hair follicle regeneration.
Fig.1 Diagram of skin epithelial stem cells. (Goodell, 2015)
Multiple Epidermal Populations with Stem Cell Activity
The bulge region, initially characterized as the hair follicle stem cell reservoir, contains cells with a high proliferative capability in vitro and sluggish cycling in vivo, as shown by their ability to retain nucleotide analogs or tagged histone in pulse-chase assays. Such bulge cells in mice are distinguished by CD34 and nuclear factor of activated T cells, cytoplasmic calcineurin-dependent 1 (NFATC1) expression, and bulge cells and hair germ express keratin 15, keratin 19, transcription factor 3 (TCF3), TCF4, LIM homeobox 2 (LHX2), SOX9 (SRY-box transcription factor 9), and leucine-rich repeat-coupled receptor 5 (LGR5). In addition, when isolated bulge cells are joined with newborn dermal cells in transplantation trials on immunodeficient mice, they can reconstruct all skin epithelial lineages, including the IFE, hair follicle, and sebaceous gland. Thus, bulge cells were once believed to be the real multipotent stem cells at the epidermal hierarchy's top.
Subsequently, it was discovered that cells in the isthmus, which are marked by LGR6 (leucine-rich repeat-containing G protein-coupled receptor 6), as well as cells in the junctional zone in the upper isthmus, which are marked by leucine-rich repeat and immunoglobulin-like domains 1 (LRIG1) and placenta-expressed transcript 1 (PLET1), have high proliferative capacities in vitro. In transplantation studies, these cells were able to contribute to all three skin epithelial lineages. Various populations of cells with unique markers were able to rebuild all skin epithelial lineages, according to these findings. The research subsequently questioned whether the stem cell potential of these heterogeneous populations was indicative of the function of endogenous stem cells.
Fig.2 Different epidermal stem cell populations reside in the IFE, telogen hair follicle, and sweat glands. (Liu, 2013)
The Fate-determining Role of Microenvironment
Stem cell habitats, which sustain and govern stem cell function, contain a variety of cell types, although the particular biological composition of each niche is distinct. Activation of hair follicle stem cells in the skin, for example, requires the dermal papilla. In addition, adipocytes, nerves, and the arrector pili muscle have all been demonstrated to influence the properties or behavior of hair follicle stem cells. Therefore, they are all potential components of the hair follicle stem cell niche.
Different microenvironments likely influence stem cell behavior by endowing them with distinct proliferative properties and regulating the expression of their molecular markers. For melanocyte stem cells, an additional stem cell population in the hair follicle, the function of the microenvironment in determining stem cell destiny has been demonstrated.
References
- Goodell, M.A.; et al. Somatic stem cell heterogeneity: diversity in the blood, skin and intestinal stem cell compartments. Nature Reviews Molecular Cell Biology. 2015, 16: 299-309.
- Liu, S.; et al. Epidermal development in mammals: key regulators, signals from beneath, and stem cells. International Journal of Molecular Sciences. 2013, 14(6): 10869-10895.
