New Insights Into Stem Cells and Skin Biology
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
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
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
- Barrandon Y, Green H. Three clonal types of keratinocyte with
different capacities for multiplication. Proc Natl Acad Sci U S
- Mackenzie IC. Retroviral transduction of murine epidermal stem
cells demonstrates clonal units of epidermal structure. J
Invest Dermatol. 1997; 109(3):377-83.
- Bickenbach JR, Mackenzie IC. Identification and localization of
label-retaining cells in hamster epithelia. J Invest
- Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside
in the bulge area of pilosebaceous unit: implications for
follicular stem cells, hair cycle, and skin
carcinogenesis. Cell. 1990;61(7):1329-37.
- Rochat A, Kobayashi K, Barrandon Y. Location of stem cells of
human hair follicles by clonal analysis. Cell.
- Oshima H, Rochat A, Kedzia C, et al. Morphogenesis and renewal
of hair follicles from adult multipotent stem cells. Cell.
- Tumbar T, Guasch G, Greco V, et al. Defining the epithelial
stem cell niche in skin. Science.
- Ito M, Liu Y, Yang Z, et al. Stem cells in the hair follicle
bulge contribute to wound repair but not to homeostasis of the
epidermis. Nat Med. 2005;11(12):1351-4.
- Claudinot S, Nicolas M, Oshima H, et al. Long-term renewal of
hair follicles from clonogenic multipotent stem cells. Proc
Natl Acad Sci U S A. 2005;102(41):14677-82.
- Silva-Vargas V, Lo Celso C, Giangreco A, et al. Beta-catenin
and Hedgehog signal strength can specify number and location of
hair follicles in adult epidermis without recruitment of bulge stem
cells. Dev Cell. 2005;9(1):121-31.
- Lowry WE, Blanpain C, Nowak JA, et al. Defining the impact of
beta-catenin/Tcf transactivation on epithelial stem cells.
Genes Dev. 2005 Jul;19(13):1596-611.
- Huelsken J, Vogel R, Erdmann B, et al. Beta-catenin controls
hair follicle morphogenesis and stem cell differentiation in the
skin. Cell. 2001;105(4):533-45.
- DasGupta R, Fuchs E. Multiple roles for activated LEF/TCF
transcription complexes during hair follicle development and
differentiation. Development. 1999;126(20):4557-68.
- Takeda H, Lyle S, Lazar AJ, et al. Human sebaceous tumors
harbor inactivating mutations in LEF1. Nat Med.
- Benitah SA, Frye M, Glogauer M, et al. Stem cell depletion
through epidermal deletion of Rac1. Science.
- Lechler T, Fuchs E. Asymmetric cell divisions promote
stratification and differentiation of mammalian skin.
- Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of
endothelial progenitor cells responsible for postnatal
vasculogenesis in physiological and pathological
neovascularization. Circ Res. 1999;85(3):221-8.
- Fathke C, Wilson L, Hutter J, et al. Contribution of bone
marrow-derived cells to skin: collagen deposition and wound repair.
Stem Cells. 2004;22(5):812-22.
- Borue X, Lee S, Grove J, et al. Bone marrow-derived cells
contribute to epithelial engraftment during wound healing. Am J
Pathol. 2004 Nov;165(5):1767-72.
- Harris RG, Herzog EL, Bruscia EM, et al. Lack of a fusion
requirement for development of bone marrow-derived epithelia.
Science. 2004 Jul 2;305(5680):90-3.
- Mavilio F, Pellegrini G, Ferrari S, et al. Correction of
junctional epidermolysis bullosa by transplantation of genetically
modified epidermal stem cells. Nature Medicine,