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Clinical Updates

New Insights Into Stem Cells and Skin Biology

Selim Aractingi, Kiarash Khosrotehrani

Tuesday, May 01, 2007

The skin contains a broad variety of cell types such as epithelial, mesenchymal, neural, vascular, and immune cells. Its main function is to establish a lipid-protein barrier resulting from the terminal differentiation of the epidermal cells, the keratinocytes. In addition, these cells are the main constituent of hair follicles adjacent to which resides another epithelial component of the skin: the sebaceous glands. The renewal and terminal differentiation of keratinocytes in hair follicles as well as in the interfollicular epidermis is a continuous process throughout life. It requires the permanent contribution of epidermal stem cells to the pool of amplifying keratinocytes. In addition to the physiological situation, in the presence of a wound, different progenitors participate in the establishment of angiogenesis, the granulation tissue, and finally the epidermal keratinocytes. In the past several years, many studies of the biology of epidermal stem cells have been conducted. We will summarize recent findings describing the contribution of different populations of stem cells to the homeostasis of the skin and to its response to wounds.

The epidermis consists in multiple layers of keratinocytes. From the basal membrane, these cells actively divide and are able to undergo terminal differentiation by condensing their cytoplasm and losing intracellular organels and nuclear content by undergoing cell death to become a lipid-protein layer within 2 weeks. Early studies of cultured keratinocytes have described the presence of stem cells as a population of cells, named holoclones, that are able to proliferate and form colonies on numerous (more than 130) passages without entering terminal differentiation.1 Grafting retrovirally tagged cells from these culture experiments into a mouse further proved their "stemness": A single cell could give rise to cells able to reconstitute an entire column of the epidermis from basal keratinocytes to the terminally differentiated corneocytes.2 Choosing another approach to locate keratinocyte stem cells in situ, investigators used the low proliferation activity of stem cells to locate them. This property allowed the stem cells to retain DNA labels in opposition to the transit amplifying cells: The latter population originates immediately from the stem cell and enters active proliferation. It was shown that label-retaining cells reside within the basal layer of the interfollicular epidermis.3 However, most label-retaining cells gathered in a region of the hair follicle named the bulge.4 In addition, dissection of human and rat hair also demonstrated that cells from the bulge region had the highest proliferation capacity.5 Bulge cells were also able to reconstitute all layers of the epidermis when transplanted in mice. Finally, bulge cells were shown to be multipotents since they could differentiate into hair follicle and infundibular epidermal keratinocytes as well as sebaceous glands.6 The description of these categories of stem cells has encouraged investigators to identify reliable stem cell markers. Transcriptional profiling of candidate stem cells in mice identified CD34, keratin 15, and alpha6, or beta1 integrins as some of the most reliable markers.7

It was speculated that bulge cells, being multipotent, are the source that gives rise to the epidermal stem cells found in interfollicular epidermis. However, recent studies show that in a model where bulge cells carry a suicide gene and can be genetically deleted, the interfollicular epidermis structure and proliferation is not impaired, suggesting that interfollicular epidermal stem cells do not originate from bulge cells.8 Similarly, transplantation of bulge cells in neonatal skin resulted in hair follicles but not in interfollicular epidermis.9 Finally, the multipotency of interfollicular epidermal stem cells has as well been suggested. Induced expression of activated beta-catenin in the interfollicular epidermis results in the development of hair follicle-containing bulge region,10 arguing that these stem cells, if exposed to the appropriate signals, have multipotent capacities as well. These very recent studies will probably open new areas of investigation on the mutual importance of these 2 stem cell populations.

This observation as well as many other well-conducted studies brought into light the importance of the beta-catenin signalling pathway in epidermal stem cell determination. High beta-catenin signalling in the epidermis results, as said earlier, in hair follicle formation. In contrast, beta-catenin deletion in the epidermis gives rise to sebaceous cysts.11,12 Beta-catenin activation, maintenance, degradation, and effector functions are regulated by many other factors. Wnt is the soluble extracellular signal triggering its stabilization and is an essential element of embryonic development of hair placodes.13 Once stabilized, beta-catenin interacts with Lef/Tcf family members of transcription factor. The presence of beta-catenin in this transcriptional complex allows hair follicle development. However, activation of Lef/Tcf in the absence of beta-catenin results in sebaceous cysts and tumors.14 Besides stem cell determination and proliferation, stem cell maintenance has been as well studied. Rac1, a rho GTPase oncogene, important in cell adhesion and growth factor responses, has been proved essential in stem cell maintenance, since its epidermal deletion results in the terminal differentiation of all keratinocytes and sebaceous epithelial cells, resulting in stem cell depletion.15 It seems that during epidermal cell division, an asymmetric transfer of cytoplasmic proteins such as protein kinase C family is observed and is dependent on p63.16 This asymmetric division results in the maintenance of an epidermal stem cell and generates a transit-amplifying cell.

Many studies have investigated the contribution of non-epidermal stem cells to the skin. Especially, in pathological situations such as wound healing, many different progenitor cells may be involved. In fact, the initial angiogenic steps of a wound mobilize endothelial progenitor cells from bone marrow. These cells form neovessels in the affected skin but do not persist long term.17 Others have also shown the contribution of bone marrow-derived cells to the dermal fibroblasts during wound healing.18 Finally and more strikingly, epidermal cells could also derive from bone marrow cells.19 This new epidermal phenotype did not result from a cellular fusion event.20 However, the bone marrow cells did not engraft as epidermal stem cells since the bone marrow-derived keratinocytes were isolated in the epidermis and did not repopulate columns of epidermis.

In conclusion, skin homeostasis is dependent on the activity of epidermal multipotent stem cells in the interfollicular epidermis as well as in the hair follicle bulge. In pathological situations such as wound healing, bone marrow-derived stem cells may well contribute to different populations of the skin including the epidermis. Cutaneous biology is therefore an excellent model for the study of stem cells, allowing rapid and exciting progress in the last decade resulting already in clinical applications. In fact, autologous keratinocyte stem cells are commercially available after culture and are currently being used for wound management. This also suggests that the use of bone marrow derived cells for epidermal reconstitution is not suitable. Finally, correction of genetic disorders of keratinocytes is another milestone that could result from the better isolation and manipulation of keratinocyte stem cells as has been recently reported.21


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